The Multifactorial role of Peripheral Nervous System in Bone Growth

NASA Astrophysics Data System (ADS)

Gkiatas, Ioannis; Papadopoulos, Dimitrios; Pakos, Emilios E.; Kostas-Agnantis, Ioannis; Gelalis, Ioannis; Vekris, Marios; Korompilias, Anastasios

2017-09-01

Bone alters its metabolic and anabolic activities in response to the variety of systemic and local factors such as hormones and growth factors. Classical observations describing abundance of the nerve fibers in bone also predict a paradigm that the nervous system influences bone metabolism and anabolism. Since 1916 several investigators tried to analyze the effect of peripheral nervous system in bone growth and most of them advocated for the positive effect of innervation in the bones of growing organisms. Moreover, neuronal tissue controls bone formation and remodeling. The purpose of this mini-review is to present the most recent data concerning the influence of innervation on bone growth, the current understanding of the skeletal innervation and their proposed physiological effects on bone metabolism as well as the implication of denervation in human skeletal biology in the developing organism since the peripheral neural trauma as well as peripheral neuropathies are common and they have impact on the growing skeleton.

Growth plate-derived hedgehog-signal-responsive cells provide skeletal tissue components in growing bone.

PubMed

Haraguchi, Ryuma; Kitazawa, Riko; Imai, Yuuki; Kitazawa, Sohei

2018-04-01

Longitudinal bone growth progresses by continuous bone replacement of epiphyseal cartilaginous tissue, known as "growth plate", produced by columnar proliferated- and differentiated-epiphyseal chondrocytes. The endochondral ossification process at the growth plate is governed by paracrine signals secreted from terminally differentiated chondrocytes (hypertrophic chondrocytes), and hedgehog signaling is one of the best known regulatory signaling pathways in this process. Here, to investigate the developmental relationship between longitudinal endochondral bone formation and osteogenic progenitors under the influence of hedgehog signaling at the growth plate, genetic lineage tracing was carried out with the use of Gli1 CreERT2 mice line to follow the fate of hedgehog-signal-responsive cells during endochondral bone formation. Gli1 CreERT2 genetically labeled cells are detected in hypertrophic chondrocytes and osteo-progenitors at the chondro-osseous junction (COJ); these progeny then commit to the osteogenic lineage in periosteum, trabecular and cortical bone along the developing longitudinal axis. Furthermore, in ageing bone, where longitudinal bone growth ceases, hedgehog-signal responsiveness and its implication in osteogenic lineage commitment is significantly weakened. These results show, for the first time, evidence of the developmental contribution of endochondral progenitors under the influence of epiphyseal chondrocyte-derived secretory signals in longitudinally growing bone. This study provides a precise outline for assessing the skeletal lineage commitment of osteo-progenitors in response to growth-plate-derived regulatory signals during endochondral bone formation.

Beyond the functional matrix hypothesis: a network null model of human skull growth for the formation of bone articulations.

PubMed

Esteve-Altava, Borja; Rasskin-Gutman, Diego

2014-09-01

Craniofacial sutures and synchondroses form the boundaries among bones in the human skull, providing functional, developmental and evolutionary information. Bone articulations in the skull arise due to interactions between genetic regulatory mechanisms and epigenetic factors such as functional matrices (soft tissues and cranial cavities), which mediate bone growth. These matrices are largely acknowledged for their influence on shaping the bones of the skull; however, it is not fully understood to what extent functional matrices mediate the formation of bone articulations. Aiming to identify whether or not functional matrices are key developmental factors guiding the formation of bone articulations, we have built a network null model of the skull that simulates unconstrained bone growth. This null model predicts bone articulations that arise due to a process of bone growth that is uniform in rate, direction and timing. By comparing predicted articulations with the actual bone articulations of the human skull, we have identified which boundaries specifically need the presence of functional matrices for their formation. We show that functional matrices are necessary to connect facial bones, whereas an unconstrained bone growth is sufficient to connect non-facial bones. This finding challenges the role of the brain in the formation of boundaries between bones in the braincase without neglecting its effect on skull shape. Ultimately, our null model suggests where to look for modified developmental mechanisms promoting changes in bone growth patterns that could affect the development and evolution of the head skeleton. © 2014 Anatomical Society.

THE EFFECT OF THE GROWTH HORMONE FROM THE ANTERIOR LOBE OF THE PITUITARY ON BONE UNDER CONDITIONS OF IRRADIATION (in Russian)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ivanova, E.A.

1963-05-21

Young rats 3 to 4 days old were given an x-ray dose of 1000 r on the left hind leg. A daily dose of 200 gamma of growth hormone obtained from the pituitary of a bull was administered, until the animals were killed on the 36th, 41st, and 44th days after the irradiation. The length of the tibia in the left and right legs was determined by x rays. In the irradiated animals, the ratio of the length of the left tibia to the right tibia was about 0.50, and the introduction of growth hormone into the rat had onlymore » a slight effect on tibial growth. The bones were then fixed in a Zenkerformalin fluid, and cytological studies were carried out. These studies show that irradiation of the extremity of a four-day rat with an x-ray dose of 2000 r resulted in deep disturbances in the cartilage bone with subsequent arrest in the development of the bone. The introduction of growth hormone ameliorated the changes in bone structure, but did not result in normal bone development. (TTT)« less

Connective tissue growth factor is expressed in bone marrow stromal cells and promotes interleukin-7-dependent B lymphopoiesis.

PubMed

Cheung, Laurence C; Strickland, Deborah H; Howlett, Meegan; Ford, Jette; Charles, Adrian K; Lyons, Karen M; Brigstock, David R; Goldschmeding, Roel; Cole, Catherine H; Alexander, Warren S; Kees, Ursula R

2014-07-01

Hematopoiesis occurs in a complex bone marrow microenvironment in which bone marrow stromal cells provide critical support to the process through direct cell contact and indirectly through the secretion of cytokines and growth factors. We report that connective tissue growth factor (Ctgf, also known as Ccn2) is highly expressed in murine bone marrow stromal cells. In contrast, connective tissue growth factor is barely detectable in unfractionated adult bone marrow cells. While connective tissue growth factor has been implicated in hematopoietic malignancies, and is known to play critical roles in skeletogenesis and regulation of bone marrow stromal cells, its role in hematopoiesis has not been described. Here we demonstrate that the absence of connective tissue growth factor in mice results in impaired hematopoiesis. Using a chimeric fetal liver transplantation model, we show that absence of connective tissue growth factor has an impact on B-cell development, in particular from pro-B to more mature stages, which is linked to a requirement for connective tissue growth factor in bone marrow stromal cells. Using in vitro culture systems, we demonstrate that connective tissue growth factor potentiates B-cell proliferation and promotes pro-B to pre-B differentiation in the presence of interleukin-7. This study provides a better understanding of the functions of connective tissue growth factor within the bone marrow, showing the dual regulatory role of the growth factor in skeletogenesis and in stage-specific B lymphopoiesis. Copyright© Ferrata Storti Foundation.

Connective tissue growth factor is expressed in bone marrow stromal cells and promotes interleukin-7-dependent B lymphopoiesis

PubMed Central

Cheung, Laurence C.; Strickland, Deborah H.; Howlett, Meegan; Ford, Jette; Charles, Adrian K.; Lyons, Karen M.; Brigstock, David R.; Goldschmeding, Roel; Cole, Catherine H.; Alexander, Warren S.; Kees, Ursula R.

2014-01-01

Hematopoiesis occurs in a complex bone marrow microenvironment in which bone marrow stromal cells provide critical support to the process through direct cell contact and indirectly through the secretion of cytokines and growth factors. We report that connective tissue growth factor (Ctgf, also known as Ccn2) is highly expressed in murine bone marrow stromal cells. In contrast, connective tissue growth factor is barely detectable in unfractionated adult bone marrow cells. While connective tissue growth factor has been implicated in hematopoietic malignancies, and is known to play critical roles in skeletogenesis and regulation of bone marrow stromal cells, its role in hematopoiesis has not been described. Here we demonstrate that the absence of connective tissue growth factor in mice results in impaired hematopoiesis. Using a chimeric fetal liver transplantation model, we show that absence of connective tissue growth factor has an impact on B-cell development, in particular from pro-B to more mature stages, which is linked to a requirement for connective tissue growth factor in bone marrow stromal cells. Using in vitro culture systems, we demonstrate that connective tissue growth factor potentiates B-cell proliferation and promotes pro-B to pre-B differentiation in the presence of interleukin-7. This study provides a better understanding of the functions of connective tissue growth factor within the bone marrow, showing the dual regulatory role of the growth factor in skeletogenesis and in stage-specific B lymphopoiesis. PMID:24727816

Epiphyseal abnormalities, trabecular bone loss and articular chondrocyte hypertrophy develop in the long bones of postnatal Ext1-deficient mice.

PubMed

Sgariglia, Federica; Candela, Maria Elena; Huegel, Julianne; Jacenko, Olena; Koyama, Eiki; Yamaguchi, Yu; Pacifici, Maurizio; Enomoto-Iwamoto, Motomi

2013-11-01

Long bones are integral components of the limb skeleton. Recent studies have indicated that embryonic long bone development is altered by mutations in Ext genes and consequent heparan sulfate (HS) deficiency, possibly due to changes in activity and distribution of HS-binding/growth plate-associated signaling proteins. Here we asked whether Ext function is continuously required after birth to sustain growth plate function and long bone growth and organization. Compound transgenic Ext1(f/f);Col2CreERT mice were injected with tamoxifen at postnatal day 5 (P5) to ablate Ext1 in cartilage and monitored over time. The Ext1-deficient mice exhibited growth retardation already by 2weeks post-injection, as did their long bones. Mutant growth plates displayed a severe disorganization of chondrocyte columnar organization, a shortened hypertrophic zone with low expression of collagen X and MMP-13, and reduced primary spongiosa accompanied, however, by increased numbers of TRAP-positive osteoclasts at the chondro-osseous border. The mutant epiphyses were abnormal as well. Formation of a secondary ossification center was significantly delayed but interestingly, hypertrophic-like chondrocytes emerged within articular cartilage, similar to those often seen in osteoarthritic joints. Indeed, the cells displayed a large size and round shape, expressed collagen X and MMP-13 and were surrounded by an abundant Perlecan-rich pericellular matrix not seen in control articular chondrocytes. In addition, ectopic cartilaginous outgrowths developed on the lateral side of mutant growth plates over time that resembled exostotic characteristic of children with Hereditary Multiple Exostoses, a syndrome caused by Ext mutations and HS deficiency. In sum, the data do show that Ext1 is continuously required for postnatal growth and organization of long bones as well as their adjacent joints. Ext1 deficiency elicits defects that can occur in human skeletal conditions including trabecular bone loss, osteoarthritis and HME. © 2013.

Quantitation of Bone Growth Rate Variability in Rats Exposed to Micro-(near zero G) and Macrogravity (2G)

NASA Technical Reports Server (NTRS)

Bromage, Timothy G.; Doty, Stephen B.; Smolyar, Igor; Holton, Emily

1997-01-01

Our stated primary objective is to quantify the growth rate variability of rat lamellar bone exposed to micro- (near zero G: e.g., Cosmos 1887 & 2044; SLS-1 & SLS-2) and macrogravity (2G). The primary significance of the proposed work is that an elegant method will be established that unequivocally characterizes the morphological consequences of gravitational factors on developing bone. The integrity of this objective depends upon our successful preparation of thin sections suitable for imaging individual bone lamellae, and our imaging and quantitation of growth rate variability in populations of lamellae from individual bone samples.

A novel adaptive algorithm for 3D finite element analysis to model extracortical bone growth.

PubMed

Cheong, Vee San; Blunn, Gordon W; Coathup, Melanie J; Fromme, Paul

2018-02-01

Extracortical bone growth with osseointegration of bone onto the shaft of massive bone tumour implants is an important clinical outcome for long-term implant survival. A new computational algorithm combining geometrical shape changes and bone adaptation in 3D Finite Element simulations has been developed, using a soft tissue envelope mesh, a novel concept of osteoconnectivity, and bone remodelling theory. The effects of varying the initial tissue density, spatial influence function and time step were investigated. The methodology demonstrated good correspondence to radiological results for a segmental prosthesis.

Bone marrow vascular endothelial growth factor level per platelet count might be a significant predictor for the treatment outcomes of patients with diffuse large B-cell lymphomas.

PubMed

Kim, Jung Sun; Gang, Ga Won; Lee, Se Ryun; Sung, Hwa Jung; Park, Young; Kim, Dae Sik; Choi, Chul Won; Kim, Byung Soo

2015-10-01

Developing a parameter to predict bone marrow invasion by non-Hodgkin's lymphoma is an important unmet medical need for treatment decisions. This study aimed to confirm the validity of the hypothesis that bone marrow plasma vascular endothelial growth factor level might be correlated with the risk of bone marrow involvement and the prognosis of patients with diffuse large B-cell non-Hodgkin's lymphoma. Forty-nine diffuse large B-cell lymphoma patients treated with rituximab, cyclophosphamide, daunorubicin, vincristine and prednisolone regimen were enrolled. Vascular endothelial growth factor level was measured with enzyme-linked immunosorbent assay. The validity of bone marrow plasma vascular endothelial growth factor level and bone marrow vascular endothelial growth factor level per platelet count for predicting treatment response and survival after initial rituximab, cyclophosphamide, daunorubicin, vincristine and prednisolone combined chemotherapy was assessed. Bone marrow plasma vascular endothelial growth factor level per platelet count was significantly associated with old age (≥ 65 years), poor performance score (≥ 2), high International prognosis index (≥ 3) and bone marrow invasion. The patients with high bone marrow plasma vascular endothelial growth factor level per platelet count (≥ 3.01) showed a significantly lower complete response rate than the others. On Kaplan-Meier survival curves, the patients with high bone marrow plasma vascular endothelial growth factor levels (≥ 655 pg/ml) or high bone marrow plasma vascular endothelial growth factor level per platelet count (≥ 3.01) demonstrated a significantly shorter overall survival and progression-free survival than the others. In the patients without bone marrow involvement, bone marrow plasma vascular endothelial growth factor level per platelet count had a significant relationship with overall survival and progression-free survival. Multivariate analysis revealed that the patients without BM invasion showing high level of bone marrow plasma vascular endothelial growth factor per platelet count had significantly shorter progression-free survival and overall survival. Bone marrow plasma vascular endothelial growth factor level per platelet count might be associated with bone marrow invasion by diffuse large B-cell lymphoma and is correlated with clinical outcomes after treatment. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

FGF signaling in the osteoprogenitor lineage non-autonomously regulates postnatal chondrocyte proliferation and skeletal growth

PubMed Central

Karuppaiah, Kannan; Yu, Kai; Lim, Joohyun; Chen, Jianquan; Smith, Craig; Long, Fanxin

2016-01-01

ABSTRACT Fibroblast growth factor (FGF) signaling is important for skeletal development; however, cell-specific functions, redundancy and feedback mechanisms regulating bone growth are poorly understood. FGF receptors 1 and 2 (Fgfr1 and Fgfr2) are both expressed in the osteoprogenitor lineage. Double conditional knockout mice, in which both receptors were inactivated using an osteoprogenitor-specific Cre driver, appeared normal at birth; however, these mice showed severe postnatal growth defects that include an ∼50% reduction in body weight and bone mass, and impaired longitudinal bone growth. Histological analysis showed reduced cortical and trabecular bone, suggesting cell-autonomous functions of FGF signaling during postnatal bone formation. Surprisingly, the double conditional knockout mice also showed growth plate defects and an arrest in chondrocyte proliferation. We provide genetic evidence of a non-cell-autonomous feedback pathway regulating Fgf9, Fgf18 and Pthlh expression, which led to increased expression and signaling of Fgfr3 in growth plate chondrocytes and suppression of chondrocyte proliferation. These observations show that FGF signaling in the osteoprogenitor lineage is obligately coupled to chondrocyte proliferation and the regulation of longitudinal bone growth. PMID:27052727

Harold Goldstein (R) and Dan Leiser (L) discuss bone implant development in the the Shuttle Tile

NASA Technical Reports Server (NTRS)

1993-01-01

Harold Goldstein (R) and Dan Leiser (L) discuss bone implant development in the the Shuttle Tile Laboratory N-242. A spin-off of Ames research on both bone density in microgravity and on thermal protection foams is the bone-growth implant shown in 1993.

Skeletal development of mice lacking bone sialoprotein (BSP)--impairment of long bone growth and progressive establishment of high trabecular bone mass.

PubMed

Bouleftour, Wafa; Boudiffa, Maya; Wade-Gueye, Ndeye Marième; Bouët, Guénaëlle; Cardelli, Marco; Laroche, Norbert; Vanden-Bossche, Arnaud; Thomas, Mireille; Bonnelye, Edith; Aubin, Jane E; Vico, Laurence; Lafage-Proust, Marie Hélène; Malaval, Luc

2014-01-01

Adult Ibsp-knockout mice (BSP-/-) display shorter stature, lower bone turnover and higher trabecular bone mass than wild type, the latter resulting from impaired bone resorption. Unexpectedly, BSP knockout also affects reproductive behavior, as female mice do not construct a proper "nest" for their offsprings. Multiple crossing experiments nonetheless indicated that the shorter stature and lower weight of BSP-/- mice, since birth and throughout life, as well as their shorter femur and tibia bones are independent of the genotype of the mothers, and thus reflect genetic inheritance. In BSP-/- newborns, µCT analysis revealed a delay in membranous primary ossification, with wider cranial sutures, as well as thinner femoral cortical bone and lower tissue mineral density, reflected in lower expression of bone formation markers. However, trabecular bone volume and osteoclast parameters of long bones do not differ between genotypes. Three weeks after birth, osteoclast number and surface drop in the mutants, concomitant with trabecular bone accumulation. The growth plates present a thinner hypertrophic zone in newborns with lower whole bone expression of IGF-1 and higher IHH in 6 days old BSP-/- mice. At 3 weeks the proliferating zone is thinner and the hypertrophic zone thicker in BSP-/- than in BSP+/+ mice of either sex, maybe reflecting a combination of lower chondrocyte proliferation and impaired cartilage resorption. Six days old BSP-/- mice display lower osteoblast marker expression but higher MEPE and higher osteopontin(Opn)/Runx2 ratio. Serum Opn is higher in mutants at day 6 and in adults. Thus, lack of BSP alters long bone growth and membranous/cortical primary bone formation and mineralization. Endochondral development is however normal in mutant mice and the accumulation of trabecular bone observed in adults develops progressively in the weeks following birth. Compensatory high Opn may allow normal endochondral development in BSP-/- mice, while impairing primary mineralization.

The p27 Pathway Modulates the Regulation of Skeletal Growth and Osteoblastic Bone Formation by Parathyroid Hormone-Related Peptide.

PubMed

Zhu, Min; Zhang, Jing; Dong, Zhan; Zhang, Ying; Wang, Rong; Karaplis, Andrew; Goltzman, David; Miao, Dengshun

2015-11-01

Parathyroid hormone-related peptide (PTHrP) 1-84 knock-in mice (Pthrp KI) develop skeletal growth retardation and defective osteoblastic bone formation. To further examine the mechanisms underlying this phenotype, microarray analyses of differential gene expression profiles were performed in long bone extracts from Pthrp KI mice and their wild-type (WT) littermates. We found that the expression levels of p27, p16, and p53 were significantly upregulated in Pthrp KI mice relative to WT littermates. To determine whether p27 was involved in the regulation by PTHrP of skeletal growth and development in vivo, we generated compound mutant mice, which were homozygous for both p27 deletion and the Pthrp KI mutation (p27(-/-) Pthrp KI). We then compared p27(-/-) Pthrp KI mice with p27(-/-), Pthrp KI, and WT littermates. Deletion of p27 in Pthrp KI mice resulted in a longer lifespan, increased body weight, and improvement in skeletal growth. At 2 weeks of age, skeletal parameters, including length of long bones, size of epiphyses, numbers of proliferating cell nuclear antigen (PCNA)-positive chondrocytes, bone mineral density, trabecular bone volume, osteoblast numbers, and alkaline phosphatase (ALP)-, type I collagen-, and osteocalcin-positive bone areas were increased in p27(-/-) mice and reduced in both Pthrp KI and p27(-/-) Pthrp KI mice compared with WT mice; however, these parameters were increased in p27(-/-) Pthrp KI mice compared with Pthrp KI mice. As well, protein expression levels of PTHR, IGF-1, and Bmi-1, and the numbers of total colony-forming unit fibroblastic (CFU-f) and ALP-positive CFU-f were similarly increased in p27(-/-) Pthrp KI mice compared with Pthrp KI mice. Our results demonstrate that deletion of p27 in Pthrp KI mice can partially rescue defects in skeletal growth and osteoblastic bone formation by enhancing endochondral bone formation and osteogenesis. These studies, therefore, indicate that the p27 pathway may function downstream in the action of PTHrP to regulate skeletal growth and development. © 2015 American Society for Bone and Mineral Research.

Bone marrow fat: linking adipocyte-induced inflammation with skeletal metastases

PubMed Central

Hardaway, Aimalie L.; Herroon, Mackenzie K.; Rajagurubandara, Erandi

2014-01-01

Adipocytes are important but underappreciated components of bone marrow microenvironment, and their numbers greatly increase with age, obesity, and associated metabolic pathologies. Age and obesity are also significant risk factors for development of metastatic prostate cancer. Adipocytes are metabolically active cells that secrete adipokines, growth factors, and inflammatory mediators; influence behavior and function of neighboring cells; and have a potential to disturb local milleu and dysregulate normal bone homeostasis. Increased marrow adiposity has been linked to bone marrow inflammation and osteoporosis of the bone, but its effects on growth and progression of prostate tumors that have metastasized to the skeleton are currently not known. This review focuses on fat-bone relationship in a context of normal bone homeostasis and metastatic tumor growth in bone. We discuss effects of marrow fat cells on bone metabolism, hematopoiesis, and inflammation. Special attention is given to CCL2- and COX-2-driven pathways and their potential as therapeutic targets for bone metastatic disease. PMID:24398857

Developing a novel therapeutic strategy targeting Kallikrein-4 to inhibit prostate cancer growth and metastasis

DTIC Science & Technology

Kallikrein-related peptidase 4 (KLK4) is a rational therapeutic target for prostate cancer (PCa) as it is up-regulated in both localised and bone ...in PCa homing to bone . We therefore hypothesize that blockade of KLK4 activity will inhibit PCa growth and prevent metastasis to secondary sites like... bone . This project aims to develop a novel therapeutic strategy targeting KLK4 specifically in PCa. KLK4 siRNA is incorporated into a novel polymeric

Invited review of a workshop: anabolic hormones in bone: basic research and therapeutic potential.

PubMed

Margolis, R N; Canalis, E; Partridge, N C

1996-03-01

Age-, postmenopause-, and disease-related conditions that result in low bone mass represent important public health issues. Maintenance of bone mass is a balance between bone resorption and formation and is influenced by diet, body composition, activity level, and the interactions between and among a large number of hormones, growth factors, and cytokines. Recent research has emphasized establishing a more complete understanding of the hormonal regulation of bone and developing anabolic agents with therapeutic potential for the treatment of low bone mass. The NIDDK at the NIH recently sponsored a Workshop, entitled Anabolic Hormones in Bone: Basic Research and Therapeutic Potential, that attempted to define the current state of the art knowledge of hormones, growth factors, and cytokines that affect bone mass, with particular emphasis on those that could potentially have a role as anabolic agents in bone. This review presents a condensed proceedings of that workshop along with a summary of the optimal requisites for the development of anabolic agents with therapeutic potential in bone.

A c-fms tyrosine kinase inhibitor, Ki20227, suppresses osteoclast differentiation and osteolytic bone destruction in a bone metastasis model.

PubMed

Ohno, Hiroaki; Kubo, Kazuo; Murooka, Hideko; Kobayashi, Yoshiko; Nishitoba, Tsuyoshi; Shibuya, Masabumi; Yoneda, Toshiyuki; Isoe, Toshiyuki

2006-11-01

In bone metastatic lesions, osteoclasts play a key role in the development of osteolysis. Previous studies have shown that macrophage colony-stimulating factor (M-CSF) is important for the differentiation of osteoclasts. In this study, we investigated whether an inhibitor of M-CSF receptor (c-Fms) suppresses osteoclast-dependent osteolysis in bone metastatic lesions. We developed small molecule inhibitors against ligand-dependent phosphorylation of c-Fms and examined the effects of these compounds on osteolytic bone destruction in a bone metastasis model. We discovered a novel quinoline-urea derivative, Ki20227 (N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]-2-methoxyphenyl}-N'-[1-(1,3-thiazole-2-yl)ethyl]urea), which is a c-Fms tyrosine kinase inhibitor. The IC(50)s of Ki20227 to inhibit c-Fms, vascular endothelial growth factor receptor-2 (KDR), stem cell factor receptor (c-Kit), and platelet-derived growth factor receptor beta were found to be 2, 12, 451, and 217 nmol/L, respectively. Ki20227 did not inhibit other kinases tested, such as fms-like tyrosine kinase-3, epidermal growth factor receptor, or c-Src (c-src proto-oncogene product). Ki20227 was also found to inhibit the M-CSF-dependent growth of M-NFS-60 cells but not the M-CSF-independent growth of A375 human melanoma cells in vitro. Furthermore, in an osteoclast-like cell formation assay using mouse bone marrow cells, Ki20227 inhibited the development of tartrate-resistant acid phosphatase-positive osteoclast-like cells in a dose-dependent manner. In in vivo studies, oral administration of Ki20227 suppressed osteoclast-like cell accumulation and bone resorption induced by metastatic tumor cells in nude rats following intracardiac injection of A375 cells. Moreover, Ki20227 decreased the number of tartrate-resistant acid phosphatase-positive osteoclast-like cells on bone surfaces in ovariectomized (ovx) rats. These findings suggest that Ki20227 inhibits osteolytic bone destruction through the suppression of M-CSF-induced osteoclast accumulation in vivo. Therefore, Ki20227 may be a useful therapeutic agent for osteolytic disease associated with bone metastasis and other bone diseases.

Recurrence of a Unicameral Bone Cyst in the Femoral Diaphysis.

PubMed

Kim, Hyun Se; Lim, Kyung Sup; Seo, Sung Wook; Jang, Seung Pil; Shim, Jong Sup

2016-12-01

Diaphyseal unicameral bone cysts of the long bone are generally known to originate near the growth plate and migrate from the metaphysis to the diaphysis during skeletal growth. In the case of unicameral bone cysts of diaphyseal origin, recurrence at the same location is extremely rare. We report a case of recurrence of a unicameral bone cyst in the diaphysis of the femur that developed 8 years after treatment with curettage and bone grafting. We performed bone grafting and lengthening of the affected femur with an application of the Ilizarov apparatus over an intramedullary nail to treat the cystic lesion and limb length discrepancy simultaneously.

Recurrence of a Unicameral Bone Cyst in the Femoral Diaphysis

PubMed Central

Kim, Hyun Se; Lim, Kyung Sup; Seo, Sung Wook; Jang, Seung Pil

2016-01-01

Diaphyseal unicameral bone cysts of the long bone are generally known to originate near the growth plate and migrate from the metaphysis to the diaphysis during skeletal growth. In the case of unicameral bone cysts of diaphyseal origin, recurrence at the same location is extremely rare. We report a case of recurrence of a unicameral bone cyst in the diaphysis of the femur that developed 8 years after treatment with curettage and bone grafting. We performed bone grafting and lengthening of the affected femur with an application of the Ilizarov apparatus over an intramedullary nail to treat the cystic lesion and limb length discrepancy simultaneously. PMID:27904734

Associations between variants of bone morphogenetic protein 7 gene and growth traits in chickens.

PubMed

Wang, Yan; Guo, Fuyou; Qu, Hao; Luo, Chenglong; Wang, Jie; Shu, Dingming

2018-04-18

1. Enhancing bone strength to solve leg disorders in poultry has become an important goal in broiler production. 2. Bone morphogenetic protein 7 (BMP7), a member of the BMP family, represents an attractive therapeutic target for bone regeneration in humans and plays critical roles in skeletal development. 3. The objective of this study was to investigate the relationship between BMP7 gene expression, single nucleotide polymorphisms (SNPs) and growth traits in chickens. Here, a SNP (c.1995T>C) in the chicken (Gallus gallus) BMP7 gene was identified, that was associated with growth and carcass traits. 4. Genotyping revealed that the T allele occurred more frequently in breeds with high growth rates, whereas the C allele was predominant in those with low growth rates. The expression level of BMP7 in the thigh bone of birds with the TT genotype was significantly higher than in those with the CC genotype at 21, 42 and 91 days of age. 5. These findings suggest that selecting the birds with the TT genotype of SNP c.1995T>C could improve bone growth, could reduce leg disorders in fast-growing birds. The SNP c.1995T>C may serve as a selective marker for improving bone growth and increasing the consistency of body weights in poultry breeding.

Zoledronic acid has differential antitumor activity in the pre- and postmenopausal bone microenvironment in vivo.

PubMed

Ottewell, Penelope D; Wang, Ning; Brown, Hannah K; Reeves, Kimberly J; Fowles, C Anne; Croucher, Peter I; Eaton, Colby L; Holen, Ingunn

2014-06-01

Clinical trials in early breast cancer have suggested that benefits of adjuvant bone-targeted treatments are restricted to women with established menopause. We developed models that mimic pre- and postmenopausal status to investigate effects of altered bone turnover on growth of disseminated breast tumor cells. Here, we report a differential antitumor effect of zoledronic acid (ZOL) in these two settings. Twleve-week-old female Balb/c-nude mice with disseminated MDA-MB-231 breast tumor cells in bone underwent sham operation or ovariectomy (OVX), mimicking the pre- and postmenopausal bone microenvironment, respectively. To determine the effects of bone-targeted therapy, sham/OVX animals received saline or 100 μg/kg ZOL weekly. Tumor growth was assessed by in vivo imaging and effects on bone by real-time PCR, micro-CT, histomorphometry, and measurements of bone markers. Disseminated tumor cells were detected by two-photon microscopy. OVX increased bone resorption and induced growth of disseminated tumor cells in bone. Tumors were detected in 83% of animals following OVX (postmenopausal model) compared with 17% following sham operation (premenopausal model). OVX had no effect on tumors outside of bone. OVX-induced tumor growth was completely prevented by ZOL, despite the presence of disseminated tumor cells. ZOL did not affect tumor growth in bone in the sham-operated animals. ZOL increased bone volume in both groups. This is the first demonstration that tumor growth is driven by osteoclast-mediated mechanisms in models that mimic post- but not premenopausal bone, providing a biologic rationale for the differential antitumor effects of ZOL reported in these settings. Clin Cancer Res; 20(11); 2922-32. ©2014 AACR. ©2014 American Association for Cancer Research.

Growth, sexual and bone development in a boy with bilateral anorchia under testosterone treatment guided by the development of his monozygotic twin.

PubMed

Vandewalle, Sara; Van Caenegem, Eva; Craen, Margarita; Taes, Youri; Kaufman, Jean-Marc; T'Sjoen, Guy

2018-03-28

Sex steroids are essential for sexual maturation, linear growth and bone development. However, there is no consensus on the optimal timing, dosage and dosage interval of testosterone therapy to induce pubertal development and achieve a normal adult height and bone mass in children with hypogonadism. A monozygotic monochorial male twin pair, of which one boy was diagnosed with anorchia at birth due to testicular regression syndrome was followed from the age of 3 until the age of 18 years. Low dose testosterone substitution (testosterone esters 25 mg/2 weeks) was initiated in the affected twin based on the start of pubertal development in the healthy twin and then gradually increased accordingly. Both boys were followed until age 18 and were compared as regards to linear growth, sexual maturation, bone maturation and bone development. Before puberty induction both boys had a similar weight and height. During puberty, a slightly faster weight and height gain was observed in the affected twin. Both boys ended up however, with a similar and normal (near) adult height and weight and experienced a normal development of secondary sex characteristics. At the age of 17 and 18 years, bone mineral density, body composition and volumetric bone parameters at the forearm and calf were evaluated in both boys. The affected boy had a higher lean mass and muscle cross-sectional area. The bone mineral density at the lumbar spine and whole body was similar. Trabecular and cortical volumetric bone parameters were comparable. At one cortical site (proximal radius), however, the affected twin had a smaller periosteal and endosteal circumference with a thicker cortex. In conclusion, a low dose testosterone substitution in bilateral anorchia led to a normal onset of pubertal development and (near) adult height. Furthermore, there was no difference in bone mineral density at the age of 17 and 18 years.

Epiphyseal abnormalities, trabecular bone loss and articular chondrocyte hypertrophy develop in the long bones of postnatal Ext1-deficient mice1

PubMed Central

Sgariglia, Federica; Candela, Maria Elena; Huegel, Julianne; Jacenko, Olena; Koyama, Eiki; Yamaguchi, Yu; Pacifici, Maurizio; Enomoto-Iwamoto, Motomi

2014-01-01

Long bones are integral components of the limb skeleton. Recent studies have indicated that embryonic long bone development is altered by mutations in Ext genes and consequent heparan sulfate (HS) deficiency, possibly due to changes in activity and distribution of HS-binding/growth plate-associated signaling proteins. Here we asked whether Ext function is continuously required after birth to sustain growth plate function and long bone growth and organization. Compound transgenic Ext1f/f;Col2CreERT mice were injected with tamoxifen at postnatal day 5 (P5) to ablate Ext1 in cartilage and monitored over time. The Ext1-deficient mice exhibited growth retardation already by 2 weeks post-injection, as did their long bones. Mutant growth plates displayed a severe disorganization of chondrocyte columnar organization, a shortened hypertrophic zone with low expression of collagen X and MMP-13, and reduced primary spongiosa accompanied, however, by increased numbers of TRAP-positive osteoclasts at the chondro-osseous border. The mutant epiphyses were abnormal as well. Formation of a secondary ossification center was significantly delayed but interestingly, hypertrophic-like chondrocytes emerged within articular cartilage, similar to those often seen in osteoarthritic joints. Indeed, the cells displayed a large size and round shape, expressed collagen X and MMP-13 and were surrounded by an abundant Perlecan-rich pericellular matrix not seen in control articular chondrocytes. In addition, ectopic cartilaginous by EXT mutations and HS deficiency. In sum, the data do show that Ext1 is continuously required for postnatal growth and organization of long bones as well as their adjacent joints. Ext1 deficiency elicits defects that can occur in human skeletal conditions including trabecular bone loss, osteoarthritis and HME. PMID:23958822

[Impact of thyroid diseases on bone].

PubMed

Tsourdi, E; Lademann, F; Siggelkow, H

2018-05-09

Thyroid hormones are key regulators of skeletal development in childhood and bone homeostasis in adulthood, and thyroid diseases have been associated with increased osteoporotic fractures. Hypothyroidism in children leads to an impaired skeletal maturation and mineralization, but an adequate and timely substitution with thyroid hormones stimulates bone growth. Conversely, hyperthyroidism at a young age accelerates skeletal development, but may also cause short stature because of a premature fusion of the growth plates. Hypothyroidism in adults causes an increase in the duration of the remodeling cycle and, thus, leads to low bone turnover and enhanced mineralization, but an association with a higher fracture risk is less well established. In adults, a surplus of thyroid hormones enhances bone turnover, mostly due to an increased bone resorption driven by osteoclasts. Thus, hyperthyroidism is a well-recognized cause of high-bone turnover secondary osteoporosis, resulting in an increased susceptibility to fragility fractures. Subclinical hyperthyroidism, especially resulting from endogenous disease, also has an adverse effect on bone mineral density and is associated with fractures. In most patients with overt or subclinical hyperthyroidism restoration of the euthyroid status reverses bone loss. In postmenopausal women who receive thyroid-stimulating hormone suppression therapy because of thyroid cancer, antiresorptive treatments may be indicated. Overall, extensive data support the importance of a euthyroid status for bone mineral accrual and growth in childhood as well as maintenance of bone health in adulthood.

Endothelial Notch activity promotes angiogenesis and osteogenesis in bone

NASA Astrophysics Data System (ADS)

Ramasamy, Saravana K.; Kusumbe, Anjali P.; Wang, Lin; Adams, Ralf H.

2014-03-01

Blood vessel growth in the skeletal system and osteogenesis seem to be coupled, suggesting the existence of molecular crosstalk between endothelial and osteoblastic cells. Understanding the nature of the mechanisms linking angiogenesis and bone formation should be of great relevance for improved fracture healing or prevention of bone mass loss. Here we show that vascular growth in bone involves a specialized, tissue-specific form of angiogenesis. Notch signalling promotes endothelial cell proliferation and vessel growth in postnatal long bone, which is the opposite of the well-established function of Notch and its ligand Dll4 in the endothelium of other organs and tumours. Endothelial-cell-specific and inducible genetic disruption of Notch signalling in mice not only impaired bone vessel morphology and growth, but also led to reduced osteogenesis, shortening of long bones, chondrocyte defects, loss of trabeculae and decreased bone mass. On the basis of a series of genetic experiments, we conclude that skeletal defects in these mutants involved defective angiocrine release of Noggin from endothelial cells, which is positively regulated by Notch. Administration of recombinant Noggin, a secreted antagonist of bone morphogenetic proteins, restored bone growth and mineralization, chondrocyte maturation, the formation of trabeculae and osteoprogenitor numbers in endothelial-cell-specific Notch pathway mutants. These findings establish a molecular framework coupling angiogenesis, angiocrine signals and osteogenesis, which may prove significant for the development of future therapeutic applications.

Hox11 genes regulate postnatal longitudinal bone growth and growth plate proliferation.

PubMed

Pineault, Kyriel M; Swinehart, Ilea T; Garthus, Kayla N; Ho, Edward; Yao, Qing; Schipani, Ernestina; Kozloff, Kenneth M; Wellik, Deneen M

2015-10-23

Hox genes are critical regulators of skeletal development and Hox9-13 paralogs, specifically, are necessary for appendicular development along the proximal to distal axis. Loss of function of both Hoxa11 and Hoxd11 results in severe malformation of the forelimb zeugopod. In the radius and ulna of these mutants, chondrocyte development is perturbed, growth plates are not established, and skeletal growth and maturation fails. In compound mutants in which one of the four Hox11 alleles remains wild-type, establishment of a growth plate is preserved and embryos develop normally through newborn stages, however, skeletal phenotypes become evident postnatally. During postnatal development, the radial and ulnar growth rate slows compared to wild-type controls and terminal bone length is reduced. Growth plate height is decreased in mutants and premature growth plate senescence occurs along with abnormally high levels of chondrocyte proliferation in the reserve and proliferative zones. Compound mutants additionally develop an abnormal curvature of the radius, which causes significant distortion of the carpal elements. The progressive bowing of the radius appears to result from physical constraint caused by the disproportionately slower growth of the ulna than the radius. Collectively, these data are consistent with premature depletion of forelimb zeugopod progenitor cells in the growth plate of Hox11 compound mutants, and demonstrate a continued function for Hox genes in postnatal bone growth and patterning. © 2015. Published by The Company of Biologists Ltd.

Role of IGF-I Signaling in Muscle Bone Interactions

PubMed Central

Bikle, Daniel D; Tahimic, Candice; Chang, Wenhan; Wang, Yongmei; Philippou, Anastassios; Barton, Elisabeth R.

2015-01-01

Skeletal muscle and bone rely on a number of growth factors to undergo development, modulate growth, and maintain physiological strength. A major player in these actions is insulin-like growth factor I (IGF-I). However, because this growth factor can directly enhance muscle mass and bone density, it alters the state of the musculoskeletal system indirectly through mechanical crosstalk between these two organ systems. Thus, there are clearly synergistic actions of IGF-I that extend beyond the direct activity through its receptor. This review will cover the production and signaling of IGF-I as it pertains to muscle and bone, the chemical and mechanical influences that arise from IGF-I activity, and the potential for therapeutic strategies based on IGF-I. PMID:26453498

Multidisciplinary characterization of the long-bone cortex growth patterns through sheep's ontogeny.

PubMed

Cambra-Moo, Oscar; Nacarino-Meneses, Carmen; Díaz-Güemes, Idoia; Enciso, Silvia; García Gil, Orosia; Llorente Rodríguez, Laura; Rodríguez Barbero, Miguel Ángel; de Aza, Antonio H; González Martín, Armando

2015-07-01

Bone researches have studied extant and extinct taxa extensively trying to disclose a complete view of the complex structural and chemical transformations that model and remodel the macro and microstructure of bone during growth. However, to approach bone growth variations is not an easy task, and many aspects related with histological transformations during ontogeny remain unresolved. In the present study, we conduct a holistic approach using different techniques (polarized microscopy, Raman spectroscopy and X-ray diffraction) to examine the histomorphological and histochemical variations in the cortical bone of sheep specimens from intrauterine to adult stages, using environmentally controlled specimens from the same species. Our results suggest that during sheep bone development, the most important morphological (shape and size) and chemical transformations in the cortical bone occur during the first weeks of life; synchronized but dissimilar variations are established in the forelimb and hind limb cortical bone; and the patterns of bone tissue maturation in both extremities are differentiated in the adult stage. All of these results indicate that standardized histological models are useful not only for evaluating many aspects of normal bone growth but also to understand other important influences on the bones, such as pathologies that remain unknown. Copyright © 2015 Elsevier Inc. All rights reserved.

Atmospheric pressure as a force that fills developing bones with marrow and air.

PubMed

Kurbel, Sven; Radić, Radivoje; Kristek, Branka; Ivezić, Zdravko; Selthofer, Robert; Kotromanović, Zeljko

2004-01-01

Many theories try to explain the existence and function of paranasal sinuses. This paper is an attempt to correlate process of paranasal sinus development in human with bone pneumatization processes in animals. It is here proposed that this mechanism starts in utero and continues after birth. During endochondral development, a solid hyaline cartilage model transforms into long bones. Central chondrocytes hypertrophy and their lacunae become confluent. Dissolving of the cartilage intercellular matrix forms a primitive marrow cavity. It is soon invaded by the periostal bud. Once circulation is established in the developing bone, the dissolved hyaline matrix can be slowly washed away from the bone cavity. Circulation in the bone cavity can develop slight subatmospheric pressures, similar to negative interstitial pressures in subcutaneous tissues. The amniotic fluid conducts atmospheric pressure to the fetal body. The pressure is trying to fill enlarging bone cavities through the existing vascular openings, or to create new openings. Bone walls of developing paranasal bones are to weak to resist the pressure gradient on their walls. New openings form on the weakest spots allowing airway mucosa to form initial paranasal sinuses. The enlarging cavities of long bones that are remote from the body surface and airway also develop a slightly subatmospheric pressure that fills them with cellular elements. These elements enter bone through the feeding vessels and form bone marrow. During after birth skeletal growth, bone remodeling shapes paranasal sinuses in a process of slow evolution that do not require measurable pressure gradients. When two sinuses come in vicinity, their growth rate declines, since the remaining thin and fragile bone lamella between them does not retract anymore.

Achondroplasia: Development, Pathogenesis, and Therapy

PubMed Central

Ornitz, David M.; Legeai-Mallet, Laurence

2016-01-01

Autosomal dominant mutations in Fibroblast Growth Factor Receptor 3 (FGFR3) cause Achondroplasia (Ach), the most common form of dwarfism in humans, and related chondrodysplasia syndromes that include Hypochondroplasia (Hch), Severe Achondroplasia with Developmental Delay and Acanthosis Nigricans (SADDAN), and Thanatophoric dysplasia (TD). FGFR3 is expressed in chondrocytes and mature osteoblasts where it functions to regulate bone growth. Analysis of the mutations in FGFR3 revealed increased signaling through a combination of mechanisms that include stabilization of the receptor, enhanced dimerization, and enhanced tyrosine kinase activity. Paradoxically, increased FGFR3 signaling profoundly suppresses proliferation and maturation of growth plate chondrocytes resulting in decreased growth plate size, reduced trabecular bone volume, and resulting decreased bone elongation. In this review we discuss the molecular mechanisms that regulate growth plate chondrocytes, the pathogenesis of Ach, and therapeutic approaches that are being evaluated to improve endochondral bone growth in people with Ach and related conditions. PMID:27987249

True Color Image Analysis For Determination Of Bone Growth In Fluorochromic Biopsies

NASA Astrophysics Data System (ADS)

Madachy, Raymond J.; Chotivichit, Lee; Huang, H. K.; Johnson, Eric E.

1989-05-01

A true color imaging technique has been developed for analysis of microscopic fluorochromic bone biopsy images to quantify new bone growth. The technique searches for specified colors in a medical image for quantification of areas of interest. Based on a user supplied training set, a multispectral classification of pixel values is performed and used for segmenting the image. Good results were obtained when compared to manual tracings of new bone growth performed by an orthopedic surgeon. At a 95% confidence level, the hypothesis that there is no difference between the two methods can be accepted. Work is in progress to test bone biopsies with different colored stains and further optimize the analysis process using three-dimensional spectral ordering techniques.

Osteoimmunology: Influence of the Immune System on Bone Regeneration and Consumption.

PubMed

Limmer, Andreas; Wirtz, Dieter C

2017-06-01

Background Stimulating bone regeneration is a central aim in orthopaedic and trauma surgery. Although the replacement of bone with artificial materials like cement or apatite helps to keep up bone stability, new bone often cannot be regenerated. Increasing research efforts have led to the clinical application of growth factors stimulating bone growth (e.g. bone morphogenic protein, BMP) and inhibitors preventing bone consumption (e.g. RANKL blocking antibodies). These factors mostly concentrate on stimulating osteoblast or preventing osteoclast activity. Current Situation It is widely accepted that osteoblasts and osteoclasts are central players in bone regeneration. This concept assumes that osteoblasts are responsible for bone growth while osteoclasts cause bone consumption by secreting matrix-degrading enzymes such as cathepsin K and matrix metalloproteinases (MMP). However, according to new research results, bone growth or consumption are not regulated by single cell types. It is rather the interaction of various cell types that regulates bone metabolism. While factors secreted by osteoblasts are essential for osteoclast differentiation and activation, factors secreted by activated osteoclasts are essential for osteoblast activity. In addition, recent research results imply that the influence of the immune system on bone metabolism has long been neglected. Factors secreted by macrophages or T cells strongly influence bone growth or degradation, depending on the bone microenvironment. Infections, sterile inflammation or tumour metastases not only affect bone cells directly, but also influence immune cells such as T cells indirectly. Furthermore, immune cells and bone are mechanistically regulated by similar factors such as cytokines, chemokines and transcription factors, suggesting that the definition of bone and immune cells has to be thought over. Outlook Bone and the immune system are regulated by similar mechanisms. These newly identified similarities between bone and the immune system imply that medication developed for tumour and autoimmune patients could also be applied in bone diseases. Georg Thieme Verlag KG Stuttgart · New York.

The development of inter-strain variation in cortical and trabecular traits during growth of the mouse lumbar vertebral body.

PubMed

Ramcharan, M A; Faillace, M E; Guengerich, Z; Williams, V A; Jepsen, K J

2017-03-01

How cortical and trabecular bone co-develop to establish a mechanically functional structure is not well understood. Comparing early postnatal differences in morphology of lumbar vertebral bodies for three inbred mouse strains identified coordinated changes within and between cortical and trabecular traits. These early coordinate changes defined the phenotypic differences among the inbred mouse strains. Age-related changes in cortical and trabecular traits have been well studied; however, very little is known about how these bone tissues co-develop from day 1 of postnatal growth to establish functional structures by adulthood. In this study, we aimed to establish how cortical and trabecular tissues within the lumbar vertebral body change during growth for three inbred mouse strains that express wide variation in adult bone structure and function. Bone traits were quantified for lumbar vertebral bodies of female A/J, C57BL/6J (B6), and C3H/HeJ (C3H) inbred mouse strains from 1 to 105 days of age (n = 6-10 mice/age/strain). Inter-strain differences in external bone size were observed as early as 1 day of age. Reciprocal and rapid changes in the trabecular bone volume fraction and alignment in the direction of axial compression were observed by 7 days of age. Importantly, the inter-strain difference in adult trabecular bone volume fraction was established by 7 days of age. Early variation in external bone size and trabecular architecture was followed by progressive increases in cortical area between 28 and 105 days of age, with the greatest increases in cortical area seen in the mouse strain with the lowest trabecular mass. Establishing the temporal changes in bone morphology for three inbred mouse strains revealed that genetic variation in adult trabecular traits were established early in postnatal development. Early variation in trabecular architecture preceded strain-specific increases in cortical area and changes in cortical thickness. This study established the sequence of how cortical and trabecular traits co-develop during growth, which is important for identifying critical early ages to further focus on intervention studies that optimize adult bone strength.

The Skeletal Site-Specific Role of Connective Tissue Growth Factor in Prenatal Osteogenesis

PubMed Central

Lambi, Alex G.; Pankratz, Talia L.; Mundy, Christina; Gannon, Maureen; Barbe, Mary F.; Richtsmeier, Joan T.; Popoff, Steven N.

2013-01-01

Background Connective tissue growth factor (CTGF/CCN2) is a matricellular protein that is highly expressed during bone development. Mice with global CTGF ablation (knockout, KO) have multiple skeletal dysmorphisms and perinatal lethality. A quantitative analysis of the bone phenotype has not been conducted. Results We demonstrated skeletal site-specific changes in growth plate organization, bone microarchitecture, and shape and gene expression levels in CTGF KO compared with wild-type mice. Growth plate malformations included reduced proliferation zone and increased hypertrophic zone lengths. Appendicular skeletal sites demonstrated decreased metaphyseal trabecular bone, while having increased mid-diaphyseal bone and osteogenic expression markers. Axial skeletal analysis showed decreased bone in caudal vertebral bodies, mandibles, and parietal bones in CTGF KO mice, with decreased expression of osteogenic markers. Analysis of skull phenotypes demonstrated global and regional differences in CTGF KO skull shape resulting from allometric (size-based) and nonallometric shape changes. Localized differences in skull morphology included increased skull width and decreased skull length. Dysregulation of the transforming growth factor-β-CTGF axis coupled with unique morphologic traits provides a potential mechanistic explanation for the skull phenotype. Conclusions We present novel data on a skeletal phenotype in CTGF KO mice, in which ablation of CTGF causes site-specific aberrations in bone formation. PMID:23073844

The skeletal vascular system - Breathing life into bone tissue.

PubMed

Stegen, Steve; Carmeliet, Geert

2017-08-26

During bone development, homeostasis and repair, a dense vascular system provides oxygen and nutrients to highly anabolic skeletal cells. Characteristic for the vascular system in bone is the serial organization of two capillary systems, each typified by specific morphological and physiological features. Especially the arterial capillaries mediate the growth of the bone vascular system, serve as a niche for skeletal and hematopoietic progenitors and couple angiogenesis to osteogenesis. Endothelial cells and osteoprogenitor cells interact not only physically, but also communicate to each other by secretion of growth factors. A vital angiogenic growth factor is vascular endothelial growth factor and its expression in skeletal cells is controlled by osteogenic transcription factors and hypoxia signaling, whereas the secretion of angiocrine factors by endothelial cells is regulated by Notch signaling, blood flow and possibly hypoxia. Bone loss and impaired fracture repair are often associated with reduced and disorganized blood vessel network and therapeutic targeting of the angiogenic response may contribute to enhanced bone regeneration. Copyright © 2017 Elsevier Inc. All rights reserved.

Early development and osteoporosis and bone health.

PubMed

Dennison, E M; Cooper, C; Cole, Z A

2010-06-01

Osteoporosis is a skeletal disorder characterized by low bone mass and micro-architectural deterioration of bone tissue with a consequent increase in bone fragility and susceptibility to fracture. Evidence is now accumulating from human studies that programming of bone growth might be an important contributor to the later risk of osteoporotic fracture. Body weight in infancy is a determinant of adult bone mineral content, as well as of the basal levels of activity of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) and hypothalamo-pituitary-adrenal (HPA) axes, and recent work has suggested a central role for vitamin D. Epidemiological studies have shown that maternal smoking and nutrition during pregnancy influence intrauterine skeletal mineralization. Childhood growth rates have been directly linked to the risk of hip fracture many decades later, and now evidence is emerging from experimental animal studies that support these observational data. Recent studies have also highlighted epigenetic phenomena as potential mechanisms underlying the findings from epidemiological studies.

Nanocellulose-collagen-apatite composite associated with osteogenic growth peptide for bone regeneration.

PubMed

Saska, Sybele; Teixeira, Lucas Novaes; de Castro Raucci, Larissa Moreira Spinola; Scarel-Caminaga, Raquel Mantuaneli; Franchi, Leonardo Pereira; Dos Santos, Raquel Alves; Santagneli, Silvia Helena; Capela, Marisa Veiga; de Oliveira, Paulo Tambasco; Takahashi, Catarina Satie; Gaspar, Ana Maria Minarelli; Messaddeq, Younès; Ribeiro, Sidney José Lima; Marchetto, Reinaldo

2017-10-01

Despite advances in the field of biomaterials for bone repair/regeneration, some challenges for developing an ideal bone substitute need to be overcome. Herein, this study synthesized and evaluated in vitro a nanocomposite based on bacterial cellulose (BC), collagen (COL), apatite (Ap) and osteogenic growth peptide (OGP) or its C-terminal pentapeptide [OGP(10-14)] for bone regeneration purposes. The BC-COL nanocomposites were successfully obtained by carbodiimide-mediated coupling as demonstrated by spectroscopy analysis. SEM, FTIR and 31 P NMR analyses revealed that in situ synthesis to apatite was an effective route for obtaining of bone-like apatite. The OGP-containing (BC-COL)-Ap stimulated the early development of the osteoblastic phenotype. Additionally, the association among collagen, apatite, and OGP peptides enhanced cell growth compared with OGP-containing BC-Ap. Furthermore, none of the nanocomposites showed cytotoxic, genotoxic or mutagenic effects. These promising results suggest that the (BC-COL)-Ap associated with OGP peptides might be considered a potential candidate for bone tissue engineering applications. Copyright © 2017 Elsevier B.V. All rights reserved.

[The laboratory evaluation of pathogenic factors under retarded consolidation of fractures of bones of lower extremities].

PubMed

Stogov, V M; Kireeva, E A; Karasev, A G

2014-12-01

The study was carried out to comparatively analyze metabolic profile and content of growth factors in blood serum of patients with retarded consolidation of fractures of bones of lower extremities. The evaluation was applied to concentration of metabolites, growth factors and enzyme activity of blood serum in 13 patients with retarded consolidation of fractures of thigh and shank bones (main group). The comparative group included 14 patients with solid fractures of thigh and shank bones. The analysis established that as compared to patients with solid fractures of bones, in patients with retarded consolidation of fractures blood serum contained reliably higher concentration of triglycerides, products of glycolysis, epidermal growth factor and transforming growth factors TGF-α and TGF-β2. The content of vitamin E and insullin-like growth factor (IGF-1) was decreased The given markers can be labeled as potential markers of diagnostic and prognosis of development of retarded consolidation of fractures.

Role of IGF1 and EFN-EPH signaling in skeletal metabolism.

PubMed

Lindsey, Richard C; Rundle, Charles H; Mohan, Subburaman

2018-07-01

Insulin-like growth factor 1(IGF1) and ephrin ligand (EFN)-receptor (EPH) signaling are both crucial for bone cell function and skeletal development and maintenance. IGF1 signaling is the major mediator of growth hormone-induced bone growth, but a host of different signals and factors regulate IGF1 signaling at the systemic and local levels. Disruption of the Igf1 gene results in reduced peak bone mass in both experimental animal models and humans. Additionally, EFN-EPH signaling is a complex system which, particularly through cell-cell interactions, contributes to the development and differentiation of many bone cell types. Recent evidence has demonstrated several ways in which the IGF1 and EFN-EPH signaling pathways interact with and depend upon each other to regulate bone cell function. While much remains to be elucidated, the interaction between these two signaling pathways opens a vast array of new opportunities for investigation into the mechanisms of and potential therapies for skeletal conditions such as osteoporosis and fracture repair. © 2018 Society for Endocrinology.

The bcl-2 knockout mouse exhibits marked changes in osteoblast phenotype and collagen deposition in bone as well as a mild growth plate phenotype

PubMed Central

BOOT-HANDFORD, R. P.; MICHAELIDIS, T. M.; HILLARBY, M. C.; ZAMBELLI, A.; DENTON, J.; HOYLAND, J. A.; FREEMONT, A. J.; GRANT, M. E.; WALLIS, G. A.

1998-01-01

Histological examination of long bones from 1-day-old bcl-2 knockout and age-matched control mice revealed no obvious differences in length of bone, growth plate architecture or stage of endochondral ossification. In 35-day-old bcl-2 knockout mice that are growth retarded or ‘dwarfed’, the proliferative zone of the growth plate appeared slightly thinner and the secondary centres of ossification less well developed than their age-matched wild-type controls. The most marked histological effects of bcl-2 ablation were on osteoblasts and bone. 35-day-old knockout mouse bones exhibited far greater numbers of osteoblasts than controls and the osteoblasts had a cuboidal phenotype in comparison with the normal flattened cell appearance. In addition, the collagen deposited by the osteoblasts in the bcl-2 knockout mouse bone was disorganized in comparison with control tissue and had a pseudo-woven appearance. The results suggest an important role for Bcl-2 in controlling osteoblast phenotype and bone deposition in vivo. PMID:10193316

Controlled release of drugs in electrosprayed nanoparticles for bone tissue engineering.

PubMed

Jayaraman, Praveena; Gandhimathi, Chinnasamy; Venugopal, Jayarama Reddy; Becker, David Laurence; Ramakrishna, Seeram; Srinivasan, Dinesh Kumar

2015-11-01

Generating porous topographic substrates, by mimicking the native extracellular matrix (ECM) to promote the regeneration of damaged bone tissues, is a challenging process. Generally, scaffolds developed for bone tissue regeneration support bone cell growth and induce bone-forming cells by natural proteins and growth factors. Limitations are often associated with these approaches such as improper scaffold stability, and insufficient cell adhesion, proliferation, differentiation, and mineralization with less growth factor expression. Therefore, the use of engineered nanoparticles has been rapidly increasing in bone tissue engineering (BTE) applications. The electrospray technique is advantageous over other conventional methods as it generates nanomaterials of particle sizes in the micro/nanoscale range. The size and charge of the particles are controlled by regulating the polymer solution flow rate and electric voltage. The unique properties of nanoparticles such as large surface area-to-volume ratio, small size, and higher reactivity make them promising candidates in the field of biomedical engineering. These nanomaterials are extensively used as therapeutic agents and for drug delivery, mimicking ECM, and restoring and improving the functions of damaged organs. The controlled and sustained release of encapsulated drugs, proteins, vaccines, growth factors, cells, and nucleotides from nanoparticles has been well developed in nanomedicine. This review provides an insight into the preparation of nanoparticles by electrospraying technique and illustrates the use of nanoparticles in drug delivery for promoting bone tissue regeneration. Copyright © 2015 Elsevier B.V. All rights reserved.

Postnatal soluble FGFR3 therapy rescues achondroplasia symptoms and restores bone growth in mice.

PubMed

Garcia, Stéphanie; Dirat, Béatrice; Tognacci, Thomas; Rochet, Nathalie; Mouska, Xavier; Bonnafous, Stéphanie; Patouraux, Stéphanie; Tran, Albert; Gual, Philippe; Le Marchand-Brustel, Yannick; Gennero, Isabelle; Gouze, Elvire

2013-09-18

Achondroplasia is a rare genetic disease characterized by abnormal bone development, resulting in short stature. It is caused by a single point mutation in the gene coding for fibroblast growth factor receptor 3 (FGFR3), which leads to prolonged activation upon ligand binding. To prevent excessive intracellular signaling and rescue the symptoms of achondroplasia, we have developed a recombinant protein therapeutic approach using a soluble form of human FGFR3 (sFGFR3), which acts as a decoy receptor and prevents FGF from binding to mutant FGFR3. sFGFR3 was injected subcutaneously to newborn Fgfr3(ach/+) mice-the mouse model of achondroplasia-twice per week throughout the growth period during 3 weeks. Effective maturation of growth plate chondrocytes was restored in bones of treated mice, with a dose-dependent enhancement of skeletal growth in Fgfr3(ach/+) mice. This resulted in normal stature and a significant decrease in mortality and associated complications, without any evidence of toxicity. These results describe a new approach for restoring bone growth and suggest that sFGFR3 could be a potential therapy for children with achondroplasia and related disorders.

Correspondence between theoretical models and dual energy x-ray absorptiometry measurements of femoral cross-sectional growth during adolescence

NASA Technical Reports Server (NTRS)

van der Meulen, M. C.; Marcus, R.; Bachrach, L. K.; Carter, D. R.

1997-01-01

We have developed an analytical model of long bone cross-sectional ontogeny in which appositional growth of the diaphysis is primarily driven by mechanical stimuli associated with increasing body mass during growth and development. In this study, our goal was to compare theoretical predictions of femoral diaphyseal structure from this model with measurements of femoral bone mineral and geometry by dual energy x-ray absorptiometry. Measurements of mid-diaphyseal femoral geometry and structure were made previously in 101 Caucasian adolescents and young adults 9-26 years of age. The data on measured bone mineral content and calculated section modulus were compared with the results of our analytical model of cross-sectional development of the human femur over the same age range. Both bone mineral content and section modulus showed good correspondence with experimental measurements when the relationships with age and body mass were examined. Strong linear relationships were evident for both parameters when examined as a function of body mass.

Is Greulich and Pyle atlas still a good reference for bone age assessment?

NASA Astrophysics Data System (ADS)

Zhang, Aifeng; Tsao, Sinchai; Sayre, James W.; Gertych, Arkadiusz; Liu, Brent J.; Huang, H. K.

2007-03-01

The most commonly used method for bone age assessment in clinical practice is the book atlas matching method developed by Greulich and Pyle in the 1950s. Due to changes in both population diversity and nutrition in the United States, this atlas may no longer be a good reference. An updated data set becomes crucial to improve the bone age assessment process. Therefore, a digital hand atlas was built with 1,100 children hand images, along with patient information and radiologists' readings, of normal Caucasian (CAU), African American (BLK), Hispanic (HIS), and Asian (ASI) males (M) and females (F) with ages ranging from 0 - 18 years. This data was collected from Childrens' Hospital Los Angeles. A computer-aided-diagnosis (CAD) method has been developed based on features extracted from phalangeal regions of interest (ROIs) and carpal bone ROIs from this digital hand atlas. Using the data collected along with the Greulich and Pyle Atlas-based readings and CAD results, this paper addresses this question: "Do different ethnicities and gender have different bone growth patterns?" To help with data analysis, a novel web-based visualization tool was developed to demonstrate bone growth diversity amongst differing gender and ethnic groups using data collected from the Digital Atlas. The application effectively demonstrates a discrepancy of bone growth pattern amongst different populations based on race and gender. It also has the capability of helping a radiologist determine the normality of skeletal development of a particular patient by visualizing his or her chronological age, radiologist reading, and CAD assessed bone age relative to the accuracy of the P&G method.

Reversing sex steroid deficiency and optimizing skeletal development in the adolescent with gonadal failure.

PubMed

Vanderschueren, Dirk; Vandenput, Liesbeth; Boonen, Steven

2005-01-01

During puberty, the acquisition of skeletal mass and areal bone mineral density (BMD) mainly reflects an increase in bone size (length and perimeters) and not true volumetric BMD. Sexual dimorphism in bone mass and areal BMD is also explained by differences in bone size (longer and wider bones in males) and not by differences in volumetric BMD. Androgens stimulate skeletal growth by activation of the androgen receptor, whereas estrogens (following aromatization of androgens and stimulation of estrogen receptors) have a biphasic effect on skeletal growth during puberty. Recent evidence from clinical cases has shown that many of the growth-promoting effects of the sex steroids are mediated through estrogens rather than androgens. In addition, skeletal maturation and epiphyseal fusion are also estrogen-dependent in both sexes. Nevertheless, independent actions of androgens in these processes also occur. Both sex steroids maintain volumetric BMD during puberty. Androgens interact with the growth hormone (GH)-insulin-like growth factor-I (IGF-I) axis neonatally, resulting in a sexual dimorphic GH pattern during puberty, whereas estrogens stimulate GH and hereby IGF-I in both sexes. Hypogonadism in adolescents impairs not only bone size but also maintenance of volumetric BMD, hereby severely reducing peak areal BMD. Delayed puberty in boys and Turner's syndrome in women impair both bone length and size, reducing areal BMD. Whether volumetric BMD is also reduced and whether fracture risk is increased in these conditions remains controversial. Replacing sex steroids according to a biphasic pattern (starting at low doses and ending at high-normal doses) seems the safest approach to reach targeted height and to optimize bone development.

FGF2 High Molecular Weight Isoforms Contribute to Osteoarthropathy in Male Mice

PubMed Central

Meo Burt, Patience; Xiao, Liping; Dealy, Caroline; Fisher, Melanie C.

2016-01-01

Humans with X-linked hypophosphatemia (XLH) and Hyp mice, the murine homolog of the disease, develop severe osteoarthropathy and the precise factors that contribute to this joint degeneration remain largely unknown. Fibroblast growth factor 2 (FGF2) is a key regulatory growth factor in osteoarthritis. Although there are multiple FGF2 isoforms the potential involvement of specific FGF2 isoforms in joint degradation has not been investigated. Mice that overexpress the high molecular weight FGF2 isoforms in bone (HMWTg mice) phenocopy Hyp mice and XLH subjects and Hyp mice overexpress the HMWFGF2 isoforms in osteoblasts and osteocytes. Given that Hyp mice and XLH subjects develop osteoarthropathies we examined whether HMWTg mice also develop knee joint degeneration at 2, 8, and 18 mo compared with VectorTg (control) mice. HMWTg mice developed spontaneous osteoarthropathy as early as age 2 mo with thinning of subchondral bone, osteophyte formation, decreased articular cartilage thickness, abnormal mineralization within the joint, increased cartilage degradative enzymes, hypertrophic markers, and angiogenesis. FGF receptors 1 and 3 and fibroblast growth factor 23 were significantly altered compared with VectorTg mice. In addition, gene expression of growth factors and cytokines including bone morphogenetic proteins, Insulin like growth factor 1, Interleukin 1 beta, as well as transcription factors Sex determining region Y box 9, hypoxia inducible factor 1, and nuclear factor kappa B subunit 1 were differentially modulated in HMWTg compared with VectorTg. This study demonstrates that overexpression of the HMW isoforms of FGF2 in bone results in catabolic activity in joint cartilage and bone that leads to osteoarthropathy. PMID:27732085

Mesoporous bioactive glasses: structure characteristics, drug/growth factor delivery and bone regeneration application

PubMed Central

Wu, Chengtie; Chang, Jiang

2012-01-01

The impact of bone diseases and trauma in the whole world has increased significantly in the past decades. Bioactive glasses are regarded as an important bone regeneration material owing to their generally excellent osteoconductivity and osteostimulativity. A new class of bioactive glass, referred to as mesoporous bioglass (MBG), was developed 7 years ago, which possess a highly ordered mesoporous channel structure and a highly specific surface area. The study of MBG for drug/growth factor delivery and bone tissue engineering has grown significantly in the past several years. In this article, we review the recent advances of MBG materials, including the preparation of different forms of MBG, composition–structure relationship, efficient drug/growth factor delivery and bone tissue engineering application. By summarizing our recent research, the interaction of MBG scaffolds with bone-forming cells, the effect of drug/growth factor delivery on proliferation and differentiation of tissue cells and the in vivo osteogenesis of MBG scaffolds are highlighted. The advantages and limitations of MBG for drug delivery and bone tissue engineering have been compared with microsize bioactive glasses and nanosize bioactive glasses. The future perspective of MBG is discussed for bone regeneration application by combining drug delivery with bone tissue engineering and investigating the in vivo osteogenesis mechanism in large animal models. PMID:23741607

DNA damage checkpoint pathway modulates the regulation of skeletal growth and osteoblastic bone formation by parathyroid hormone-related peptide.

PubMed

Zhang, Ying; Chen, Guangpei; Gu, Zhen; Sun, Haijian; Karaplis, Andrew; Goltzman, David; Miao, Dengshun

2018-01-01

We previously demonstrated that parathyroid hormone-related peptide (PTHrP) 1-84 knockin ( Pthrp KI) mice, which lacked a PTHrP nuclear localization sequence (NLS) and C-terminus, displayed early senescence, defective osteoblastic bone formation, and skeletal growth retardation. However, the mechanism of action of the PTHrP NLS and C-terminus in regulating development of skeleton is still unclear. In this study, we examined alterations of oxidative stress and DNA damage response-related molecules in Pthrp KI skeletal tissue. We found that ROS levels, protein expression levels of γ-H2AX, a DNA damage marker, and the DNA damage response markers p-Chk2 and p53 were up-regulated, whereas gene expression levels of anti-oxidative enzymes were down-regulated significantly. We therefore further disrupted the DNA damage response pathway by deleting the Chk2 in Pthrp KI (Chk2 -/- KI) mice and did comparison with WT, Chk2 -/- and Pthrp KI littermates. The Pthrp KI mice with Chk2 deletion exhibited a longer lifespan, improvement in osteoblastic bone formation and skeletal growth including width of growth plates and length of long bones, trabecular and epiphyseal bone volume, BMD, osteoblast numbers, type I collagen and ALP positive bone areas, the numbers of total colony-forming unit fibroblasts (CFU-f), ALP + CFU-f and the expression levels of osteogenic genes. In addition, the genes associated with anti-oxidative enzymes were up-regulated significantly, whereas the tumor suppressor genes related to senescence were down-regulated in Chk2 -/- KI mice compared to Pthrp KI mice. Our results suggest that Chk2 deletion in Pthrp KI mice can somewhat rescue defects in osteoblastic bone formation and skeletal growth by enhancing endochondral bone formation and osteogenesis. These studies therefore indicate that the DNA damage checkpoint pathway may be a target for the nuclear action of PTHrP to regulate skeletal development and growth.

Long bone histology of the subterranean rodent Bathyergus suillus (Bathyergidae): ontogenetic pattern of cortical bone thickening.

PubMed

Montoya-Sanhueza, Germán; Chinsamy, Anusuya

2017-02-01

Patterns of bone development in mammals are best known from terrestrial and cursorial groups, but there is a considerable gap in our understanding of how specializations for life underground affect bone growth and development. Likewise, studies of bone microstructure in wild populations are still scarce, and they often include few individuals and tend to be focused on adults. For these reasons, the processes generating bone microstructural variation at intra- and interspecific levels are not fully understood. This study comprehensively examines the bone microstructure of an extant population of Cape dune molerats, Bathyergus suillus (Bathyergidae), the largest subterranean mammal endemic to the Western Cape of South Africa. The aim of this study is to investigate the postnatal bone growth of B. suillus using undecalcified histological sections (n = 197) of the femur, humerus, tibia-fibula, ulna and radius, including males and females belonging to different ontogenetic and reproductive stages (n = 42). Qualitative histological features demonstrate a wide histodiversity with thickening of the cortex mainly resulting from endosteal and periosteal bone depositions, whilst there is scarce endosteal resorption and remodeling throughout ontogeny. This imbalanced bone modeling allows the tissues deposited during ontogeny to remain relatively intact, thus preserving an excellent record of growth. The distribution of the different bone tissues observed in the cortex depends on ontogenetic status, anatomical features (e.g. muscle attachment structures) and location on the bone (e.g. anterior or lateral). The type of bone microstructure and modeling is discussed in relation to digging behavior, reproduction and physiology of this species. This study is the first histological assessment describing the process of cortical thickening in long bones of a fossorial mammal. © 2016 Anatomical Society.

Achondroplasia: Development, pathogenesis, and therapy.

PubMed

Ornitz, David M; Legeai-Mallet, Laurence

2017-04-01

Autosomal dominant mutations in fibroblast growth factor receptor 3 (FGFR3) cause achondroplasia (Ach), the most common form of dwarfism in humans, and related chondrodysplasia syndromes that include hypochondroplasia (Hch), severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), and thanatophoric dysplasia (TD). FGFR3 is expressed in chondrocytes and mature osteoblasts where it functions to regulate bone growth. Analysis of the mutations in FGFR3 revealed increased signaling through a combination of mechanisms that include stabilization of the receptor, enhanced dimerization, and enhanced tyrosine kinase activity. Paradoxically, increased FGFR3 signaling profoundly suppresses proliferation and maturation of growth plate chondrocytes resulting in decreased growth plate size, reduced trabecular bone volume, and resulting decreased bone elongation. In this review, we discuss the molecular mechanisms that regulate growth plate chondrocytes, the pathogenesis of Ach, and therapeutic approaches that are being evaluated to improve endochondral bone growth in people with Ach and related conditions. Developmental Dynamics 246:291-309, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Symposium on ‘Nutrition and health in children and adolescents’ Session 1: Nutrition in growth and development

PubMed Central

Prentice, Ann; Schoenmakers, Inez; Laskey, M. Ann; de Bono, Stephanie; Ginty, Fiona; Goldberg, Gail R.

2007-01-01

The growth and development of the human skeleton requires an adequate supply of many different nutritional factors. Classical nutrient deficiencies are associated with stunting (e.g. energy, protein, Zn), rickets (e.g. vitamin D) and other bone abnormalities (e.g. Cu, Zn, vitamin C). In recent years there has been interest in the role nutrition may play in bone growth at intakes above those required to prevent classical deficiencies, particularly in relation to optimising peak bone mass and minimising osteoporosis risk. There is evidence to suggest that peak bone mass and later fracture risk are influenced by the pattern of growth in childhood and by nutritional exposures in utero, in infancy and during childhood and adolescence. Of the individual nutrients, particular attention has been paid to Ca, vitamin D, protein and P. There has also been interest in several food groups, particularly dairy products, fruit and vegetables and foods contributing to acid–base balance. However, it is not possible at the present time to define dietary reference values using bone health as a criterion, and the question of what type of diet constitutes the best support for optimal bone growth and development remains open. Prudent recommendations (Department of Health, 1998; World Health Organization/Food and Agriculture Organization, 2003) are the same as those for adults, i.e. to consume a Ca intake close to the reference nutrient intake, optimise vitamin D status through adequate summer sunshine exposure (and diet supplementation where appropriate), be physically active, have a body weight in the healthy range, restrict salt intake and consume plenty of fruit and vegetables. PMID:17181901

The Influence of Primary Microenvironment on Prostate Cancer Osteoblastic Bone Lesion Development

DTIC Science & Technology

2015-09-01

for inhibiting PCa bone lesion development: 3a. Basic fibroblast growth factor (bFGF) in PC3 bone metastasis: bFGF was identified by cytokine...II receptor (TβRII) knockout (Tgfbr2 KO) mouse models. Col1creERT/Tgfbr2 KO (Col/Tgfbr2 KO), which have TGF-β signaling specific KO in fibroblasts ... fibroblasts and osteoblasts in the bone by Colcre/Tgfbr2 KO, or in the myeloid lineage cells, including osteoclasts in the bone by LysMcre/Tgfbr2 KO

Importance of dual delivery systems for bone tissue engineering.

PubMed

Farokhi, Mehdi; Mottaghitalab, Fatemeh; Shokrgozar, Mohammad Ali; Ou, Keng-Liang; Mao, Chuanbin; Hosseinkhani, Hossein

2016-03-10

Bone formation is a complex process that requires concerted function of multiple growth factors. For this, it is essential to design a delivery system with the ability to load multiple growth factors in order to mimic the natural microenvironment for bone tissue formation. However, the short half-lives of growth factors, their relatively large size, slow tissue penetration, and high toxicity suggest that conventional routes of administration are unlikely to be effective. Therefore, it seems that using multiple bioactive factors in different delivery systems can develop new strategies for improving bone tissue regeneration. Combination of these factors along with biomaterials that permit tunable release profiles would help to achieve truly spatiotemporal regulation during delivery. This review summarizes the various dual-control release systems that are used for bone tissue engineering. Copyright © 2015 Elsevier B.V. All rights reserved.

Regulation of Long Bone Growth in Vertebrates; It Is Time to Catch Up

PubMed Central

Joyner, Alexandra L.

2015-01-01

The regulation of organ size is essential to human health and has fascinated biologists for centuries. Key to the growth process is the ability of most organs to integrate organ-extrinsic cues (eg, nutritional status, inflammatory processes) with organ-intrinsic information (eg, genetic programs, local signals) into a growth response that adapts to changing environmental conditions and ensures that the size of an organ is coordinated with the rest of the body. Paired organs such as the vertebrate limbs and the long bones within them are excellent models for studying this type of regulation because it is possible to manipulate one member of the pair and leave the other as an internal control. During development, growth plates at the end of each long bone produce a transient cartilage model that is progressively replaced by bone. Here, we review how proliferation and differentiation of cells within each growth plate are tightly controlled mainly by growth plate-intrinsic mechanisms that are additionally modulated by extrinsic signals. We also discuss the involvement of several signaling hubs in the integration and modulation of growth-related signals and how they could confer remarkable plasticity to the growth plate. Indeed, long bones have a significant ability for “catch-up growth” to attain normal size after a transient growth delay. We propose that the characterization of catch-up growth, in light of recent advances in physiology and cell biology, will provide long sought clues into the molecular mechanisms that underlie organ growth regulation. Importantly, catch-up growth early in life is commonly associated with metabolic disorders in adulthood, and this association is not completely understood. Further elucidation of the molecules and cellular interactions that influence organ size coordination should allow development of novel therapies for human growth disorders that are noninvasive and have minimal side effects. PMID:26485225

Cyclic hydrostatic pressure stimulates enhanced bone development in the foetal chick femur in vitro.

PubMed

Henstock, J R; Rotherham, M; Rose, J B; El Haj, A J

2013-04-01

Mechanical loading of bone and cartilage in vivo results in the generation of cyclic hydrostatic forces as bone compression is transduced to fluid pressure in the canalicular network and the joint synovium. It has therefore been suggested that hydrostatic pressure is an important stimulus by which osteochondral cells and their progenitors sense and respond to mechanical loading in vivo. In this study, hydrostatic pressure regimes of 0-279kPa at 0.005-2Hz were applied to organotypically cultured ex vivo chick foetal femurs (e11) for 1hour per day in a custom designed bioreactor for 14days and bone formation assessed by X-ray microtomography and qualified by histology. We found that the mineralised portion of the developing femur cultured under any cyclic hydrostatic pressure regime was significantly larger and/or denser than unstimulated controls but that constant (non-cycling) hydrostatic pressure had no effect on bone growth. Further experiments showed that the increase in bone formation was directly proportional to stimulation frequency (R(2)=0.917), but independent of the magnitude of the pressure applied, whilst even very low frequencies of stimulation (0.005Hz) had significant effects on bone growth. Expression of Type-II collagen in both epiphyses and diaphysis was significantly upregulated (1.48-fold and 1.95-fold respectively), together with osteogenic genes (osteonectin and osteopontin) and the osteocyte maturation marker CD44. This work demonstrates that cyclic hydrostatic pressure promotes bone growth and mineralisation in a developmental model and supports the hypothesis that hydrostatic forces play an important role in regulating bone growth and remodelling in vivo. Copyright © 2013 Elsevier Inc. All rights reserved.

Effects of Gymnastics Activities on Bone Accrual during Growth: A Systematic Review.

PubMed

Jürimäe, Jaak; Gruodyte-Raciene, Rita; Baxter-Jones, Adam D G

2018-06-01

The amount of bone gained during childhood and adolescence impacts greatly on lifetime skeletal health. The purpose of this review is to summarize current evidence of the effects of gymnastics activities on bone mineral accrual during growth and to describe possible factors that influence bone mineral gains. The PubMed and SportDiscus databases were searched, and a total of 24 articles met the selection criteria and were included in this review. Artistic and rhythmic gymnasts presented higher bone mineral density and content values compared to untrained controls, despite possible negative effects associated with hormonal levels, dietary restrictions and body fat. The results suggest that gymnasts had similar bone turnover values compared to untrained controls. High-intensity mechanical loading of gymnastics activity appears to increase bone development and counterbalance negative effects, such as later pubertal development, lower body fat mass and lower hormone levels. In conclusion, gymnasts present higher bone mineral values in comparison with untrained controls. The osteogenic effect of gymnastics athletic activity has a positive influence on bone mineral accrual and overcomes the possible negative influence of high athletic activity that may cause negative energy balance and low body fat mass which are associated with lower bone accrual.

Image analysis for skeletal evaluation of carpal bones

NASA Astrophysics Data System (ADS)

Ko, Chien-Chuan; Mao, Chi-Wu; Lin, Chi-Jen; Sun, Yung-Nien

1995-04-01

The assessment of bone age is an important field to the pediatric radiology. It provides very important information for treatment and prediction of skeletal growth in a developing child. So far, various computerized algorithms for automatically assessing the skeletal growth have been reported. Most of these methods made attempt to analyze the phalangeal growth. The most fundamental step in these automatic measurement methods is the image segmentation that extracts bones from soft-tissue and background. These automatic segmentation methods of hand radiographs can roughly be categorized into two main approaches that are edge and region based methods. This paper presents a region-based carpal-bone segmentation approach. It is organized into four stages: contrast enhancement, moment-preserving thresholding, morphological processing, and region-growing labeling.

The Role of Peripheral Nerve Function in Age-Related Bone Loss and Changes in Bone Adaptation

DTIC Science & Technology

2015-12-01

scratch response in development of spontaneous dermatitis in NC/Nga mice. Br J Dermatol 2004;151:335-45. 32. Nakano T, Andoh T, Sasaki A, Nojima H, Kuraishi... contact a stripe of brain derived neurotrophic factor becomes the axon [16]. During neuron growth, mitochondria, membrane vesicles, proteins involved in...epiphyseal bone marrow [27]. The CGRP containing neurons in rat femurs near the growth plate come in contact with osteoclasts [21]. Neuropeptide

Conditional expression of constitutively active estrogen receptor {alpha} in chondrocytes impairs longitudinal bone growth in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ikeda, Kazuhiro; Tsukui, Tohru; Imazawa, Yukiko

2012-09-07

Highlights: Black-Right-Pointing-Pointer Conditional transgenic mice expressing constitutively active estrogen receptor {alpha} (caER{alpha}) in chondrocytes were developed. Black-Right-Pointing-Pointer Expression of caER{alpha} in chondrocytes impaired longitudinal bone growth in mice. Black-Right-Pointing-Pointer caER{alpha} affects chondrocyte proliferation and differentiation. Black-Right-Pointing-Pointer This mouse model is useful for understanding the physiological role of ER{alpha}in vivo. -- Abstract: Estrogen plays important roles in the regulation of chondrocyte proliferation and differentiation, which are essential steps for longitudinal bone growth; however, the mechanisms of estrogen action on chondrocytes have not been fully elucidated. In the present study, we generated conditional transgenic mice, designated as caER{alpha}{sup ColII}, expressing constitutively activemore » mutant estrogen receptor (ER) {alpha} in chondrocytes, using the chondrocyte-specific type II collagen promoter-driven Cre transgenic mice. caER{alpha}{sup ColII} mice showed retardation in longitudinal growth, with short bone lengths. BrdU labeling showed reduced proliferation of hypertrophic chondrocytes in the proliferating layer of the growth plate of tibia in caER{alpha}{sup ColII} mice. In situ hybridization analysis of type X collagen revealed that the maturation of hypertrophic chondrocytes was impaired in caER{alpha}{sup ColII} mice. These results suggest that ER{alpha} is a critical regulator of chondrocyte proliferation and maturation during skeletal development, mediating longitudinal bone growth in vivo.« less

Hydrogel Delivery of Mesenchymal Stem Cell–Expressing Bone Morphogenetic Protein-2 Enhances Bone Defect Repair

PubMed Central

Hsiao, Hui-Yi; Yang, Shu-Rui; Brey, Eric M.; Chu, I-Ming

2016-01-01

Background: The application of bone tissue engineering for repairing bone defects has gradually shown some satisfactory progress. One of the concerns raising scientific attention is the poor supply of growth factors. A number of growth factor delivery approaches have been developed for promoting bone formation. However, there is no systematic comparison of those approaches on efficiency of neobone formation. In this study, the approaches using periosteum, direct supply of growth factors, or gene transfection of growth factors were evaluated to determine the osteogenic capacity on the repair of bone defect. Methods: In total, 42 male 21-week-old Sprague-Dawley rats weighing 250 to 400 g were used as the bone defect model to evaluate the bone repair efficiency. Various tissue engineered constructs of poly(ethylene glycol)-poly(l-lactic acid) (PEG-PLLA) copolymer hydrogel with periosteum, with external supply of bone morphogenetic protein-2 (BMP2), or with BMP2-transfected bone marrow–derived mesenchymal stem cells (BMMSCs) were filled in a 7-mm bone defect region. Animals were euthanized at 3 months, and the hydrogel constructs were harvested. The evaluation with histological staining and radiography analysis were performed for the volume of new bone formation. Results: The PEG-PLLA scaffold with BMMSCs promotes bone regeneration with the addition of periosteum. The group with BMP2-transfected BMMSCs demonstrated the largest volume of new bone among all the testing groups. Conclusions: Altogether, the results of this study provide the evidence that the combination of PEG-PLLA hydrogels with BMMSCs and sustained delivery of BMP2 resulted in the maximal bone regeneration. PMID:27622106

The Effect of Prepubertal Calcium Carbonate Supplementation on Skeletal Development in Gambian Boys—A 12-Year Follow-Up Study

PubMed Central

Cole, T. J.; Laskey, M. A.; Ceesay, M.; Mendy, M. B.; Sawo, Y.; Prentice, A.

2014-01-01

Context: Calcium intake during growth is essential for future bone health but varies widely between individuals and populations. The impact on bone of increasing calcium intake is unknown in a population where low calcium intake, stunting, and delayed puberty are common. Objective: To determine the effect of prepubertal calcium supplementation on mean age at peak velocity for bone growth and mineral accrual. Design and Setting: Prospective follow-up of boys in rural Gambia, West Africa, who had participated in a double-blind, randomized, placebo-controlled trial of calcium supplementation. Participants: Eighty boys, initially aged 8.0–11.9 years, were followed up for 12 years. Interventions: Subjects received 1 year of calcium carbonate supplementation (1000 mg daily, 5 d/wk). Main Outcome Measures: Dual-energy x-ray absorptiometry measurements were carried out for whole body (WB), lumbar spine, and total hip bone mineral content, bone area (BA), and WB lean mass. Super imposition by translation and rotation models was made to assess bone growth. Results: Age at peak velocity was consistently earlier in the calcium group compared to the placebo group, for WB bone mineral content (mean, −6.2 [SE, 3.1]; P = .05), WB BA (mean, −7.0 [SE, 3.2] mo; P = .03), lumbar spine and total hip BA. By young adulthood, supplementation did not change the amount of bone accrued (mineral or size) or the rate of bone growth. Conclusions: Twelve months of prepubertal calcium carbonate supplementation in boys with a low calcium diet advanced the adolescent growth spurt but had no lasting effect on bone mineral or bone size. There is a need for caution when applying international recommendations to different populations. PMID:24762110

ARC-1993-A93-0511-7

NASA Image and Video Library

1993-10-07

Harold Goldstein (R) and Dan Leiser (L) discuss bone implant development in the the Shuttle Tile Laboratory N-242. A spin-off of Ames research on both bone density in microgravity and on thermal protection foams is the bone-growth implant shown in 1993.

Bone mineral density in elite adolescent female figure skaters

USDA-ARS?s Scientific Manuscript database

Elite adolescent figure skaters must accommodate both the physical demands of competitive training and the accelerated rate of bone growth that is associated with adolescence. Although, these athletes apparently undergo sufficient physical activity to develop healthy bones, it is possible that other...

Orthopedic surgery and bone fracture pain are both significantly attenuated by sustained blockade of nerve growth factor

PubMed Central

Majuta, Lisa A.; Longo, Geraldine; Fealk, Michelle N.; McCaffrey, Gwen; Mantyh, Patrick W.

2015-01-01

The number of patients suffering from postoperative pain due to orthopedic surgery and bone fracture is projected to dramatically increase because the human life span, weight, and involvement in high-activity sports continue to rise worldwide. Joint replacement or bone fracture frequently results in skeletal pain that needs to be adequately controlled for the patient to fully participate in needed physical rehabilitation. Currently, the 2 major therapies used to control skeletal pain are nonsteroidal anti-inflammatory drugs and opiates, both of which have significant unwanted side effects. To assess the efficacy of novel therapies, mouse models of orthopedic and fracture pain were developed and evaluated here. These models, orthopedic surgery pain and bone fracture pain, resulted in skeletal pain–related behaviors that lasted 3 weeks and 8 to 10 weeks, respectively. These skeletal pain behaviors included spontaneous and palpation-induced nocifensive behaviors, dynamic weight bearing, limb use, and voluntary mechanical loading of the injured hind limb. Administration of anti–nerve growth factor before orthopedic surgery or after bone fracture attenuated skeletal pain behaviors by 40% to 70% depending on the end point being assessed. These data suggest that nerve growth factor is involved in driving pain due to orthopedic surgery or bone fracture. These animal models may be useful in developing an understanding of the mechanisms that drive postoperative orthopedic and bone fracture pain and the development of novel therapies to treat these skeletal pains. PMID:25599311

Automated Cell Detection and Morphometry on Growth Plate Images of Mouse Bone

PubMed Central

Ascenzi, Maria-Grazia; Du, Xia; Harding, James I; Beylerian, Emily N; de Silva, Brian M; Gross, Ben J; Kastein, Hannah K; Wang, Weiguang; Lyons, Karen M; Schaeffer, Hayden

2014-01-01

Microscopy imaging of mouse growth plates is extensively used in biology to understand the effect of specific molecules on various stages of normal bone development and on bone disease. Until now, such image analysis has been conducted by manual detection. In fact, when existing automated detection techniques were applied, morphological variations across the growth plate and heterogeneity of image background color, including the faint presence of cells (chondrocytes) located deeper in tissue away from the image’s plane of focus, and lack of cell-specific features, interfered with identification of cell. We propose the first method of automated detection and morphometry applicable to images of cells in the growth plate of long bone. Through ad hoc sequential application of the Retinex method, anisotropic diffusion and thresholding, our new cell detection algorithm (CDA) addresses these challenges on bright-field microscopy images of mouse growth plates. Five parameters, chosen by the user in respect of image characteristics, regulate our CDA. Our results demonstrate effectiveness of the proposed numerical method relative to manual methods. Our CDA confirms previously established results regarding chondrocytes’ number, area, orientation, height and shape of normal growth plates. Our CDA also confirms differences previously found between the genetic mutated mouse Smad1/5CKO and its control mouse on fluorescence images. The CDA aims to aid biomedical research by increasing efficiency and consistency of data collection regarding arrangement and characteristics of chondrocytes. Our results suggest that automated extraction of data from microscopy imaging of growth plates can assist in unlocking information on normal and pathological development, key to the underlying biological mechanisms of bone growth. PMID:25525552

Effects of Gymnastics Activities on Bone Accrual during Growth: A Systematic Review

PubMed Central

Jürimäe, Jaak; Gruodyte-Raciene, Rita; Baxter-Jones, Adam D. G.

2018-01-01

The amount of bone gained during childhood and adolescence impacts greatly on lifetime skeletal health. The purpose of this review is to summarize current evidence of the effects of gymnastics activities on bone mineral accrual during growth and to describe possible factors that influence bone mineral gains. The PubMed and SportDiscus databases were searched, and a total of 24 articles met the selection criteria and were included in this review. Artistic and rhythmic gymnasts presented higher bone mineral density and content values compared to untrained controls, despite possible negative effects associated with hormonal levels, dietary restrictions and body fat. The results suggest that gymnasts had similar bone turnover values compared to untrained controls. High-intensity mechanical loading of gymnastics activity appears to increase bone development and counterbalance negative effects, such as later pubertal development, lower body fat mass and lower hormone levels. In conclusion, gymnasts present higher bone mineral values in comparison with untrained controls. The osteogenic effect of gymnastics athletic activity has a positive influence on bone mineral accrual and overcomes the possible negative influence of high athletic activity that may cause negative energy balance and low body fat mass which are associated with lower bone accrual. Key points Children and adolescent gymnasts present higher bone mineral density and content values compared to untrained controls, despite a variety of possible negative factors. Gymnastics activity with high-impact mechanical loading appears to be especially osteogenic to achieve maximum possible peak bone accrual during growth and maturation. Skeletal benefits of gymnastics activity in childhood are maintained for several years after retirement from gymnastics trainings in young adulthood. PMID:29769826

Assessing a relationship between bone microstructure and growth rate: a fluorescent labelling study in the king penguin chick (Aptenodytes patagonicus).

PubMed

de Margerie, E; Robin, J-P; Verrier, D; Cubo, J; Groscolas, R; Castanet, J

2004-02-01

Microstructure-function relationships remain poorly understood in primary bone tissues. The relationship between bone growth rate and bone tissue type, although documented in some species by previous works, remains somewhat unclear and controversial. We assessed this relationship in a species with extreme adaptations, the king penguin (Aptenodytes patagonicus). These birds have a peculiar growth, interrupted 3 months after hatching by the austral winter. Before this interruption, chicks undergo extremely rapid statural and ponderal growth. We recorded experimentally (by means of fluorescent labelling) the growth rate of bone tissue in four long bones (humerus, radius, femur and tibiotarsus) of four king penguin chicks during their fastest phase of growth (3-5 weeks after hatching) and identified the associated bone tissue types ('laminar', 'longitudinal', 'reticular' or 'radial' fibro-lamellar bone tissue). We found the highest bone tissue growth rate known to date, up to 171 microm day(-1) (mean 55 microm day(-1)). There was a highly significant relationship between bone tissue type and growth rate (P<10(-6)). Highest rates were obtained with the radial microarchitecture of fibro-lamellar bone, where cavities in the woven network are aligned radially. This result supports the heuristic value of a relationship between growth rate and bone primary microstructure. However, we also found that growth rates of bone tissue types vary according to the long bone considered (P<10(-5)) (e.g. growth rates were 38% lower in the radius than in the other long bones), a result that puts some restriction on the applicability of absolute growth rate values (e.g. to fossil species). The biomechanical disadvantages of accelerated bone growth are discussed in relation to the locomotor behaviour of the chicks during their first month of life.

Role of FGF/FGFR signaling in skeletal development and homeostasis: learning from mouse models

PubMed Central

Su, Nan; Jin, Min; Chen, Lin

2014-01-01

Fibroblast growth factor (FGF)/fibroblast growth factor receptor (FGFR) signaling plays essential roles in bone development and diseases. Missense mutations in FGFs and FGFRs in humans can cause various congenital bone diseases, including chondrodysplasia syndromes, craniosynostosis syndromes and syndromes with dysregulated phosphate metabolism. FGF/FGFR signaling is also an important pathway involved in the maintenance of adult bone homeostasis. Multiple kinds of mouse models, mimicking human skeleton diseases caused by missense mutations in FGFs and FGFRs, have been established by knock-in/out and transgenic technologies. These genetically modified mice provide good models for studying the role of FGF/FGFR signaling in skeleton development and homeostasis. In this review, we summarize the mouse models of FGF signaling-related skeleton diseases and recent progresses regarding the molecular mechanisms, underlying the role of FGFs/FGFRs in the regulation of bone development and homeostasis. This review also provides a perspective view on future works to explore the roles of FGF signaling in skeletal development and homeostasis. PMID:26273516

Oxandrolone treatment of constitutional short stature in boys during adolescence: effect on linear growth, bone age, pubic hair, and testicular development.

PubMed

Marti-Henneberg, C; Niirianen, A K; Rappaport, R

1975-05-01

Seventeen constitutionally short boys were studied throughout puberty. Nine received oxandrolone (0.1 mg/kg/day). Treatment was started before onset of puberty. Eight boys served as control subjects. No significant increase in linear growth or skeletal maturation was observed in the treated group. Likewise the peak height velocity was unchanged. Pubic hair developed similarly in both groups in relation to chronologic and skeletal age. The only significant difference was a diminution in testicular volume index during treatment after bone age of 12 years and until bone age of 14 6/12 years.

Dietary 2-oxoglutarate prevents bone loss caused by neonatal treatment with maximal dexamethasone dose

PubMed Central

Tomaszewska, Ewa; Muszyński, Siemowit; Blicharski, Tomasz; Pierzynowski, Stefan G

2017-01-01

Synthetic glucocorticoids (GCs) are widely used in the variety of dosages for treatment of premature infants with chronic lung disease, respiratory distress syndrome, allergies, asthma, and other inflammatory and autoimmune conditions. Yet, adverse effects such as glucocorticoid-induced osteoporosis and growth retardation are recognized. Conversely, 2-oxoglutarate (2-Ox), a precursor of glutamine, glutamate, and collagen amino acids, exerts protective effects on bone development. Our aim was to elucidate the effect of dietary administered 2-Ox on bone loss caused by neonatal treatment with clinically relevant maximal therapeutic dexamethasone (Dex) dose. Long bones of neonatal female piglets receiving Dex, Dex+2-Ox, or untreated were examined through measurements of mechanical properties, density, mineralization, geometry, histomorphometry, and histology. Selected hormones, bone turnover, and growth markers were also analyzed. Neonatal administration of clinically relevant maximal dose of Dex alone led to over 30% decrease in bone mass and the ultimate strength (P < 0.001 for all). The length (13 and 7% for femur and humerus, respectively) and other geometrical parameters (13–45%) decreased compared to the control (P < 0.001 for all). Dex impaired bone growth and caused hormonal imbalance. Dietary 2-Ox prevented Dex influence and vast majority of assessed bone parameters were restored almost to the control level. Piglets receiving 2-Ox had heavier, denser, and stronger bones; higher levels of growth hormone and osteocalcin concentration; and preserved microarchitecture of trabecular bone compared to the Dex group. 2-Ox administered postnatally had a potential to maintain bone structure of animals simultaneously treated with maximal therapeutic doses of Dex, which, in our opinion, may open up a new opportunity in developing combined treatment for children treated with GCs. Impact statement The present study has showed, for the first time, that dietary 2-oxoglutarate (2-Ox) administered postnatally has a potential to improve/maintain bone structure of animals simultaneously treated with maximal therapeutic doses of dexamethasone (Dex). It may open the new direction in searching and developing combined treatment for children treated with glucocorticoids (GCs) since growing group of children is exposed to synthetic GCs and adverse effects such as glucocorticoid-induced osteoporosis and growth retardation are recognized. Currently proposed combined therapies have numerous side effects. Thus, this study proposed a new direction in combined therapies utilizing dietary supplementation with glutamine derivative. Impairment caused by Dex in presented long bones animal model was prevented by dietary supplementation with 2-Ox and vast majority of assessed bone parameters were restored almost to the control level. These results support previous thesis on the regulatory mechanism of nutrient utilization regulated by glutamine derivatives and enrich the nutritional science. PMID:28178857

Comparative anatomy of the dorsal hump in mature Pacific salmon.

PubMed

Susuki, Kenta; Ban, Masatoshi; Ichimura, Masaki; Kudo, Hideaki

2017-07-01

Mature male Pacific salmon (Genus Oncorhynchus) demonstrate prominent morphological changes, such as the development of a dorsal hump. The degree of dorsal hump formation depends on the species in Pacific salmon. It is generally accepted that mature males of sockeye (O. nerka) and pink (O. gorbuscha) salmon develop most pronounced dorsal humps. The internal structure of the dorsal hump in pink salmon has been confirmed in detail. In this study, the dorsal hump morphologies were analyzed in four Pacific salmon species inhabiting Japan, masu (O. masou), sockeye, chum (O. keta), and pink salmon. The internal structure of the dorsal humps also depended on the species; sockeye and pink salmon showed conspicuous development of connective tissue and growth of bone tissues in the dorsal tissues. Masu and chum salmon exhibited less-pronounced increases in connective tissues and bone growth. Hyaluronic acid was clearly detected in dorsal hump connective tissue by histochemistry, except for in masu salmon. The lipid content in dorsal hump connective tissue was richer in masu and chum salmon than in sockeye and pink salmon. These results revealed that the patterns of dorsal hump formation differed among species, and especially sockeye and pink salmon develop pronounced dorsal humps through both increases in the amount of connective tissue and the growth of bone tissues. In contrast, masu and chum salmon develop their dorsal humps by the growth of bone tissues, rather than the development of connective tissue. © 2017 Wiley Periodicals, Inc.

Vertical bone growth following autotransplantation of the developing maxillary third molar to replace a retained mandibular permanent molar: a case report.

PubMed

Plakwicz, Paweł; Czochrowska, Ewa Monika; Milczarek, Anna; Zadurska, Malgorzata

2014-01-01

A retained permanent mandibular first molar caused arrested development and a defect of the alveolar bone in a 16-year-old girl. Extraction of the ankylosed tooth was immediately followed by autotransplantation of the developing maxillary third molar. At the 3-year follow-up examination the interproximal bone level at the autotransplanted molar was equal to that of the neighboring teeth. Cone beam computed tomography showed bone at the labial aspect of the transplant. The eruption of the autotransplanted tooth stimulated vertical alveolar bone development and repaired the bone defect. Additionally, there was closure of the posterior open bite that was initially present at the ankylosed molar site.

The potential role of the osteoblast in the development of periprosthetic osteolysis: review of in vitro osteoblast responses to wear debris, corrosion products, and cytokines and growth factors.

PubMed

Vermes, C; Glant, T T; Hallab, N J; Fritz, E A; Roebuck, K A; Jacobs, J J

2001-12-01

Limited information is available on the responses of osteoblasts to wear debris, corrosion products, and cytokines and on the roles of altered osteoblast functions in the development of periprosthetic bone loss. Wear debris-challenged osteoblasts exhibit altered functions resulting in the loss of their capacity to produce bone matrix and to replace the resorbed bone. Also, osteoblasts may secrete cytokines, which act in a paracrine fashion to recruit inflammatory cells into the periprosthetic space and to stimulate osteoclastic bone resorption. These effects may be mediated in part by ionic metal dissolution products. We review the mechanisms by which altered osteoblast functions, in response to particulate wear debris, corrosion products, and cytokines and growth factors, may contribute to the development and the progression of periprosthetic osteolysis.

Holographic nondestructive testing in bone growth disturbance studies

NASA Astrophysics Data System (ADS)

Silvennoinen, Raimo V. J.; Nygren, Kaarlo

1993-09-01

We used isolated radioulnar bones of subadult European moose collected in various environmental pollution areas of Finland. The bones were radiographed and outer dimensions measured. By using small caudo-cranial bending forces, the bones were tested by using HNDT. For bone mineral studies, samples were taken from the mandibles of the same animals. Results showed, that the bones obtained from the heavily polluted area showed biomechanical response comparable to the bones developed partially without mothers milk. Differences were also seen in morphometrical and radiological studies. The mineral contents studied did not differ significantly from randomly collected samples of the same age category. We therefore conclude that environmental factors may influence the bone matrix development.

Development of a Preclinical Orthotopic Xenograft Model of Ewing Sarcoma and Other Human Malignant Bone Disease Using Advanced In Vivo Imaging

PubMed Central

Batey, Michael A.; Almeida, Gilberto S.; Wilson, Ian; Dildey, Petra; Sharma, Abhishek; Blair, Helen; Hide, I. Geoff; Heidenreich, Olaf; Vormoor, Josef; Maxwell, Ross J.; Bacon, Chris M.

2014-01-01

Ewing sarcoma and osteosarcoma represent the two most common primary bone tumours in childhood and adolescence, with bone metastases being the most adverse prognostic factor. In prostate cancer, osseous metastasis poses a major clinical challenge. We developed a preclinical orthotopic model of Ewing sarcoma, reflecting the biology of the tumour-bone interactions in human disease and allowing in vivo monitoring of disease progression, and compared this with models of osteosarcoma and prostate carcinoma. Human tumour cell lines were transplanted into non-obese diabetic/severe combined immunodeficient (NSG) and Rag2−/−/γc−/− mice by intrafemoral injection. For Ewing sarcoma, minimal cell numbers (1000–5000) injected in small volumes were able to induce orthotopic tumour growth. Tumour progression was studied using positron emission tomography, computed tomography, magnetic resonance imaging and bioluminescent imaging. Tumours and their interactions with bones were examined by histology. Each tumour induced bone destruction and outgrowth of extramedullary tumour masses, together with characteristic changes in bone that were well visualised by computed tomography, which correlated with post-mortem histology. Ewing sarcoma and, to a lesser extent, osteosarcoma cells induced prominent reactive new bone formation. Osteosarcoma cells produced osteoid and mineralised “malignant” bone within the tumour mass itself. Injection of prostate carcinoma cells led to osteoclast-driven osteolytic lesions. Bioluminescent imaging of Ewing sarcoma xenografts allowed easy and rapid monitoring of tumour growth and detection of tumour dissemination to lungs, liver and bone. Magnetic resonance imaging proved useful for monitoring soft tissue tumour growth and volume. Positron emission tomography proved to be of limited use in this model. Overall, we have developed an orthotopic in vivo model for Ewing sarcoma and other primary and secondary human bone malignancies, which resemble the human disease. We have shown the utility of small animal bioimaging for tracking disease progression, making this model a useful assay for preclinical drug testing. PMID:24409320

Pleiotrophin Commits Human Bone Marrow Mesenchymal Stromal Cells towards Hypertrophy during Chondrogenesis

PubMed Central

Bouderlique, Thibault; Henault, Emilie; Lebouvier, Angelique; Frescaline, Guilhem; Bierling, Phillipe; Rouard, Helene; Courty, José

2014-01-01

Pleiotrophin (PTN) is a growth factor present in the extracellular matrix of the growth plate during bone development and in the callus during bone healing. Bone healing is a complicated process that recapitulates endochondral bone development and involves many cell types. Among those cells, mesenchymal stromal cells (MSC) are able to differentiate toward chondrogenic and osteoblastic lineages. We aimed to determine PTN effects on differentiation properties of human bone marrow stromal cells (hBMSC) under chondrogenic induction using histological analysis and quantitative reverse transcription polymerase chain reaction. PTN dramatically potentiated chondrogenic differentiation as indicated by a strong increase of collagen 2 protein, and cartilage-related gene expression. Moreover, PTN increased transcription of hypertrophic chondrocyte markers such as MMP13, collagen 10 and alkaline phosphatase and enhanced calcification and the content of collagen 10 protein. These effects are dependent on PTN receptors signaling and PI3 K pathway activation. These data suggest a new role of PTN in bone regeneration as an inducer of hypertrophy during chondrogenic differentiation of hBMSC. PMID:24516627

Derivation and application of a mathematical model for long bone growth.

PubMed

Seetharam, Suneil; Bhatia, Sujata K

2012-01-01

The objective of this work was to develop a mathematical model of long bone growth and to gain insights regarding growth disorders. A cell balance (mass balance of moving cells) assessment was performed on the three regions of the growth plate, to determine the variables (including number of proliferating cells, and division rate of proliferating cells) that influence tibia growth rate. Once this relationship was established, clinical data were used to understand how tibia growth rate and number of proliferating cells change with time. These equations were then inserted into the model to determine how cell division rate changes with time. The model was utilized to determine the influence of growth time, and to measure changes in vitamin C deficiency, Indian hedgehog (IHH) expression, and bone morphogenetic protein-2 (BMP-2) implants on tibia length. According to the model, a 10-month discrepancy in growth time between the two tibias is required to produce clinically significant leg asymmetry. In addition, vitamin C deficiency, IHH overexpression, and BMP-2 implants can all affect tibia length. These bioactive molecules have the greatest effect on tibia growth rate when these perturbations occur early in life for extended periods of time. The results are significant for modeling and predicting the effects of perturbations, including bioactive implants, on long bone growth.

Persistent injury-associated anemia: the role of the bone marrow microenvironment.

PubMed

Millar, Jessica K; Kannan, Kolenkode B; Loftus, Tyler J; Alamo, Ines G; Plazas, Jessica; Efron, Philip A; Mohr, Alicia M

2017-06-15

The regulation of erythropoiesis involves hematopoietic progenitor cells, bone marrow stroma, and the microenvironment. Following severe injury, a hypercatecholamine state develops that is associated with increased mobilization of hematopoietic progenitor cells to peripheral blood and decreased growth of bone marrow erythroid progenitor cells that manifests clinically as a persistent injury-associated anemia. Changes within the bone marrow microenvironment influence the development of erythroid progenitor cells. Therefore, we sought to determine the effects of lung contusion, hemorrhagic shock, and chronic stress on the hematopoietic cytokine response. Bone marrow was obtained from male Sprague-Dawley rats (n = 6/group) killed 7 d after lung contusion followed by hemorrhagic shock (LCHS) or LCHS followed by daily chronic restraint stress (LCHS/CS). End point polymerase chain reaction was performed for interleukin-1β, interleukin-10, stem cell factor, transforming growth factor-β, high-mobility group box-1 (HMGB-1), and B-cell lymphoma-extra large. Seven days following LCHS and LCHS/CS, bone marrow expression of prohematopoietic cytokines (interleukin-1β, interleukin-10, stem cell factor, and transforming growth factor-β) was significantly decreased, and bone marrow expression of HMGB-1 was significantly increased. B-cell lymphoma-extra large bone marrow expression was not affected by LCHS or LCHS/CS (naïve: 44 ± 12, LCHS: 44 ± 12, LCHS/CS: 37 ± 1, all P > 0.05). The bone marrow microenvironment was significantly altered following severe trauma in a rodent model. Prohematopoietic cytokines were downregulated, and the proinflammatory cytokine HMGB-1 had increased bone marrow expression. Modulation of the bone marrow microenvironment may represent a therapeutic strategy following severe trauma to alleviate persistent injury-associated anemia. Copyright © 2017 Elsevier Inc. All rights reserved.

Molecular cloning and chromosomal mapping of bone marrow stromal cell surface gene, BST2, that may be involved in pre-B-cell growth

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ishikawa, Jun; Kaisho, Tsuneyasu; Tomizawa, Hitoshi

1995-04-10

Bone marrow stromal cells regulate B-cell growth and development through their surface molecules and cytokines. In this study, we generated a mAb, RS38, that recognized a novel human membrane protein, BST-2, expressed on bone marrow stromal cell lines and synovial cell lines. We cloned a cDNA encoding BST-2 from a rheumatoid arthritis-derived synovial cell line. BST-2 is a 30- to 36-kDa type II transmembrane protein, consisting of 180 amino acids. The BST-2 gene (HGMW-approved symbol BST2) is located on chromosome 19p13.2. BST-2 is expressed not only on certain bone marrow stromal cell lines but also on various normal tissues, althoughmore » its expression pattern is different from that of another bone marrow stromal cell surface molecule, BST-1. BST-2 surface expression on fibroblast cell lines facilitated the stromal cell-dependent growth of a murine bone marrow-derived pre-B-cell line, DW34. The results suggest that BST-2 may be involved in pre-B-cell growth. 45 refs., 7 figs., 2 tabs.« less

Dietary isoflavones act on bone marrow osteoprogenitor cells and stimulate ovary development before influencing bone mass in pre-pubertal piglets.

PubMed

De Wilde, Anne; Maria Rassi, Claudia; Cournot, Giulia; Colin, Colette; Lacroix, Herminie C; Chaumaz, Gilles; Coxam, Veronique; Bennetau-Pelissero, Catherine; Pointillart, Alain; Lieberherr, Michele

2007-07-01

Food containing soybeans provide isoflavone phytoestrogens that can preserve bone mass in postmenopausal women, and prevent bone loss in ovariectomized rats. But their effects on bone remain unclear, particularly on bone formation during growth. Two groups of eight pre-pubertal piglets were fed a basal or an isoflavone-enriched (S800) diet for 6 weeks. The S800 diet contained 800 mg SoyLifetrade mark/kg, providing 2.8 mg isoflavones/kg body weight/day. Several bones were collected and tested for bone strength and density. Bone marrow was collected from humeri together with blood samples and genital tracts. The plasma concentrations of isoflavones were increased in the pigs fed S800, but growth rate, body weight, plasma bone markers, bone mineral density, and strength were all unaffected. In contrast, cultured stromal cells from S800 pigs had more alkaline phosphatase-rich cells and mineralized nodules, secreted more osteocalcin, osteoprotegerin and RANK-L, synthesized more osteoprotegerin, and RANK-L. Cultured mononucleated nonadherent bone marrow cells from S800 pigs developed fewer tartrate-resistant acid phosphatase mononucleated cells (osteoclast progenitors) when cultured with 1,25(OH)(2)D(3), and resorbed a smaller area of dentine slices. Freshly isolated bone marrow osteoclast progenitors from S800 pigs had more caspase-3 cleavage activity, and synthesized less RANK. Both osteoclast and osteoblast progenitors had ERalpha and ERbeta, whose syntheses were stimulated by the S800 diet. The S800 piglets had heavier ovaries with more follicles, but their uterus weight was unaffected. We conclude that dietary isoflavones have no detectable effect on the bone mass of growing female piglets, but act on bone marrow osteoprogenitors via ERs--mainly ERbeta, and stimulate ovary development.

In vitro characterization of MG-63 osteoblast-like cells cultured on organic-inorganic lyophilized gelatin sponges for early bone healing.

PubMed

Rodriguez, Isaac A; Saxena, Gunjan; Hixon, Katherine R; Sell, Scott A; Bowlin, Gary L

2016-08-01

The development of three-dimensional porous scaffolds with enhanced osteogenic and angiogenic potential would be beneficial for inducing early-stage bone regeneration. Previous studies have demonstrated the advantages of mineralized and nonmineralized acellular 1-Ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDC) cross-linked gelatin sponges enhanced with preparations rich in growth factors, hydroxyapatite, and chitin whiskers. In this study, those same scaffolds were mineralized and dynamically seeded with MG-63 cells. Cell proliferation, protein/cytokine secretion, and compressive mechanical properties of scaffolds were evaluated. It was found that mineralization and the addition of growth factors increased cell proliferation compared to gelatin controls. Cells on all scaffolds responded in an appropriate bone regenerative fashion as shown through osteocalcin secretion and little to no secretion of bone resorbing markers. However, compressive mechanical properties of cellularized scaffolds were not significantly different from acellular scaffolds. The combined results of increased cellular attachment, infiltration, and bone regenerative protein/cytokine secretion on scaffolds support the need for the addition of a bone-like mineral surface. Cellularized scaffolds containing growth factors reported similar advantages and mechanical values in the range of native tissues present in the early stages of bone healing. These results suggest that the developed composite sponges exhibited cellular responses and mechanical properties appropriate for promoting early bone healing in various applications. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2011-2019, 2016. © 2016 Wiley Periodicals, Inc.

Macrodamage Accumulation Model for a Human Femur

PubMed Central

2017-01-01

The objective of this study was to more fully understand the mechanical behavior of bone tissue that is important to find an alternative material to be used as an implant and to develop an accurate model to predict the fracture of the bone. Predicting and preventing bone failure is an important area in orthopaedics. In this paper, the macrodamage accumulation models in the bone tissue have been investigated. Phenomenological models for bone damage have been discussed in detail. In addition, 3D finite element model of the femur prepared from imaging data with both cortical and trabecular structures is delineated using MIMICS and ANSYS® and simulated as a composite structure. The damage accumulation occurring during cyclic loading was analyzed for fatigue scenario. We found that the damage accumulates sooner in the multiaxial than in the uniaxial loading condition for the same number of cycles, and the failure starts in the cortical bone. The damage accumulation behavior seems to follow a three-stage growth: a primary phase, a secondary phase of damage growth marked by linear damage growth, and a tertiary phase that leads to failure. Finally, the stiffness of the composite bone comprising the cortical and trabecular bone was significantly different as expected. PMID:28951659

Development of an efficient, non-viral transfection method for studying gene function and bone growth in human primary cranial suture mesenchymal cells reveals that the cells respond to BMP2 and BMP3.

PubMed

Dwivedi, Prem P; Anderson, Peter J; Powell, Barry C

2012-08-03

Achieving efficient introduction of plasmid DNA into primary cultures of mammalian cells is a common problem in biomedical research. Human primary cranial suture cells are derived from the connective mesenchymal tissue between the bone forming regions at the edges of the calvarial plates of the skull. Typically they are referred to as suture mesenchymal cells and are a heterogeneous population responsible for driving the rapid skull growth that occurs in utero and postnatally. To better understand the molecular mechanisms involved in skull growth, and in abnormal growth conditions, such as craniosynostosis, caused by premature bony fusion, it is essential to be able to easily introduce genes into primary bone forming cells to study their function. A comparison of several lipid-based techniques with two electroporation-based techniques demonstrated that the electroporation method known as nucleofection produced the best transfection efficiency. The parameters of nucleofection, including cell number, amount of DNA and nucleofection program, were optimized for transfection efficiency and cell survival. Two different genes and two promoter reporter vectors were used to validate the nucleofection method and the responses of human primary suture mesenchymal cells by fluorescence microscopy, RT-PCR and the dual luciferase assay. Quantification of bone morphogenetic protein (BMP) signalling using luciferase reporters demonstrated robust responses of the cells to both osteogenic BMP2 and to the anti-osteogenic BMP3. A nucleofection protocol has been developed that provides a simple and efficient, non-viral alternative method for in vitro studies of gene and protein function in human skull growth. Human primary suture mesenchymal cells exhibit robust responses to BMP2 and BMP3, and thus nucleofection can be a valuable method for studying the potential competing action of these two bone growth factors in a model system of cranial bone growth.

Growth factor delivery: How surface interactions modulate release in vitro and in vivo

PubMed Central

King, William J.; Krebsbach, Paul H.

2013-01-01

Biomaterial scaffolds have been extensively used to deliver growth factors to induce new bone formation. The pharmacokinetics of growth factor delivery has been a critical regulator of their clinical success. This review will focus on the surface interactions that control the non-covalent incorporation of growth factors into scaffolds and the mechanisms that control growth factor release from clinically relevant biomaterials. We will focus on the delivery of recombinant human bone morphogenetic protein-2 from materials currently used in the clinical practice, but also suggest how general mechanisms that control growth factor incorporation and release delineated with this growth factor could extend to other systems. A better understanding of the changing mechanisms that control growth factor release during the different stages of preclinical development could instruct the development of future scaffolds for currently untreatable injuries and diseases. PMID:22433783

Growth plate expression profiling: Large and small breed dogs provide new insights in endochondral bone formation.

PubMed

Teunissen, Michelle; Riemers, Frank M; van Leenen, Dik; Groot Koerkamp, Marian J A; Meij, Björn P; Alblas, Jacqueline; Penning, Louis C; Miranda-Bedate, Alberto; Tryfonidou, Marianna A

2018-01-01

The difference in the adult height of mammals, and hence in endochondral bone formation, is not yet fully understood and may serve to identify targets for bone and cartilage regeneration. In line with this hypothesis, the intra-species disparity between the adult height of Great Danes and Miniature Poodles was investigated at a transcriptional level. Microarray analysis of the growth plate of five Great Danes and five Miniature Poodles revealed 2,981 unique genes that were differentially expressed, including many genes with an unknown role in skeletal development. A signaling pathway impact analysis indicated activation of the cell cycle, extracellular matrix receptor interaction and the tight junction pathway, and inhibition of pathways associated with inflammation and the complement cascade. In additional validation steps, the gene expression profile of the separate growth plate zones for both dog breeds were determined. Given that the BMP signaling is known for its crucial role in skeletal development and fracture healing, and BMP-2 is used in orthopaedic and spine procedures for bone augmentation, further investigations concentrated on the BMP pathway.The canonical BMP-2 and BMP-6 signaling pathway was activated in the Great Danes compared to Miniature Poodles. In conclusion, investigating the differential expression of genes involved in endochondral bone formation in small and large breed dogs, could be a game changing strategy to provide new insights in growth plate development and identify new targets for bone and cartilage regeneration. © 2017 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals, Inc. on behalf of the Orthopaedic Research Society. J Orthop Res 36:138-148, 2018. © 2017 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodicals Inc. on behalf of the Orthopaedic Research Society.

Dietary induced serum phenolic acids promote bone growth via p38 MAPK / Beta-Catenin Canonical Wnt signaling

USDA-ARS?s Scientific Manuscript database

Diet and nutritional status are critical factors that influences bone development. In this report, we demonstrate that a mixture of phenolic acids found in the serum of young rats fed blueberries (BB), significantly stimulated osteoblast differentiation, resulting in significantly increased bone mas...

Exercise training, menstrual irregularities and bone development in children and adolescents.

PubMed

Eliakim, Alon; Beyth, Yoram

2003-08-01

Weight bearing physical activity plays an important role in bone development. This is particularly important in children and adolescents since bone mineral density reaches about 90% of its peak by the end of the second decade, and because about one quarter of adult bone is accumulated during the two years surrounding the peak bone growth velocity. Recent studies suggested that the exercise-induced increase in bone mineralization is maturity dependent, and that there is a "window of opportunity" and a critical period for bone response to weight bearing exercise during early puberty and premenarchal years. This supports the idea that increase in physical activity during childhood and adolescence can prevent bone disorders (like osteoporosis) later in life. In contrast, strenuous physical activity may affect the female reproductive system and lead to "athletic amenorrhea". The prevalence of "athletic amenorrhea" is 4-20 times higher than the general population. As a consequence, bone demineralization may develop with increased risk of skeletal fragility, fractures, vertebral instability, and curvature. Menstrual abnormalities in the female athlete result from hypothalamic suppression of the spontaneous pulsatile secretion of gonadotropin releasing hormone. Recent studies suggested that reduced energy availability (increased energy expenditure with inadequate caloric intake) is the main cause of the central suppression of the hypothalamic pituitary-gonadal axis. Therefore, effort should be made to optimize the nutritional state of female athletes, and if not successful, to reduce the training load in order to prevent menstrual abnormalities, and deleterious bone effects in particular during the critical period of rapid bone growth.

Bone Growth, Mechanical Stimulus and IGF-1

DTIC Science & Technology

2006-10-01

suffer a bone fracture by the time they reach skeletal maturity. While strenuous physical activity and occupational hazards are key factors in the...females with low bone density. Ultimately, this information could be of great benefit to enhance musculoskeletal development and decrease the risk ...pathogenesis of these fractures , several studies indicate that teenagers who sustain fractures also have decreased bone mass. Therefore, the use of low

Combined treatment with a transforming growth factor beta inhibitor (1D11) and bortezomib improves bone architecture in a mouse model of myeloma-induced bone disease

PubMed Central

Nyman, Jeffry S.; Merkel, Alyssa R.; Uppuganti, Sasidhar; Nayak, Bijaya; Rowland, Barbara; Makowski, Alexander J.; Oyajobi, Babatunde O.; Sterling, Julie A.

2016-01-01

Multiplemyeloma (MM) patients frequently develop tumor-induced bone destruction, yet no therapy completely eliminates the tumor or fully reverses bone loss. Transforming growth factor-β (TGF-β) activity often contributes to tumor-induced bone disease, and pre-clinical studies have indicated that TGF-β inhibition improves bone volume and reduces tumor growth in bone metastatic breast cancer. We hypothesized that inhibition of TGF-β signaling also reduces tumor growth, increases bone volume, and improves vertebral body strength in MM-bearing mice. We treated myeloma tumor-bearing (immunocompetent KaLwRij and immunocompromised Rag2 −/−) mice with a TGF-β inhibitory (1D11) or control (13C4) antibody, with or without the anti-myeloma drug bortezomib, for 4 weeks after inoculation of murine 5TGM1 MM cells. TGF-β inhibition increased trabecular bone volume, improved trabecular architecture, increased tissue mineral density of the trabeculae as assessed by ex vivo micro-computed tomography, and was associated with significantly greater vertebral body strength in biomechanical compression tests. Serum monoclonal paraprotein titers and spleen weights showed that 1D11 monotherapy did not reduce overall MM tumor burden. Combination therapy with 1D11 and bortezomib increased vertebral body strength, reduced tumor burden, and reduced cortical lesions in the femoral metaphysis, although it did not significantly improve cortical bone strength in three-point bending tests of the mid-shaft femur. Overall, our data provides rationale for evaluating inhibition of TGF-β signaling in combination with existing anti-myeloma agents as a potential therapeutic strategy to improve outcomes in patients with myeloma bone disease. PMID:27423464

Combined treatment with a transforming growth factor beta inhibitor (1D11) and bortezomib improves bone architecture in a mouse model of myeloma-induced bone disease.

PubMed

Nyman, Jeffry S; Merkel, Alyssa R; Uppuganti, Sasidhar; Nayak, Bijaya; Rowland, Barbara; Makowski, Alexander J; Oyajobi, Babatunde O; Sterling, Julie A

2016-10-01

Multiple myeloma (MM) patients frequently develop tumor-induced bone destruction, yet no therapy completely eliminates the tumor or fully reverses bone loss. Transforming growth factor-β (TGF-β) activity often contributes to tumor-induced bone disease, and pre-clinical studies have indicated that TGF-β inhibition improves bone volume and reduces tumor growth in bone metastatic breast cancer. We hypothesized that inhibition of TGF-β signaling also reduces tumor growth, increases bone volume, and improves vertebral body strength in MM-bearing mice. We treated myeloma tumor-bearing (immunocompetent KaLwRij and immunocompromised Rag2-/-) mice with a TGF-β inhibitory (1D11) or control (13C4) antibody, with or without the anti-myeloma drug bortezomib, for 4weeks after inoculation of murine 5TGM1 MM cells. TGF-β inhibition increased trabecular bone volume, improved trabecular architecture, increased tissue mineral density of the trabeculae as assessed by ex vivo micro-computed tomography, and was associated with significantly greater vertebral body strength in biomechanical compression tests. Serum monoclonal paraprotein titers and spleen weights showed that 1D11 monotherapy did not reduce overall MM tumor burden. Combination therapy with 1D11 and bortezomib increased vertebral body strength, reduced tumor burden, and reduced cortical lesions in the femoral metaphysis, although it did not significantly improve cortical bone strength in three-point bending tests of the mid-shaft femur. Overall, our data provides rationale for evaluating inhibition of TGF-β signaling in combination with existing anti-myeloma agents as a potential therapeutic strategy to improve outcomes in patients with myeloma bone disease. Published by Elsevier Inc.

Prenatal lead exposure and bone growth. Doctoral thesis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hamilton, J.D.; O'Flaherty, E.J.

1990-07-24

An experimental system of lead (7439921) related prenatal and postnatal growth retardation in rats was developed. Sprague-Dawley-rats and Long-Evans-rats were used in these studies. Rats were exposed to lead in their drinking water at up to 1000 parts per million. A significant effect on fetal bone mineralization could not be excluded and there was a definite effect on fetal body weight following maternal lead exposure. Reduced food intake during the first week of lead exposure was the primary determinant of reduced body and skeletal growth in the lead exposed weanling female rats. When maternal lead exposure was continued during lactationmore » a greater degree of lead related growth retardation in rat offspring occurred than when maternal lead exposure was terminated at parturition. Combined prenatal and postnatal lead exposure impaired bone resorption and increased growth plate widths. In studies using matrix induced endochondral bone plaques, locally applied lead enhanced plaque mineralization through comineralization of lead with calcium. When lead was administered in drinking water, plaque mineralization was also enhanced through the comineralization of lead with calcium.« less

Studies on the Induction of Bone and Soft Tissue Tumours in Rats by Gamma Irradiation and the Effect of Growth Hormone and Thyroxine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cater, D. B.; Baserga, R.; Lisco, H.

1959-06-01

A single dose of 3000 roentgen of gamma irradiation from a iridium-192 teletherapy source applied to both knee joints of growing female rats induced osteosarcomata in 34 out of 116 rats. Fifty rats developed sarcomata of soft tissues, 10 cancer of the skin, and 12 had mammary cancers. Eighty days after irradiation, ten-week courses of growth hormone, thyroxine, growth hormone followed by thyroxine, and saline were given to study the effect of hormone treatment on the incidence and induction period of radiationinduced bone sarcomata. Twelve out of 30 growthhormone-treated rats developed bone sarcomata compared with 7 out of 31 inmore » the saline injected group. Thyroxine treatment significantly reduced the mean latent period of radiation-induced osteosarcomata. The incidence of other types of malignant tumors was not affected by the hormone treatments.« less

Coating with a Modular Bone Morphogenetic Peptide Promotes Healing of a Bone-Implant Gap in an Ovine Model

PubMed Central

Lu, Yan; Lee, Jae Sung; Nemke, Brett; Graf, Ben K.; Royalty, Kevin; Illgen, Richard; Vanderby, Ray; Markel, Mark D.; Murphy, William L.

2012-01-01

Despite the potential for growth factor delivery strategies to promote orthopedic implant healing, there is a need for growth factor delivery methods that are controllable and amenable to clinical translation. We have developed a modular bone growth factor, herein termed “modular bone morphogenetic peptide (mBMP)”, which was designed to efficiently bind to the surface of orthopedic implants and also stimulate new bone formation. The purpose of this study was to coat a hydroxyapatite-titanium implant with mBMP and evaluate bone healing across a bone-implant gap in the sheep femoral condyle. The mBMP molecules efficiently bound to a hydroxyapatite-titanium implant and 64% of the initially bound mBMP molecules were released in a sustained manner over 28 days. The results demonstrated that the mBMP-coated implant group had significantly more mineralized bone filling in the implant-bone gap than the control group in C-arm computed tomography (DynaCT) scanning (25% more), histological (35% more) and microradiographic images (50% more). Push-out stiffness of the mBMP group was nearly 40% greater than that of control group whereas peak force did not show a significant difference. The results of this study demonstrated that mBMP coated on a hydroxyapatite-titanium implant stimulates new bone formation and may be useful to improve implant fixation in total joint arthroplasty applications. PMID:23185610

RETARDED GROWTH OF BONES OF THE FOREARM IN A GIRL FOLLOWING RADIUM THERAPY OF SKIN HEMANGIOMA (in Russian)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mirimova, T.D.

1960-07-01

A 9-month-old girl was subjected to radium therapy of skin hemangioma in the region of the forearm. Thirteen years afterwards there was revealed a considerable impairment in the growth and development of long bones that were within the field of the irradiation, resulting in the formation of a deformed shortened hand with restricted functions. (auth)

P38 MAPK / beta-catenin canonical wnt signaling mediated bone formation effects of blueberries

USDA-ARS?s Scientific Manuscript database

Appropriate nutrition is one of the critical factors that influences bone development. We studied the effects of dietary blueberry supplementation on bone growth in weanling rats. Weanling male and female rats were fed AIN-93G semi-purified diets supplemented with 10% whole blueberry powder for 14 a...

What Is a Growth Disorder? (For Parents)

MedlinePlus

... hormone, which is essential for normal bone growth. Turner syndrome , one of the most common genetic growth disorders, ... chromosome. In addition to short stature, girls with Turner syndrome usually don't undergo normal sexual development because ...

Growth hormone mediates pubertal skeletal development independent of hepatic IGF-1 production.

PubMed

Courtland, Hayden-William; Sun, Hui; Beth-On, Mordechay; Wu, Yingjie; Elis, Sebastien; Rosen, Clifford J; Yakar, Shoshana

2011-04-01

Deficiencies in either growth hormone (GH) or insulin-like growth factor 1 (IGF-1) are associated with reductions in bone size during growth in humans and animal models. Liver-specific IGF-1-deficient (LID) mice, which have 75% reductions in serum IGF-1, were created previously to separate the effects of endocrine (serum) IGF-1 from autocrine/paracrine IGF-1. However, LID mice also have two- to threefold increases in GH, and this may contribute to the observed pubertal skeletal phenotype. To clarify the role of GH in skeletal development under conditions of significantly reduced serum IGF-1 levels (but normal tissue IGF-1 levels), we studied the skeletal response of male LID and control mice to GH inhibition by pegvisomant from 4 to 8 weeks of age. Treatment of LID mice with pegvisomant resulted in significant reductions in body weight, femur length (Le), and femur total area (Tt.Ar), as well as further reductions in serum IGF-1 levels by 8 weeks of age, compared with the mean values of vehicle-treated LID mice. Reductions in both Tt.Ar and Le were proportional after treatment with pegvisomant. On the other hand, the relative amount of cortical tissue formed (RCA) in LID mice treated with pegvisomant was significantly less than that in both vehicle-treated LID and control mice, indicating that antagonizing GH action, either directly (through GH receptor signaling inhibition) or indirectly (through further reductions in serum/tissue IGF-1 levels), results in disproportionate reductions in the amount of cortical bone formed. This resulted in bones with significantly reduced mechanical properties (femoral whole-bone stiffness and work to failure were markedly decreased), suggesting that compensatory increases of GH in states of IGF-1 deficiency (LID mice) act to protect against a severe inhibition of bone modeling during growth, which otherwise would result in bones that are too weak for normal and/or extreme loading conditions. Copyright © 2011 American Society for Bone and Mineral Research.

Polymeric scaffolds as stem cell carriers in bone repair.

PubMed

Rossi, Filippo; Santoro, Marco; Perale, Giuseppe

2015-10-01

Although bone has a high potential to regenerate itself after damage and injury, the efficacious repair of large bone defects resulting from resection, trauma or non-union fractures still requires the implantation of bone grafts. Materials science, in conjunction with biotechnology, can satisfy these needs by developing artificial bones, synthetic substitutes and organ implants. In particular, recent advances in polymer science have provided several innovations, underlying the increasing importance of macromolecules in this field. To address the increasing need for improved bone substitutes, tissue engineering seeks to create synthetic, three-dimensional scaffolds made from polymeric materials, incorporating stem cells and growth factors, to induce new bone tissue formation. Polymeric materials have shown a great affinity for cell transplantation and differentiation and, moreover, their structure can be tuned in order to maintain an adequate mechanical resistance and contemporarily be fully bioresorbable. This review emphasizes recent progress in polymer science that allows relaible polymeric scaffolds to be synthesized for stem cell growth in bone regeneration. Copyright © 2013 John Wiley & Sons, Ltd.

Bone lengthening for congenital differences of the hands and digits in children.

PubMed

Matsuno, Takahiro; Ishida, Osamu; Sunagawa, Toru; Ichikawa, Makoto; Ikuta, Yoshikazu; Ochi, Mitsuo

2004-07-01

We investigated the growth of bones after lengthening to evaluate the effectiveness and usefulness of bone lengthening in congenital hand deficiencies. Bone lengthening was performed to treat congenital hand deficiencies including hypoplastic thumb, hypoplasia of the small finger, cleft hand, metacarpal synostosis, brachymetacarpia, symbrachydactyly, and amniotic band syndrome. A total of 15 patients (1-13 years old) underwent lengthening of 23 bones. The average of distraction was 10 mm. The mean follow-up period was 59 months. The length of the bones at follow-up evaluation was measured and then compared with the length of the bones immediately after lengthening. The bone growth after lengthening, the percentage of growth after lengthening, and the growth rate were compared among diagnostic groups. In the cases involving older patients the bone length changed little and the growth plates of these patients closed naturally soon after lengthening. In contrast, in the cases in which the patients were younger than 7 years old the lengthened bones grew continuously. The amount of bone growth was different for each disease in the younger patients. In patients with amniotic band syndrome the lengthened bones grew at the same rate as the bones in the hand. Other diagnoses such as symbrachydactyly had a different growth pattern in the hand. We conclude that bone lengthening is a reliable method for the correction of congenital differences of the hand. The indications for this procedure must be determined while considering the relationship between the specific disease and subsequent bone growth.

Hydrogels That Allow and Facilitate Bone Repair, Remodeling, and Regeneration

PubMed Central

Short, Aaron R.; Koralla, Deepthi; Deshmukh, Ameya; Wissel, Benjamin; Stocker, Benjamin; Calhoun, Mark; Dean, David; Winter, Jessica O.

2015-01-01

Bone defects can originate from a variety of causes, including trauma, cancer, congenital deformity, and surgical reconstruction. Success of the current “gold standard” treatment (i.e., autologous bone grafts) is greatly influenced by insufficient or inappropriate bone stock. There is thus a critical need for the development of new, engineered materials for bone repair. This review describes the use of natural and synthetic hydrogels as scaffolds for bone tissue engineering. We discuss many of the advantages that hydrogels offer as bone repair materials, including their potential for osteoconductivity, biodegradability, controlled growth factor release, and cell encapsulation. We also discuss the use of hydrogels in composite devices with metals, ceramics, or polymers. These composites are useful because of the low mechanical moduli of hydrogels. Finally, the potential for thermosetting and photo-cross-linked hydrogels as three-dimensionally (3D) printed, patient-specific devices is highlighted. Three-dimensional printing enables controlled spatial distribution of scaffold materials, cells, and growth factors. Hydrogels, especially natural hydrogels present in bone matrix, have great potential to augment existing bone tissue engineering devices for the treatment of critical size bone defects. PMID:26693013

Bone regenerative medicine: classic options, novel strategies, and future directions

PubMed Central

2014-01-01

This review analyzes the literature of bone grafts and introduces tissue engineering as a strategy in this field of orthopedic surgery. We evaluated articles concerning bone grafts; analyzed characteristics, advantages, and limitations of the grafts; and provided explanations about bone-tissue engineering technologies. Many bone grafting materials are available to enhance bone healing and regeneration, from bone autografts to graft substitutes; they can be used alone or in combination. Autografts are the gold standard for this purpose, since they provide osteogenic cells, osteoinductive growth factors, and an osteoconductive scaffold, all essential for new bone growth. Autografts carry the limitations of morbidity at the harvesting site and limited availability. Allografts and xenografts carry the risk of disease transmission and rejection. Tissue engineering is a new and developing option that had been introduced to reduce limitations of bone grafts and improve the healing processes of the bone fractures and defects. The combined use of scaffolds, healing promoting factors, together with gene therapy, and, more recently, three-dimensional printing of tissue-engineered constructs may open new insights in the near future. PMID:24628910

Hydrogels That Allow and Facilitate Bone Repair, Remodeling, and Regeneration.

PubMed

Short, Aaron R; Koralla, Deepthi; Deshmukh, Ameya; Wissel, Benjamin; Stocker, Benjamin; Calhoun, Mark; Dean, David; Winter, Jessica O

2015-10-28

Bone defects can originate from a variety of causes, including trauma, cancer, congenital deformity, and surgical reconstruction. Success of the current "gold standard" treatment (i.e., autologous bone grafts) is greatly influenced by insufficient or inappropriate bone stock. There is thus a critical need for the development of new, engineered materials for bone repair. This review describes the use of natural and synthetic hydrogels as scaffolds for bone tissue engineering. We discuss many of the advantages that hydrogels offer as bone repair materials, including their potential for osteoconductivity, biodegradability, controlled growth factor release, and cell encapsulation. We also discuss the use of hydrogels in composite devices with metals, ceramics, or polymers. These composites are useful because of the low mechanical moduli of hydrogels. Finally, the potential for thermosetting and photo-cross-linked hydrogels as three-dimensionally (3D) printed, patient-specific devices is highlighted. Three-dimensional printing enables controlled spatial distribution of scaffold materials, cells, and growth factors. Hydrogels, especially natural hydrogels present in bone matrix, have great potential to augment existing bone tissue engineering devices for the treatment of critical size bone defects.

The skeletal structure of insulin-like growth factor I-deficient mice

NASA Technical Reports Server (NTRS)

Bikle, D.; Majumdar, S.; Laib, A.; Powell-Braxton, L.; Rosen, C.; Beamer, W.; Nauman, E.; Leary, C.; Halloran, B.

2001-01-01

The importance of insulin-like growth factor I (IGF-I) for growth is well established. However, the lack of IGF-I on the skeleton has not been examined thoroughly. Therefore, we analyzed the structural properties of bone from mice rendered IGF-I deficient by homologous recombination (knockout [k/o]) using histomorphometry, peripheral quantitative computerized tomography (pQCT), and microcomputerized tomography (muCT). The k/o mice were 24% the size of their wild-type littermates at the time of study (4 months). The k/o tibias were 28% and L1 vertebrae were 26% the size of wild-type bones. Bone formation rates (BFR) of k/o tibias were 27% that of the wild-type littermates. The k/o bones responded normally to growth hormone (GH; 1.7-fold increase) and supranormally to IGF-I (5.2-fold increase) with respect to BFR. Cortical thickness of the proximal tibia was reduced 17% in the k/o mouse. However, trabecular bone volume (bone volume/total volume [BV/TV]) was increased 23% (male mice) and 88% (female mice) in the k/o mice compared with wild-type controls as a result of increased connectivity, increased number, and decreased spacing of the trabeculae. These changes were either less or not found in L1. Thus, lack of IGF-I leads to the development of a bone structure, which, although smaller, appears more compact.

Skeletal responses to spaceflight

NASA Technical Reports Server (NTRS)

Morey-Holton, Emily R.; Arnaud, Sara B.

1991-01-01

The effect of gravity on the skeletal development and on the bone composition and its regulation in vertebrates is discussed. Results are presented from spaceflight and ground studies in both man and rat on the effect of microgravity on the bone-mineral metabolism (in both species) and on bone maturation and growth (in rats). Special attention is given to a ground-based flight-simulation rat model developed at NASA's Ames Research Center for studies of bone structure at the molecular, organ, and whole-body levels and to comparisons of estimated results with spaceflight data.

Absence of the lysophosphatidic acid receptor LPA1 results in abnormal bone development and decreased bone mass☆,☆☆

PubMed Central

Gennero, Isabelle; Laurencin-Dalicieux, Sara; Conte-Auriol, Françoise; Briand-Mésange, Fabienne; Laurencin, Danielle; Rue, Jackie; Beton, Nicolas; Malet, Nicole; Mus, Marianne; Tokumura, Akira; Bourin, Philippe; Vico, Laurence; Brunel, Gérard; Oreffo, Richard O. C.; Chun, Jerold; Salles, Jean Pierre

2013-01-01

Lysophosphatidic acid (LPA) is a lipid mediator that acts in paracrine systems via interaction with a subset of G protein-coupled receptors (GPCRs). LPA promotes cell growth and differentiation, and has been shown to be implicated in a variety of developmental and pathophysiological processes. At least 6 LPA GPCRs have been identified to date: LPA1–LPA6. Several studies have suggested that local production of LPA by tissues and cells contributes to paracrine regulation, and a complex interplay between LPA and its receptors, LPA1 and LPA4, is believed to be involved in the regulation of bone cell activity. In particular, LPA1may activate both osteoblasts and osteoclasts. However, its role has not as yet been examined with regard to the overall status of bone in vivo. We attempted to clarify this role by defining the bone phenotype of LPA1(−/−) mice. These mice demonstrated significant bone defects and low bone mass, indicating that LPA1 plays an important role in osteogenesis. The LPA1(−/−) mice also presented growth and sternal and costal abnormalities, which highlights the specific roles of LPA1 during bone development. Microcomputed tomography and histological analysis demonstrated osteoporosis in the trabecular and cortical bone of LPA1(−/−) mice. Finally, bone marrow mesenchymal progenitors from these mice displayed decreased osteoblastic differentiation. These results suggest that LPA1 strongly influences bone development both qualitatively and quantitatively and that, in vivo, its absence results in decreased osteogenesis with no clear modification of osteoclasis. They open perspectives for a better understanding of the role of the LPA/LPA1 paracrine pathway in bone pathophysiology. PMID:21569876

Collagen and mineral deposition in rabbit cortical bone during maturation and growth: effects on tissue properties.

PubMed

Isaksson, Hanna; Harjula, Terhi; Koistinen, Arto; Iivarinen, Jarkko; Seppänen, Kari; Arokoski, Jari P A; Brama, Pieter A; Jurvelin, Jukka S; Helminen, Heikki J

2010-12-01

We characterized the composition and mechanical properties of cortical bone during maturation and growth and in adult life in the rabbit. We hypothesized that the collagen network develops earlier than the mineralized matrix. Growth was monitored, and the rabbits were euthanized at birth (newborn), and at 1, 3, 6, 9, and 18 months of age. The collagen network was assessed biochemically (collagen content, enzymatic and non-enzymatic cross-links) in specimens from the mid-diaphysis of the tibia and femur and biomechanically (tensile testing) from decalcified whole tibia specimens. The mineralized matrix was analyzed using pQCT and 3-point bend tests from intact femur specimens. The collagen content and the Young's modulus of the collagen matrix increased significantly until the rabbits were 3 months old, and thereafter remained stable. The amount of HP and LP collagen cross-links increased continuously from newborn to 18 months of age, whereas PEN cross-links increased after 6 months of age. Bone mineral density and the Young's modulus of the mineralized bone increased until the rabbits were at least 6 months old. We concluded that substantial changes take place during the normal process of development in both the biochemical and biomechanical properties of rabbit cortical bone. In cortical bone, the collagen network reaches its mature composition and mechanical strength prior to the mineralized matrix. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Development of a protocol to quantify local bone adaptation over space and time: Quantification of reproducibility.

PubMed

Lu, Yongtao; Boudiffa, Maya; Dall'Ara, Enrico; Bellantuono, Ilaria; Viceconti, Marco

2016-07-05

In vivo micro-computed tomography (µCT) scanning of small rodents is a powerful method for longitudinal monitoring of bone adaptation. However, the life-time bone growth in small rodents makes it a challenge to quantify local bone adaptation. Therefore, the aim of this study was to develop a protocol, which can take into account large bone growth, to quantify local bone adaptations over space and time. The entire right tibiae of eight 14-week-old C57BL/6J female mice were consecutively scanned four times in an in vivo µCT scanner using a nominal isotropic image voxel size of 10.4µm. The repeated scan image datasets were aligned to the corresponding baseline (first) scan image dataset using rigid registration. 80% of tibia length (starting from the endpoint of the proximal growth plate) was selected as the volume of interest and partitioned into 40 regions along the tibial long axis (10 divisions) and in the cross-section (4 sectors). The bone mineral content (BMC) was used to quantify bone adaptation and was calculated in each region. All local BMCs have precision errors (PE%CV) of less than 3.5% (24 out of 40 regions have PE%CV of less than 2%), least significant changes (LSCs) of less than 3.8%, and 38 out of 40 regions have intraclass correlation coefficients (ICCs) of over 0.8. The proposed protocol allows to quantify local bone adaptations over an entire tibia in longitudinal studies, with a high reproducibility, an essential requirement to reduce the number of animals to achieve the necessary statistical power. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Holographic nondestructive testing in bone growth disturbance studies

NASA Astrophysics Data System (ADS)

Silvennoinen, Raimo; Nygren, Kaarlo; Mozerov, Mikhail G.

1994-03-01

We used isolated radioulnar bones (fused radial and ulnar bones) of subadult European moose collected in various environmentally polluted areas of Finland. The bones were radiographed and holographic interference pictures, for holographic nondestructive testing (HNDT), were produced by using small caudocranial bending forces. The cortical index values were measured in the diaphyses and samples were taken for mineral studies from the mandibles of the same animals. Results indicated that the bones obtained from the heavily polluted area showed biomechanical response comparable to the bones developed partially without mothers milk. Differences were also seen in morphometrical and radiological studies. The mineral contents studied did not differ significantly from randomly collected samples of the same age category. We therefore conclude that environmental factors may influence the bone matrix development.

Congenital cutis laxa with ligamentous laxity and delayed development, Dandy-Walker malformation and minor heart and osseous defects.

PubMed

Biver, A; De Rijcke, S; Toppet, V; Ledoux-Corbusier, M; Van Maldergem, L

1994-06-01

We present a female infant exhibiting congenital cutis laxa with retardation of growth and motor development, ligamentous laxity and congenital dislocation of the hips. This connective tissue disorder was associated with Dandy-Walker malformation, atrial and ventricular defect and minor bone abnormalities including multiple wormian bones, abnormal tubulation of long bones and absent twelfth pair of ribs. This association is believed to be unique.

The Molecular and Cellular Events That Take Place during Craniofacial Distraction Osteogenesis

PubMed Central

Rachmiel, Adi

2014-01-01

Summary: Gradual bone lengthening using distraction osteogenesis principles is the gold standard for the treatment of hypoplastic facial bones. However, the long treatment time is a major disadvantage of the lengthening procedures. The aim of this study is to review the current literature and summarize the cellular and molecular events occurring during membranous craniofacial distraction osteogenesis. Mechanical stimulation by distraction induces biological responses of skeletal regeneration that is accomplished by a cascade of biological processes that may include differentiation of pluripotential tissue, angiogenesis, osteogenesis, mineralization, and remodeling. There are complex interactions between bone-forming osteoblasts and other cells present within the bone microenvironment, particularly vascular endothelial cells that may be pivotal members of a complex interactive communication network in bone. Studies have implicated number of cytokines that are intimately involved in the regulation of bone synthesis and turnover. The gene regulation of numerous cytokines (transforming growth factor-β, bone morphogenetic proteins, insulin-like growth factor-1, and fibroblast growth factor-2) and extracellular matrix proteins (osteonectin, osteopontin) during distraction osteogenesis has been best characterized and discussed. Understanding the biomolecular mechanisms that mediate membranous distraction osteogenesis may guide the development of targeted strategies designed to improve distraction osteogenesis and accelerate bone regeneration that may lead to shorten the treatment duration. PMID:25289295

[Development, physiology, and cell activity of bone].

PubMed

de Baat, P; Heijboer, M P; de Baat, C

2005-07-01

Bones are of crucial importance for the human body, providing skeletal support, serving as a home for the formation of haematopoietic cells, and reservoiring calcium and phosphate. Long bones develop by endochondral ossification. Flat bones develop by intramembranous ossification. Bone tissue contains hydroxyapatite and various extracellular proteins, producing bone matrix. Two biological mechanisms, determining the strength of bone, are modelling and remodelling. Modelling can change bone shape and size through bone formation by osteoblasts at some sites and through bone destruction by osteoclasts at other sites. Remodelling is bone turnover, also performed by osteoclasts and osteoblasts. The processes of modelling and remodelling are induced by mechanical loads, predominantly muscle loads. Osteoblasts develop from mesenchymal stem cells. Many stimulating factors are known to activate the differentiation. Mature osteoblasts synthesize bone matrix and may further differentiate into osteocytes. Osteocytes maintain structural bone integrity and allow bone to adapt to any mechanical and chemical stimulus. Osteoclasts derive from haematopoietic stem cells. A number of transcription and growth factors have been identified essential for osteoclast differentiation and function. Finally, there is a complex interaction between osteoblasts and osteoclasts. Bone destruction starts by attachment of osteoclasts to the bone surface. Following this, osteoclasts undergo specific morphological changes. The process of bone destruction starts by acid dissolution of hydroxyapatite. After that osteoclasts start to destruct the organic matrix.

Enhanced osteoblast adhesion on nanostructured selenium compacts for anti-cancer orthopedic applications.

PubMed

Tran, Phong; Webster, Thomas J

2008-01-01

Metallic bone implants possess numerous problems limiting their long-term efficacy, such as poor prolonged osseointegration, stress shielding, and corrosion under in vivo environments. Such problems are compounded for bone cancer patients since numerous patients receive orthopedic implants after cancerous bone resection. Unfortunately, current orthopedic materials were not originally developed to simultaneously increase healthy bone growth (as in traditional orthopedic implant applications) while inhibiting cancerous bone growth. The long-term objective of the present research is to investigate the use of nano-rough selenium to prevent bone cancer from re-occurring while promoting healthy bone growth for this select group of cancer patients. Selenium is a well known anti-cancer chemical. However, what is not known is how healthy bone cells interact with selenium. To determine this, selenium, spherical or semispherical shots, were pressed into cylindrical compacts and these compacts were then etched using 1N NaOH to obtain various surface structures ranging from the micron, submicron to nano scales. Changes in surface chemistry were also analyzed. Through these etching techniques, results of this study showed that biologically inspired surface roughness values were created on selenium compacts to match that of natural bone roughness. Moreover, results showed that healthy bone cell adhesion increased with greater nanometer selenium roughness (more closely matching that of titanium). In this manner, this study suggests that nano-rough selenium should be further tested for orthopedic applications involving bone cancer treatment.

Enhanced osteoblast adhesion on nanostructured selenium compacts for anti-cancer orthopedic applications

PubMed Central

Tran, Phong; Webster, Thomas J

2008-01-01

Metallic bone implants possess numerous problems limiting their long-term efficacy, such as poor prolonged osseointegration, stress shielding, and corrosion under in vivo environments. Such problems are compounded for bone cancer patients since numerous patients receive orthopedic implants after cancerous bone resection. Unfortunately, current orthopedic materials were not originally developed to simultaneously increase healthy bone growth (as in traditional orthopedic implant applications) while inhibiting cancerous bone growth. The long-term objective of the present research is to investigate the use of nano-rough selenium to prevent bone cancer from re-occurring while promoting healthy bone growth for this select group of cancer patients. Selenium is a well known anti-cancer chemical. However, what is not known is how healthy bone cells interact with selenium. To determine this, selenium, spherical or semispherical shots, were pressed into cylindrical compacts and these compacts were then etched using 1N NaOH to obtain various surface structures ranging from the micron, submicron to nano scales. Changes in surface chemistry were also analyzed. Through these etching techniques, results of this study showed that biologically inspired surface roughness values were created on selenium compacts to match that of natural bone roughness. Moreover, results showed that healthy bone cell adhesion increased with greater nanometer selenium roughness (more closely matching that of titanium). In this manner, this study suggests that nano-rough selenium should be further tested for orthopedic applications involving bone cancer treatment. PMID:18990948

Maternal high-fat diet and offspring expression levels of vitamin K-dependent proteins.

PubMed

Lanham, S A; Cagampang, F R; Oreffo, R O C

2014-12-01

Studies suggest that bone growth and development and susceptibility to vascular disease in later life are influenced by maternal nutrition during intrauterine and early postnatal life. There is evidence for a role of vitamin K-dependent proteins (VKDPs) including osteocalcin, matrix Gla protein, periostin, and growth-arrest specific- protein 6, in both bone and vascular development. We have examined whether there are alterations in these VKDPs in bone and vascular tissue from offspring of mothers subjected to a nutritional challenge: a high-fat diet during pregnancy and postnatally, using 6-week-old mouse offspring. Bone site-specific and sex-specific differences across femoral and vertebral bone in male and female offspring were observed. Overall a high-fat maternal diet and offspring diet exacerbated the bone changes observed. Sex-specific differences and tissue-specific differences were observed in VKDP levels in aorta tissue from high-fat diet-fed female offspring from high-fat diet-fed mothers displaying increased levels of Gas6 and Ggcx compared with those of female controls. In contrast, differences were seen in VKDP levels in femoral bone of female offspring with lower expression levels of Mgp in offspring of mothers fed a high-fat diet compared with those of controls. We observed a significant correlation in Mgp expression levels within the femur to measures of bone structure of the femur and vertebra, particularly in the male offspring cohort. In summary, the current study has highlighted the importance of maternal nutrition on offspring bone development and the correlation of VKDPs to bone structure.

Constitutive stimulatory G protein activity in limb mesenchyme impairs bone growth.

PubMed

Karaca, Anara; Malladi, Vijayram Reddy; Zhu, Yan; Tafaj, Olta; Paltrinieri, Elena; Wu, Joy Y; He, Qing; Bastepe, Murat

2018-05-01

GNAS mutations leading to constitutively active stimulatory G protein alpha-subunit (Gsα) cause different tumors, fibrous dysplasia of bone, and McCune-Albright syndrome, which are typically not associated with short stature. Enhanced signaling of the parathyroid hormone/parathyroid hormone-related peptide receptor, which couples to multiple G proteins including Gsα, leads to short bones with delayed endochondral ossification. It has remained unknown whether constitutive Gsα activity also impairs bone growth. Here we generated mice expressing a constitutively active Gsα mutant (Gsα-R201H) conditionally upon Cre recombinase (cGsα R201H mice). Gsα-R201H was expressed in cultured bone marrow stromal cells from cGsα R201H mice upon adenoviral-Cre transduction. When crossed with mice in which Cre is expressed in a tamoxifen-regulatable fashion (CAGGCre-ER™), tamoxifen injection resulted in mosaic expression of the transgene in double mutant offspring. We then crossed the cGsα R201H mice with Prx1-Cre mice, in which Cre is expressed in early limb-bud mesenchyme. The double mutant offspring displayed short limbs at birth, with narrow hypertrophic chondrocyte zones in growth plates and delayed formation of secondary ossification center. Consistent with enhanced Gsα signaling, bone marrow stromal cells from these mice demonstrated increased levels of c-fos mRNA. Our findings indicate that constitutive Gsα activity during limb development disrupts endochondral ossification and bone growth. Given that Gsα haploinsufficiency also leads to short bones, as in patients with Albright's hereditary osteodystrophy, these results suggest that a tight control of Gsα activity is essential for normal growth plate physiology. Copyright © 2018 Elsevier Inc. All rights reserved.

Development of sensory innervation in rat tibia: co-localization of CGRP and substance P with growth-associated protein 43 (GAP-43)

PubMed Central

Gajda, Mariusz; Litwin, Jan A; Cichocki, Tadeusz; Timmermans, Jean-Pierre; Adriaensen, Dirk

2005-01-01

The development of sensory innervation in long bones was investigated in rat tibia in fetuses on gestational days (GD) 16–21 and in neonates and juvenile individuals on postnatal days (PD) 1–28. A double immunostaining method was applied to study the co-localization of the neuronal growth marker growth-associated protein 43 (GAP-43) and the pan-neuronal marker protein gene product 9.5 (PGP 9.5) as well as that of two sensory fibre-associated neuropeptides, calcitonin gene-related peptide (CGRP) and substance P (SP). The earliest, not yet chemically coded, nerve fibres were observed on GD17 in the perichondrium of the proximal epiphysis. Further development of the innervation was characterized by the successive appearance of nerve fibres in the perichondrium/periosteum of the shaft (GD19), the bone marrow cavity and intercondylar eminence (GD21), the metaphyses (PD1), the cartilage canals penetrating into the epiphyses (PD7), and finally in the secondary ossification centres (PD10) and epiphyseal bone marrow (PD14). Maturation of the fibres, manifested by their immunoreactivity for CGRP and SP, was visible on GD21 in the epiphyseal perichondrium, the periosteum of the shaft and the bone marrow, on PD1 in the intercondylar eminence and the metaphyses, on PD7 in the cartilage canals, on PD10 in the secondary ossification centres and on PD14 in the epiphyseal bone marrow. The temporal and topographic pattern of nerve fibre appearance corresponds with the development of regions characterized by active mineralization and bone remodelling, suggesting a possible involvement of the sensory innervation in these processes. PMID:16050900

Massage therapy during early postnatal life promotes greater lean mass and bone growth, mineralization, and strength in juvenile and young adult rats.

PubMed

Chen, H; Miller, S; Shaw, J; Moyer-Mileur, L

2009-01-01

The objects of this study were to investigate the effects of massage therapy during early life on postnatal growth, body composition, and skeletal development in juvenile and young adult rats. Massage therapy was performed for 10 minutes daily from D6 to D10 of postnatal life in rat pups (MT, n=24). Body composition, bone area, mineral content, and bone mineral density were measured by dual energy X-ray absorptiometry (DXA); bone strength and intrinsic stiffness on femur shaft were tested by three-point bending; cortical and cancellous bone histomorphometric measurements were performed at D21 and D60. Results were compared to age- and gender-matched controls (C, n=24). D21 body weight, body length, lean mass, and bone area were significantly greater in the MT cohort. Greater bone mineral content was found in male MT rats; bone strength and intrinsic stiffness were greater in D60 MT groups. At D60 MT treatment promoted bone mineralization by increasing trabecular mineral apposition rate in male and endosteal mineral surface in females, and also improved micro-architecture by greater trabeculae width in males and decreasing trabecular separation in females. In summary, massage therapy during early life elicited immediate and prolonged anabolic effects on postnatal growth, lean mass and skeletal developmental in a gender-specific manner in juvenile and young adult rats.

Locomotor activity influences muscle architecture and bone growth but not muscle attachment site morphology.

PubMed

Rabey, Karyne N; Green, David J; Taylor, Andrea B; Begun, David R; Richmond, Brian G; McFarlin, Shannon C

2015-01-01

The ability to make behavioural inferences from skeletal remains is critical to understanding the lifestyles and activities of past human populations and extinct animals. Muscle attachment site (enthesis) morphology has long been assumed to reflect muscle strength and activity during life, but little experimental evidence exists to directly link activity patterns with muscle development and the morphology of their attachments to the skeleton. We used a mouse model to experimentally test how the level and type of activity influences forelimb muscle architecture of spinodeltoideus, acromiodeltoideus, and superficial pectoralis, bone growth rate and gross morphology of their insertion sites. Over an 11-week period, we collected data on activity levels in one control group and two experimental activity groups (running, climbing) of female wild-type mice. Our results show that both activity type and level increased bone growth rates influenced muscle architecture, including differences in potential muscular excursion (fibre length) and potential force production (physiological cross-sectional area). However, despite significant influences on muscle architecture and bone development, activity had no observable effect on enthesis morphology. These results suggest that the gross morphology of entheses is less reliable than internal bone structure for making inferences about an individual's past behaviour. Copyright © 2014 Elsevier Ltd. All rights reserved.

Locomotor activity influences muscle architecture and bone growth but not muscle attachment site morphology

PubMed Central

Rabey, Karyne N.; Green, David J.; Taylor, Andrea B.; Begun, David R.; Richmond, Brian G.; McFarlin, Shannon C.

2014-01-01

The ability to make behavioural inferences from skeletal remains is critical to understanding the lifestyles and activities of past human populations and extinct animals. Muscle attachment site (enthesis) morphology has long been assumed to reflect muscle strength and activity during life, but little experimental evidence exists to directly link activity patterns with muscle development and the morphology of their attachments to the skeleton. We used a mouse model to experimentally test how the level and type of activity influences forelimb muscle architecture of spinodeltoideus, acromiodeltoideus, and superficial pectoralis, bone growth rate and gross morphology of their insertion sites. Over an 11-week period, we collected data on activity levels in one control group and two experimental activity groups (running, climbing) of female wild-type mice. Our results show that both activity type and level increased bone growth rates influenced muscle architecture, including differences in potential muscular excursion (fibre length) and potential force production (physiological cross-sectional area). However, despite significant influences on muscle architecture and bone development, activity had no observable effect on enthesis morphology. These results suggest that the gross morphology of entheses is less reliable than internal bone structure for making inferences about an individual’s past behaviour. PMID:25467113

Preclinical and clinical studies on the use of growth factors for bone repair: a systematic review.

PubMed

Fisher, Daniel Mark; Wong, James Min-Leong; Crowley, Conor; Khan, Wasim S

2013-05-01

Bone healing is a complex process. Whilst the majority of fractures heal with conventional treatment, open fractures, large bone defects and non unions still provide great challenges to Orthopaedic Surgeons. Whilst autologous bone graft is seen as the gold standard, the use of growth factors is a growing area of research to find an effective alternative with lower side effects such as donor site morbidity and the finite amount available. This systematic review aims to summarize the pre clinical in-vivo studies and examine the clinical studies on the use of growth factors in bone healing. Databases: PubMed, Medline, OVID, and Cochrane library. The following key words and search terms were used: Growth Factors, Bone Healing, Bone Morphogenic Protein, Transforming Growth Factor Beta, Insulin Like Growth Factor, Platelet Derived Growth Factor, Fracture. All articles were screened based on title with abstracts and full text articles reviewed as appropriate. Reference lists were reviewed from relevant articles to ensure comprehensive and systematic review. Three tables of studies were constructed focussing on Bone Morphogenic Proteins, Platelet Rich Plasma and Growth Factors and Tissue Engineering. Bone Morphogenic Proteins and Platelet Rich Plasma, which contains multiple growth factors, have been shown in preclinical and clinical trials to be an effective alternative to autologous bone graft. Bone Morphogenic Proteins have been shown to be effective in fracture non union, and in open tibial fractures. Platelet Rich Plasma has shown promise in preclinical trials and some small clinical trials, however numbers are limited. Bone Morphogenic Proteins have been shown to be superior to Platelet Rich Protein in one trial. Combining these growth factors with tissue engineering techniques is the focus of ongoing research, and through further clinical trials the most effective techniques for enhancing bone healing will be revealed.

Leptin administration affects growth and skeletal development in a rat intrauterine growth restriction model: preliminary study.

PubMed

Bar-El Dadon, Shimrit; Shahar, Ron; Katalan, Vered; Monsonego-Ornan, Efrat; Reifen, Ram

2011-09-01

Skeletal abnormalities are one of the hallmarks of growth delay during gestation. The aim of this study was to determine changes induced by leptin in skeletal growth and development in a rat model of intrauterine growth retardation (IUGR) and to elucidate the possible underlying mechanisms. Intrauterine growth retardation was induced prepartum and the effects of leptin to mothers prenatally or to offspring postnatally were studied. Radii were harvested and tested mechanically and structurally. Tibias were evaluated for growth-plate morphometry. On day 40 postpartum, total bone length and mineral density and tibial growth-plate width and numbers of cells within its zones of offspring treated with leptin were significantly greater than in the control group. Postnatal leptin administration in an IUGR model improves the structural properties and elongation rate of bone. These findings could pave the way to preventing some phenotypic presentations of IUGR. Copyright © 2011 Elsevier Inc. All rights reserved.

Postnatal changes in the growth dynamics of the human face revealed from bone modelling patterns.

PubMed

Martinez-Maza, Cayetana; Rosas, Antonio; Nieto-Díaz, Manuel

2013-09-01

Human skull morphology results from complex processes that involve the coordinated growth and interaction of its skeletal components to keep a functional and structural balance. Previous histological works have studied the growth of different craniofacial regions and their relationship to functional spaces in humans up to 14 years old. Nevertheless, how the growth dynamics of the facial skeleton and the mandible are related and how this relationship changes through the late ontogeny remain poorly understood. To approach these two questions, we have compared the bone modelling activities of the craniofacial skeleton from a sample of subadult and adult humans. In this study, we have established for the first time the bone modelling pattern of the face and the mandible from adult humans. Our analyses reveal a patchy distribution of the bone modelling fields (overemphasized by the presence of surface islands with no histological information) reflecting the complex growth dynamics associated to the individual morphology. Subadult and adult specimens show important differences in the bone modelling patterns of the anterior region of the facial skeleton and the posterior region of the mandible. These differences indicate developmental changes in the growth directions of the whole craniofacial complex, from a predominantly downward growth in subadults that turns to a forward growth observed in the adult craniofacial skeleton. We hypothesize that these ontogenetic changes would respond to the physiological and physical requirements to enlarge the oral and nasal cavities once maturation of the brain and the closure of the cranial sutures have taken place during craniofacial development. © 2013 Anatomical Society.

A summary of the influence of exogenous estrogen administration across the lifespan on the GH/IGF-1 axis and implications for bone health.

PubMed

Southmayd, Emily A; De Souza, Mary Jane

2017-02-01

Bone growth, development, and remodeling are modulated by numerous circulating hormones. Throughout the lifespan, the extent to which each of the hormones impacts bone differs. Understanding the independent and combined impact of these hormones on controlling bone remodeling allows for the development of more informed decision making regarding pharmacology, specifically the use of hormonal medication, at all ages. Endocrine control of bone health in women is largely dictated by the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis and the hypothalamic-pituitary-ovarian (HPO) axis. Growth hormone, secreted from the pituitary gland, stimulates cells in almost every tissue to secrete IGF-1, although the majority of circulating IGF-1 is produced hepatically. Indeed, systemic IGF-1 concentrations have been found to be correlated with bone mineral density (BMD) in both pre- and post-menopausal women and is often used as a marker of bone formation. Sex steroids produced by the ovaries, namely estradiol, mediate bone resorption through binding to estrogen receptors on osteoclasts and osteoblasts. Specifically, by increasing osteoclast apoptosis and decreasing osteoblast apoptosis, adequate estrogen levels prevent excessive bone resorption, which helps to explain the rapid decline in bone mass that occurs with the menopausal decrease in estrogen production. Though there are documented correlations between endogenous estrogen concentrations and GH/IGF-1 dynamics, this relationship changes across the lifespan as sex-steroid dynamics fluctuate and, possibly, as tissue responsiveness to GH stimulation decreases. Aside from the known role of endogenous sex steroids on bone health, the impact of exogenous estrogen administration is of interest, as exogenous formulations further modulate GH and IGF-1 production. However, the effect and extent of GH and IGF-1 modulation seems to be largely dependent on age at administration and route of administration. Specifically, premenopausal women using combined oral contraceptive therapy (COC), post-menopausal women taking oral hormone therapy (HT), and both pre- and post-menopausal women using a transdermal form of estrogen therapy (COC or HT) demonstrate disparate GH/IGF-1 responses to exogenous estrogen. This review serves to summarize what is currently known regarding the influence of exogenous estrogen administration across the lifespan on the GH/IGF-1 axis and implications for bone health. Copyright © 2016 Elsevier Ltd. All rights reserved.

Methods and theory in bone modeling drift: comparing spatial analyses of primary bone distributions in the human humerus.

PubMed

Maggiano, Corey M; Maggiano, Isabel S; Tiesler, Vera G; Chi-Keb, Julio R; Stout, Sam D

2016-01-01

This study compares two novel methods quantifying bone shaft tissue distributions, and relates observations on human humeral growth patterns for applications in anthropological and anatomical research. Microstructural variation in compact bone occurs due to developmental and mechanically adaptive circumstances that are 'recorded' by forming bone and are important for interpretations of growth, health, physical activity, adaptation, and identity in the past and present. Those interpretations hinge on a detailed understanding of the modeling process by which bones achieve their diametric shape, diaphyseal curvature, and general position relative to other elements. Bone modeling is a complex aspect of growth, potentially causing the shaft to drift transversely through formation and resorption on opposing cortices. Unfortunately, the specifics of modeling drift are largely unknown for most skeletal elements. Moreover, bone modeling has seen little quantitative methodological development compared with secondary bone processes, such as intracortical remodeling. The techniques proposed here, starburst point-count and 45° cross-polarization hand-drawn histomorphometry, permit the statistical and populational analysis of human primary tissue distributions and provide similar results despite being suitable for different applications. This analysis of a pooled archaeological and modern skeletal sample confirms the importance of extreme asymmetry in bone modeling as a major determinant of microstructural variation in diaphyses. Specifically, humeral drift is posteromedial in the human humerus, accompanied by a significant rotational trend. In general, results encourage the usage of endocortical primary bone distributions as an indicator and summary of bone modeling drift, enabling quantitative analysis by direction and proportion in other elements and populations. © 2015 Anatomical Society.

Species-specific patterns of hyperostosis in marine teleost fishes

USGS Publications Warehouse

Smith-Vaniz, William F.; Kaufman, L.S.; Glowacki, J.

1995-01-01

The occurrence of swollen or hyperostotic bones in skeletal preparations, preserved museum material or whole fresh specimens of marine teleost fishes was identified in 92 species belonging to 22 families. Patterns of hyperostotic skeletal growth were typically consistent and often species-specific in all individuals larger than a certain size. The taxonomic distribution of hyperostosis in diverse phylogenetic groups suggests that it has arisen independently many times. Selected bones from two species of the family Carangidae, horse-eye jack Caranx latus Agassiz and crevalle jackCaranx hippos (Linnaeus), were examined in detail by light and electron microscopy. Nonhyperostotic bone contained osteoid-producing osteoblasts, resorbing osteoclasts, occasional osteocytes, and a rich vascular network, all characteristics of cellular bone. Thus, these fishes have a spatial juxtaposition of cellular and acellular bone tissues in adjacent and often serially homologous bone sites. The functional significance of hyperostosis is unknown, but it is a predictable manifestation of bone growth and development for the many taxa in which it occurs.

Circulating levels of IGF-1 directly regulate bone growth and density

PubMed Central

Yakar, Shoshana; Rosen, Clifford J.; Beamer, Wesley G.; Ackert-Bicknell, Cheryl L.; Wu, Yiping; Liu, Jun-Li; Ooi, Guck T.; Setser, Jennifer; Frystyk, Jan; Boisclair, Yves R.; LeRoith, Derek

2002-01-01

IGF-1 is a growth-promoting polypeptide that is essential for normal growth and development. In serum, the majority of the IGFs exist in a 150-kDa complex including the IGF molecule, IGF binding protein 3 (IGFBP-3), and the acid labile subunit (ALS). This complex prolongs the half-life of serum IGFs and facilitates their endocrine actions. Liver IGF-1–deficient (LID) mice and ALS knockout (ALSKO) mice exhibited relatively normal growth and development, despite having 75% and 65% reductions in serum IGF-1 levels, respectively. Double gene disrupted mice were generated by crossing LID+ALSKO mice. These mice exhibited further reductions in serum IGF-1 levels and a significant reduction in linear growth. The proximal growth plates of the tibiae of LID+ALSKO mice were smaller in total height as well as in the height of the proliferative and hypertrophic zones of chondrocytes. There was also a 10% decrease in bone mineral density and a greater than 35% decrease in periosteal circumference and cortical thickness in these mice. IGF-1 treatment for 4 weeks restored the total height of the proximal growth plate of the tibia. Thus, the double gene disruption LID+ALSKO mouse model demonstrates that a threshold concentration of circulating IGF-1 is necessary for normal bone growth and suggests that IGF-1, IGFBP-3, and ALS play a prominent role in the pathophysiology of osteoporosis. PMID:12235108

Premaxilla: an independent bone that can base therapeutics for middle third growth!

PubMed

Trevizan, Mariana; Consolaro, Alberto

2017-01-01

Premaxilla, in its early descriptions, had the participation of Goethe. In our face, in a certain period of growth and development processes, premaxilla is an independent and, then, a semi-independent bone to finally be totally integrated to the maxilla. Formation of the premaxilla acts as a stabilization element inside the facial skeleton comparable to the cornerstone of a Roman arch and is closely related to the development of human face and its abnormal growth with characteristic malformations. Until when the premaxillary-maxillary suture remains open and offers opportunities to orthopedically influence facial growth to exert influence over facial esthetics and function? Contact with preliminary results in 1183 skulls from anatomic museums at USP, Unicamp and Unifesp led us to question therapeutic perspectives and its clinical applicability.

In vivo tibial stiffness is maintained by whole bone morphology and cross-sectional geometry in growing female mice

PubMed Central

Main, Russell P.; Lynch, Maureen E.; van der Meulen, Marjolein C.H.

2010-01-01

Whole bone morphology, cortical geometry, and tissue material properties modulate skeletal stresses and strains that in turn influence skeletal physiology and remodeling. Understanding how bone stiffness, the relationship between applied load and tissue strain, is regulated by developmental changes in bone structure and tissue material properties is important in implementing biophysical strategies for promoting healthy bone growth and preventing bone loss. The goal of this study was to relate developmental patterns of in vivo whole bone stiffness to whole bone morphology, cross-sectional geometry, and tissue properties using a mouse axial loading model. We measured in vivo tibial stiffness in three age groups (6wks, 10wks, 16wks old) of female C57Bl/6 mice during cyclic tibial compression. Tibial stiffness was then related to cortical geometry, longitudinal bone curvature, and tissue mineral density using microcomputed tomography (microCT). Tibial stiffness and the stresses induced by axial compression were generally maintained from 6 to 16wks of age. Growth-related increases in cortical cross-sectional geometry and longitudinal bone curvature had counteracting effects on induced bone stresses and, therefore, maintained tibial stiffness similarly with growth. Tissue mineral density increased slightly from 6 to 16wks of age, and although the effects of this increase on tibial stiffness were not directly measured, its role in the modulation of whole bone stiffness was likely minor over the age range examined. Thus, whole bone morphology, as characterized by longitudinal curvature, along with cortical geometry, plays an important role in modulating bone stiffness during development and should be considered when evaluating and designing in vivo loading studies and biophysical skeletal therapies. PMID:20673665

Bioactive Nano-Fibrous Scaffolds for Bone and Cartilage Tissue Engineering

NASA Astrophysics Data System (ADS)

Feng, Kai

Scaffolds that can mimic the structural features of natural extracellular matrix and can deliver biomolecules in a controlled fashion may provide cells with a favorable microenvironment to facilitate tissue regeneration. Biodegradable nanofibrous scaffolds with interconnected pore network have previously been developed in our laboratory to mimic collagen matrix and advantageously support both bone and cartilage regeneration. This dissertation project aims to expand both the structural complexity and the biomolecule delivery capacity of such biomimetic scaffolds for tissue engineering. We first developed a nanofibrous scaffold that can release an antibiotic (doxycycline) with a tunable release rate and a tunable dosage, which was demonstrated to be able to inhibit bacterial growth over a prolonged time period. We then developed a nanofibrous tissue-engineciing scaffold that can release basic fibroblast growth factor (bFGF) in a spatially and temporally controlled fashion. In a mouse subcutaneous implantation model, the bFGF-releasing scaffold was shown to enhance cell penetration, tissue ingrowth and angiogenesis. It was also found that both the dose and the release rate of bFGF play roles in the biologic function of the scaffold. After that, we developed a nanofibrous PLLA scaffold that can release both bone morphogenetic protein 7 (BMP-7) and platelet-derived growth factor (PDGF) with distinct dosages and release kinetics. It was demonstrated that BMP-7 and PDGF could synergistically enhance bone regeneration using a mouse ectopic bone formation model and a rat periodontal fenestration defect regeneration model. The regeneration outcome was dependent on the dosage, the ratio and the release kinetics of the two growth factors. Last, we developed an anisotropic composite scaffold with an upper layer mimicking the superficial zone of cartilage and a lower layer mimicking the middle zone of cartilage. The thin superficial layer was fabricated using an electrospinning technique to support a more parallel ECM orientation to the cartilage surface. The lower layer was fabricated using a phase-separation technique to support a more isotropic ECM distribution. Human bone marrow-derived mesenchymal stem cells (hMSCs) were seeded on this complex scaffold and cultured under chondrogenic conditions. The results showed that the composite scaffold was indeed able to support anisotropic cartilage tissue structure formation.

Childhood growth predicts higher bone mass and greater bone area in early old age: findings among a subgroup of women from the Helsinki Birth Cohort Study.

PubMed

Mikkola, T M; von Bonsdorff, M B; Osmond, C; Salonen, M K; Kajantie, E; Cooper, C; Välimäki, M J; Eriksson, J G

2017-09-01

We examined the associations between childhood growth and bone properties among women at early old age. Early growth in height predicted greater bone area and higher bone mineral mass. However, information on growth did not improve prediction of bone properties beyond that predicted by body size at early old age. We examined the associations between body size at birth and childhood growth with bone area, bone mineral content (BMC), and areal bone mineral density (aBMD) in early old age. A subgroup of women (n = 178, mean 60.4 years) from the Helsinki Birth Cohort Study, born 1934-1944, participated in dual-energy X-ray absorptiometry (DXA) measurements of the lumbar spine and hip. Height and weight at 0, 2, 7, and 11 years, obtained from health care records, were reconstructed into conditional variables representing growth velocity independent of earlier growth. Weight was adjusted for corresponding height. Linear regression models were adjusted for multiple confounders. Birth length and growth in height before 7 years of age were positively associated with femoral neck area (p < 0.05) and growth in height at all age periods studied with spine bone area (p < 0.01). Growth in height before the age of 7 years was associated with BMC in the femoral neck (p < 0.01) and birth length and growth in height before the age of 7 years were associated with BMC in the spine (p < 0.05). After entering adult height into the models, nearly all associations disappeared. Weight gain during childhood was not associated with bone area or BMC, and aBMD was not associated with early growth. Optimal growth in height in girls is important for obtaining larger skeleton and consequently higher bone mass. However, when predicting bone mineral mass among elderly women, information on early growth does not improve prediction beyond that predicted by current height and weight.

Distinct growth of the nasomaxillary complex in Au. sediba.

PubMed

Lacruz, Rodrigo S; Bromage, Timothy G; O'Higgins, Paul; Toro-Ibacache, Viviana; Warshaw, Johanna; Berger, Lee R

2015-10-15

Studies of facial ontogeny in immature hominins have contributed significantly to understanding the evolution of human growth and development. The recently discovered hominin species Autralopithecus sediba is represented by a well-preserved and nearly complete facial skeleton of a juvenile (MH1) which shows a derived facial anatomy. We examined MH1 using high radiation synchrotron to interpret features of the oronasal complex pertinent to facial growth. We also analyzed bone surface microanatomy to identify and map fields of bone deposition and bone resorption, which affect the development of the facial skeleton. The oronasal anatomy (premaxilla-palate-vomer architecture) is similar to other Australopithecus species. However surface growth remodeling of the midface (nasomaxillary complex) differs markedly from Australopithecus, Paranthropus, early Homo and from KNM-WT 15000 (H. erectus/ergaster) showing a distinct distribution of vertically disposed alternating depository and resorptive fields in relation to anterior dental roots and the subnasal region. The ontogeny of the MH1 midface superficially resembles some H. sapiens in the distribution of remodeling fields. The facial growth of MH1 appears unique among early hominins representing an evolutionary modification in facial ontogeny at 1.9 my, or to changes in masticatory system loading associated with diet.

Osteoporosis in Children with Chronic Disease.

PubMed

Högler, Wolfgang; Ward, Leanne

2015-01-01

Serious illness in children and its therapy can cause osteoporosis, manifesting as vertebral and nonvertebral fractures, pain, skeletal deformity and temporary or even permanent loss of ambulation. In contrast to adults, skeletal growth in children offers tremendous potential to recover bone mineral density and to reshape fractured vertebral bodies, even without bone-targeted therapy, provided that bone health threats are transient and residual growth is sufficient. Here, we outline the principles of bone strength development and the risk factors for osteoporosis due to various paediatric systemic illnesses. We also explain why the approach to the diagnosis and monitoring of childhood osteoporosis has moved away from a bone density-centric focus to a more functional assessment. Finally, we discuss the best candidates for and current approaches to the treatment of osteoporosis in children. © 2015 S. Karger AG, Basel.

The role of embryo movement in the development of the furcula.

PubMed

Pollard, A S; Boyd, S; McGonnell, I M; Pitsillides, A A

2017-03-01

The pectoral girdle is a complex structure which varies in its morphology between species. A major component in birds is the furcula, which can be considered equivalent to a fusion of the paired clavicles found in many mammals, and the single interclavicle found in many reptiles. These elements are a remnant of the dermal skeleton and the only intramembranous bones in the trunk. Postnatally, the furcula plays important mechanical roles by stabilising the shoulder joint and acting as a mechanical spring during flight. In line with its mechanical role, previous studies indicate that, unlike many other intramembranous bones, furcula growth during development can be influenced by mechanical stimuli. This study investigated the response of individual aspects of furcula growth to both embryo immobilisation and hypermotility in the embryonic chicken. The impact of altered incubation temperature, which influences embryo motility, on crocodilian interclavicle development was also explored. We employed whole-mount bone and cartilage staining and 3D imaging by microCT to quantify the impact of rigid paralysis, flaccid paralysis and hypermobility on furcula growth in the chicken, and 3D microCT imaging to quantify the impact of reduced temperature (32-28 °C) and motility on interclavicle growth in the crocodile. This revealed that the growth rates of the clavicular and interclavicular components of the furcula differ during normal development. Total furcula area was reduced by total unloading produced by flaccid paralysis, but not by rigid paralysis which maintains static loading of embryonic bones. This suggests that dynamic loading, which is required for postnatal bone adaptation, is not a requirement for prenatal furcula growth. Embryo hypermotility also had no impact on furcula area or arm length. Furcula 3D shape did, however, differ between groups; this was marked in the interclavicular component of the furcula, the hypocleideum. Hypocleideum length was reduced by both methods of immobilisation, and interclavicle area was reduced in crocodile embryos incubated at 28 °C, which are less motile than embryos incubated at 32 °C. These data suggest that the clavicular and interclavicle components of the avian furcula respond differently to alterations in embryo movement, with the interclavicle requiring both the static and dynamic components of movement-related loading for normal growth, while static loading preserved most aspects of clavicle growth. Our data suggest that embryo movement, and the mechanical loading this produces, is important in shaping these structures during development to suit their postnatal mechanical roles. © 2016 Anatomical Society.

FOXL2 modulates cartilage, skeletal development and IGF1-dependent growth in mice.

PubMed

Marongiu, Mara; Marcia, Loredana; Pelosi, Emanuele; Lovicu, Mario; Deiana, Manila; Zhang, Yonqing; Puddu, Alessandro; Loi, Angela; Uda, Manuela; Forabosco, Antonino; Schlessinger, David; Crisponi, Laura

2015-07-02

Haploinsufficiency of the FOXL2 transcription factor in humans causes Blepharophimosis/Ptosis/Epicanthus Inversus syndrome (BPES), characterized by eyelid anomalies and premature ovarian failure. Mice lacking Foxl2 recapitulate human eyelid/forehead defects and undergo female gonadal dysgenesis. We report here that mice lacking Foxl2 also show defects in postnatal growth and embryonic bone and cartilage formation. Foxl2 (-/-) male mice at different stages of development have been characterized and compared to wild type. Body length and weight were measured and growth curves were created. Skeletons were stained with alcian blue and/or alizarin red. Bone and cartilage formation was analyzed by Von Kossa staining and immunofluorescence using anti-FOXL2 and anti-SOX9 antibodies followed by confocal microscopy. Genes differentially expressed in skull vaults were evaluated by microarray analysis. Analysis of the GH/IGF1 pathway was done evaluating the expression of several hypothalamic-pituitary-bone axis markers by RT-qPCR. Compared to wild-type, Foxl2 null mice are smaller and show skeletal abnormalities and defects in cartilage and bone mineralization, with down-regulation of the GH/IGF1 axis. Consistent with these effects, we find FOXL2 expressed in embryos at 9.5 dpc in neural tube epithelium, in head mesenchyme near the neural tube, and within the first branchial arch; then, starting at 12.5 dpc, expressed in cartilaginous tissue; and at PO and P7, in hypothalamus. Our results support FOXL2 as a master transcription factor in a spectrum of developmental processes, including growth, cartilage and bone formation. Its action overlaps that of SOX9, though they are antagonistic in female vs male gonadal sex determination but conjoint in cartilage and skeletal development.

[Issues related to secondary osteoporosis associated with growth hormone deficiency in adulthood].

PubMed

Kužma, Martin; Jackuliak, Peter; Killinger, Zdenko; Vaňuga, Peter; Payer, Juraj

Growth hormone (GH) increases linear bone growth through complex hormonal reactions, mainly mediated by insulin like growth factor 1 (IGF1) that is produced mostly by hepatocytes under influence of GH and stimulates differentiation of epiphyseal prechondrocytes. IGF1 and GH play a key role in the linear bone growth after birth and regulation of bone remodelation during the entire lifespan. It is known that adult GH deficient (GHD) patients have decreased BMD and increased risk of low-impact fractures. Most data gathered thus far on the effect of GH replacement on bone status comprise the measurement of quantitative changes of bone mass. Some animal studies with GHD showed that the bone microarchitecture, measured using computed tomography methods, is significantly compromised and improve after GH replacement. However, human studies did not show significantly decreased bone microarchitecture, but limited methodological quality does not allow firm conclusions on this subject.Key words: bone mass - bone quality - fracture - growth hormone - IGF1.

Nanotechnology controlled drug delivery for treating bone diseases.

PubMed

Yang, Lei; Webster, Thomas J

2009-08-01

Rapid developments at the intersection of nanotechnology and controlled drug delivery have triggered exceptional growth in treating various bone diseases. As a result, over the past decade, nanotechnology has contributed tremendously to controlling drug delivery for treating various bone diseases, and in many cases, has led to increased bone regeneration. In this review paper, the recent experimental progress towards using nanotechnology to treat bone-specific diseases is reviewed. Novel applications of different types of nanomaterials (from nanoparticles to 3D nanostructured scaffolds) for treating bone diseases are summarized. In addition, fundamental principles for utilizing nanomaterials to create better drug delivery systems, especially for treating bone diseases and regenerating bone, are emphasized.

[CAS in rhino-surgical procedures in the growing age].

PubMed

Schipper, J; Maier, W; Gellrich, N-C; Arapakis, I; Hochmuth, A; Laszig, R

2005-01-01

Rhinosurgery in children and adolescents meets special requirements: Limited cooperation and reduced limits for the organ dose for ionizing radiological examinations aggravate diagnostics. On the other side, bone sutures and bone growth areas have to be respected intraoperatively, and regions of bones not yet calcified have to be distinguished from possible tumor infiltration. Computer assisted surgery (CAS) can help to identify these areas safely. 5 patients, from the first to the 20 (th) year of life, suffering from tumors, malformation syndromes or therapy resistant nasal polyposis were treated with CAS in rhinosurgery. In addition to radiological diagnostics, we performed 3D computed tomography of the skull for CAS. CAS enabled us to intraoperatively respect possible areas of bone growth, to identify regions with thin, not bonily developed cranial vault and to safely distinguish bone sutures from ethmoidal cells. CAS helped the surgeon to navigate in the not yet developed paranasal sinus system. CAS is a useful complementary method in rhinosurgery of the developing skull of the child. In spite of the additional 3D computed tomography, the calculated organ dose of the ocular lense amounted to 5 millisievert, so a recommended maximal organ dose for the ocular lense of 15 millisievert was not exceeded.

An Essential Physiological Role for MCT8 in Bone in Male Mice

PubMed Central

Leitch, Victoria D.; Di Cosmo, Caterina; Liao, Xiao-Hui; O’Boy, Sam; Galliford, Thomas M.; Evans, Holly; Croucher, Peter I.; Boyde, Alan; Dumitrescu, Alexandra; Weiss, Roy E.; Refetoff, Samuel; Williams, Graham R.

2017-01-01

T3 is an important regulator of skeletal development and adult bone maintenance. Thyroid hormone action requires efficient transport of T4 and T3 into target cells. We hypothesized that monocarboxylate transporter (MCT) 8, encoded by Mct8 on the X-chromosome, is an essential thyroid hormone transporter in bone. To test this hypothesis, we determined the juvenile and adult skeletal phenotypes of male Mct8 knockout mice (Mct8KO) and Mct8D1D2KO compound mutants, which additionally lack the ability to convert the prohormone T4 to the active hormone T3. Prenatal skeletal development was normal in both Mct8KO and Mct8D1D2KO mice, whereas postnatal endochondral ossification and linear growth were delayed in both Mct8KO and Mct8D1D2KO mice. Furthermore, bone mass and mineralization were decreased in adult Mct8KO and Mct8D1D2KO mice, and compound mutants also had reduced bone strength. Delayed bone development and maturation in Mct8KO and Mct8D1D2KO mice is consistent with decreased thyroid hormone action in growth plate chondrocytes despite elevated serum T3 concentrations, whereas low bone mass and osteoporosis reflects increased thyroid hormone action in adult bone due to elevated systemic T3 levels. These studies identify an essential physiological requirement for MCT8 in chondrocytes, and demonstrate a role for additional transporters in other skeletal cells during adult bone maintenance. PMID:28637283

Ectopic bone formation and chondrodysplasia in transgenic mice carrying the rat C3(1)/T{sub AG} fusion gene

DOE Office of Scientific and Technical Information (OSTI.GOV)

Green, J.E.; Maroulakou, I.G.; Anver, M.

Transgenic mice expressing the SV40 large T-antigen (T{sup AG}) under the regultory control of the hormone-responsive rat C3(1) prostatein promoter develop unusual bone and cartilage lesions, as well as ectopic bone and cartilage formation. Two lines of transgenic animals have been propagated in which the expression of the transgene in chondrocytes results in a mild to moderate generalized disorganization of cartilage growth which appears to affect multiple tissues, including the trachea, ear pinna and articular cartilage. The epiphyseal plates are also affected with normal architecture of the zones of proliferation and maturation, but marked elongation of the zone of hypertrophy.more » Immunocytochemistry demonstrates that expression of T{sup AG} is limited to the zone of hypertropny in the epiphyseal plates, suggesting that the chondrocytes become hormone-responsive at this particular stage of differentiation. Normal mineralization and trabecular formation in long bone appears to occur. Ectopic bone and cartilage formation occurs in the foot pads of the fore- and hind- feet over the course of several months. This is preceded by proliferation of sweat gland epithelial cells followed by the appearance of nodules of cartilage and bone. The nodules are closely associated with proliferating epithelium but are not contiguous with bony structures normally found in the feet. The roles of BMP`s, growth factors, oncogenes and hormones in the development of these lesions will be presented. These transgenic animals may provide new insights into hormone-responsiveness of chondrocytes, as well as factors involved in the processes of bone and cartilage differentiation and growth. These transgenic animals may serve as a useful model for human heterotopic bone formation.« less

Prevalence of Prostate Cancer Metastases after Intravenous Inoculation Provides Clues into the Molecular Basis of Dormancy in the Bone Marrow Microenvironment1

PubMed Central

Jung, Younghun; Shiozawa, Yusuke; Wang, Jingcheng; McGregor, Natalie; Dai, Jinlu; Park, Serk In; Berry, Janice E; Havens, Aaron M; Joseph, Jeena; Kim, Jin Koo; Patel, Lalit; Carmeliet, Peter; Daignault, Stephanie; Keller, Evan T; McCauley, Laurie K; Pienta, Kenneth J; Taichman, Russell S

2012-01-01

Bone is the preferred metastasis site of advanced prostate cancer (PCa). Using an in vivo murine model of human PCa cell metastasis to bone, we noted that the majority of animals that develop skeletal metastasis have either spinal lesions or lesions in the bones of the hindlimb. Much less frequently, lesions develop in the bones of the forelimb. We therefore speculated whether the environment of the forelimb bones is not permissive for the growth of PCa. Consequently, data on tumor prevalence were normalized to account for the number of PCa cells arriving after intravascular injection, marrow cellularity, and number of hematopoietic stem cell niches. None of these factors were able to account for the observed differences in tumor prevalence. An analysis of differential gene and protein levels identified that growth arrest specific-6 (GAS6) levels were significantly greater in the forelimb versus hindlimb bone marrow. When murine RM1 cells were implanted into subcutaneous spaces in immune competent animals, tumor growth in the GAS6-/- animals was greater than in GAS6+/+ wild-type animals. In an osseous environment, the human PC3 cell line grew significantly better in vertebral body transplants (vossicles) derived from GAS6-/- animals than in vossicles derived from GAS6+/+ animals. Together, these data suggest that the differences in tumor prevalence after intravascular inoculation are a useful model to study the molecular basis of tumor dormancy. Importantly, these data suggest that therapeutic manipulation of GAS6 levels may prove useful as a therapy for metastatic disease. PMID:22745589

Differential Actions of the Endocytic Collagen Receptor uPARAP/Endo180 and the Collagenase MMP-2 in Bone Homeostasis

PubMed Central

Madsen, Daniel H.; Jürgensen, Henrik J.; Ingvarsen, Signe; Melander, Maria C.; Albrechtsen, Reidar; Hald, Andreas; Holmbeck, Kenn; Bugge, Thomas H.; Behrendt, Niels; Engelholm, Lars H.

2013-01-01

A well-coordinated remodeling of uncalcified collagen matrices is a pre-requisite for bone development and homeostasis. Collagen turnover proceeds through different pathways, either involving extracellular reactions exclusively, or being dependent on endocytic processes. Extracellular collagen degradation requires the action of secreted or membrane attached collagenolytic proteases, whereas the alternative collagen degradation pathway proceeds intracellularly after receptor-mediated uptake and delivery to the lysosomes. In this study we have examined the functional interplay between the extracellular collagenase, MMP-2, and the endocytic collagen receptor, uPARAP, by generating mice with combined deficiency of both components. In both uPARAP-deficient and MMP-2-deficient adult mice the length of the tibia and femur was decreased, along with a reduced bone mineral density and trabecular bone quality. An additional decrease in bone length was observed when combining the two deficiencies, pointing to both components being important for the remodeling processes in long bone growth. In agreement with results found by others, a different effect of MMP-2 deficiency was observed in the distinct bone structures of the calvaria. These membranous bones were found to be thickened in MMP-2-deficient mice, an effect likely to be related to an accompanying defect in the canalicular system. Surprisingly, both of the latter defects in MMP-2-deficient mice were counteracted by concurrent uPARAP deficiency, demonstrating that the collagen receptor does not support the same matrix remodeling processes as the MMP in the growth of the skull. We conclude that both uPARAP and MMP-2 take part in matrix turnover processes important for bone growth. However, in some physiological situations, these two components do not support the same step in the growth process. PMID:23940733

Increased longitudinal growth in rats on a silicon-depleted diet☆

PubMed Central

Jugdaohsingh, Ravin; Calomme, Mario R.; Robinson, Karen; Nielsen, Forrest; Anderson, Simon H.C.; D'Haese, Patrick; Geusens, Piet; Loveridge, Nigel; Thompson, Richard P.H.; Powell, Jonathan J.

2008-01-01

Silicon-deficiency studies in growing animals in the early 1970s reported stunted growth and profound defects in bone and other connective tissues. However, more recent attempts to replicate these findings have found mild alterations in bone metabolism without any adverse health effects. Thus the biological role of silicon remains unknown. Using a specifically formulated silicon-depleted diet and modern methods for silicon analysis and assessment of skeletal development, we undertook, through international collaboration between silicon researchers, an extensive study of long-term silicon depletion on skeletal development in an animal. 21-day old female Sprague–Dawley rats (n = 20) were fed a silicon-depleted diet (3.2 µg Si/g feed) for 26 weeks and their growth and skeletal development were compared with identical rats (n = 10) on the same diet but with silicon added as Si(OH)4 to their drinking water (53.2 µg Si/g water); total silicon intakes were 24 times different. A third group of rats, receiving a standard rodent stock feed (322 µg Si/g feed) and tap water (5 µg Si/g water), served as a reference group for optimal growth. A series of anthropometric and bone quality measures were undertaken during and following the study. Fasting serum silicon concentrations and especially urinary silicon excretion were significantly lower in the silicon-deprived group compared to the supplemented group (P = 0.03 and 0.004, respectively). Tibia and soft-tissue silicon contents did not differ between the two groups, but tibia silicon levels were significantly lower compared to the reference group (P < 0.0001). Outward adverse health effects were not observed in the silicon-deprived group. However, body lengths from week 18 onwards (P < 0.05) and bone lengths at necropsy (P ≤ 0.002) were longer in this group. Moreover, these measures correlated inversely with serum silicon concentrations (P ≤ 0.02). A reduction in bone growth plate thickness and an apparent increase in chondrocyte density were also observed in the silicon-deprived animals. No other differences were observed between the two groups, except for tibia phosphorus concentrations, which were lower in the silicon-deprived animals (P = 0.0003). Thus in this study we were unable to reproduce the profound deficiency state reported in rats and chicks in the early 1970s. Indeed, although silicon intake and circulating fasting serum levels differed between the silicon-deprived and silicon-supplemented animals, tibia and soft-tissue levels did not and may explain the lack of difference in bone quality and bone markers (except serum CTx) between these two groups. Markedly higher tibia silicon levels in the reference group and nutritional differences between the formulated low-Si and reference diets suggest that one or more co-factors may be absent from the low-Si diet that affect silicon incorporation into bone. However, evidence for urinary silicon conservation (to maintain tissue levels), changes in bone/body lengths, bone calcium:phosphorus ratio and differences at the growth plate with silicon deprivation are all novel and deserve further study. These results suggest that rats actively maintain body silicon levels via urinary conservation, but the low circulating serum silicon levels during silicon deficiency result in inhibition of growth plate closure and increased longitudinal growth. Silicon-responsive genes and Si transporters are being investigated in the kidneys of these rats. PMID:18550464

[Dental alveolar bone and dental arch remodeling in children: orthodontic diagnosis and treatments based on individual child arch development].

PubMed

Xiaobing, Li

2016-12-01

The etiology of malocclusions basically involves both congenital and environmental factors. Malocclusion is the result of the abnormal development of the orofacial complex (including tooth, dental alveolar bone, upper and lower jaws). Early orthodontic interceptive treatments involve the elimination of all congenital and environmental factors that contribute to the malformation of the orofacial complex, as well as interrupt the deviated development of the orofacial complex and the occlusion. Early orthodontic interceptive treatments mainly aim to use children's growth potential to correct abnormal developments of occlusions and orthodontically treat malocclusions more efficiently. The early orthodontic interceptive treatments include correcting the child's bad oral habits, training the abnormal functioned para-oral muscles, maintaining the normal eruptions of succeeding permanent teeth, applying interceptive treatments to the mal-developed teeth, and employing functional orthopedic treatments for abnormal growths of the upper and lower jaws. In orthodontics, correcting mal-positioned teeth is called orthodontic treatment, while rectifying the abnormal relationships of the upper and lower jaws is called functional orthopedic treatment. However, no clear definition is available as regards to the early orthodontic interceptive treatment of malocclusions caused by the deviated development of the dental alveolar bone. This new theory of "early dental alveolar bone and dental arch remodeling technique" was proposed by Professor Li Xiaobing of the Department of Pediatric Dentistry, Faculty of Pediatric Dentistry and Orthodontics in West China Hospital of Stomatology through his clinical analyses and investigation of his early orthodontic interceptive treatments. He defined the early orthodontic corrections of abnormal growth of dental alveolar bone as "remodel". The "early dental alveolar bone and dental arch remodeling theory and technique" is proved useful in malocclusion diagnosis and treatment planning during early orthodontic interceptive treatment with malformed dental arch. With the development of the theory and technique, the author intended to prevent and intercept the malocclusion development more effectively and efficiently. This review presents the development and clinical usages of the theory which to provide a new vision in the analysis of malocclusions on the basis of the developmental mechanism of the alveolar bone and dental arch. With clinical case illustration, the author demonstrateshis successful orthodontic clinical practices with this theory, which may contribute to the development of contemporary orthodontic theories and techniques.

Platelet-Rich Plasma in Bone Regeneration: Engineering the Delivery for Improved Clinical Efficacy

PubMed Central

Rodriguez, Isaac A.; Growney Kalaf, Emily A.; Bowlin, Gary L.; Sell, Scott A.

2014-01-01

Human bone is a tissue with a fairly remarkable inherent capacity for regeneration; however, this regenerative capacity has its limitations, and defects larger than a critical size lack the ability to spontaneously heal. As such, the development and clinical translation of effective bone regeneration modalities are paramount. One regenerative medicine approach that is beginning to gain momentum in the clinical setting is the use of platelet-rich plasma (PRP). PRP therapy is essentially a method for concentrating platelets and their intrinsic growth factors to stimulate and accelerate a healing response. While PRP has shown some efficacy in both in vitro and in vivo scenarios, to date its use and delivery have not been optimized for bone regeneration. Issues remain with the effective delivery of the platelet-derived growth factors to a localized site of injury, the activation and temporal release of the growth factors, and the rate of growth factor clearance. This review will briefly describe the physiological principles behind PRP use and then discuss how engineering its method of delivery may ultimately impact its ability to successfully translate to widespread clinical use. PMID:25050347

Fibroblast growth factor signaling in skeletal development and disease

PubMed Central

Ornitz, David M.; Marie, Pierre J.

2015-01-01

Fibroblast growth factor (FGF) signaling pathways are essential regulators of vertebrate skeletal development. FGF signaling regulates development of the limb bud and formation of the mesenchymal condensation and has key roles in regulating chondrogenesis, osteogenesis, and bone and mineral homeostasis. This review updates our review on FGFs in skeletal development published in Genes & Development in 2002, examines progress made on understanding the functions of the FGF signaling pathway during critical stages of skeletogenesis, and explores the mechanisms by which mutations in FGF signaling molecules cause skeletal malformations in humans. Links between FGF signaling pathways and other interacting pathways that are critical for skeletal development and could be exploited to treat genetic diseases and repair bone are also explored. PMID:26220993

Role of hepatocyte growth factor in the development of dendritic cells from CD34+ bone marrow cells.

PubMed

Ovali, E; Ratip, S; Kibaroglu, A; Tekelioglu, Y; Cetiner, M; Karti, S; Aydin, F; Bayik, M; Akoglu, T

2000-05-01

Hepatocyte growth factor (HGF) is known to augment the effects of stem cell factor, interleukin-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), erythropoetin, and granulocyte colony-stimulating factor, all of which are involved in hematopoiesis. HGF is also known to have a role in immune responses. The aim of this study was to investigate whether HGF is involved in the development of dendritic cells (DC) from CD34+ bone marrow cells. CD34+ cells obtained from three healthy donors were incubated in various combinations of HGF, GM-CSF, and tumor necrosis factor (TNF) for 12 days. Developing cell populations were analyzed for surface markers, morphology and functional capacities by flow cytometry, light microscopy and mixed lymphocyte reaction, respectively. Incubation with HGF alone generated greater number of dendritic cells from CD34+ bone marrow cells than incubation with GM-CSF, or a combination of GM-CSF with TNF. HGF was also found to potentiate the effect of GM-CSF on DC and monocyte development. The effects of HGF were inhibited by the concurrent use of TNF. HGF appears to be a significant factor in the development of dendritic cells from CD34+ bone marrow cells.

In vivo dynamic compression has less detrimental effect than static compression on newly formed bone of a rat caudal vertebra

PubMed Central

Benoit, A.; Mustafy, T.; Londono, I.; Grimard, G.; Aubin, C-E.; Villemure, I.

2016-01-01

Fusionless devices are currently designed to treat spinal deformities such as scoliosis by the application of a controlled mechanical loading. Growth modulation by dynamic compression was shown to preserve soft tissues. The objective of this in vivo study was to characterize the effect of static vs. dynamic loading on the bone formed during growth modulation. Controlled compression was applied during 15 days on the 7th caudal vertebra (Cd7) of rats during growth spurt. The load was sustained in the “static” group and sinusoidally oscillating in the “dynamic” group. The effect of surgery and of the device was investigated using control and sham (operated on but no load applied) groups. A high resolution CT-scan of Cd7 was acquired at days 2, 8 and 15 of compression. Growth rates, histomorphometric parameters and mineral density of the newly formed bone were quantified and compared. Static and dynamic loadings significantly reduced the growth rate by 20% compared to the sham group. Dynamic loading preserved newly formed bone histomorphometry and mineral density whereas static loading induced thicker (+31%) and more mineralized (+12%) trabeculae. A significant sham effect was observed. Growth modulation by dynamic compression constitutes a promising way to develop new treatment for skeletal deformities. PMID:27609036

Hindlimb unloading of growing rats: a model for predicting skeletal changes during space flight.

PubMed

Morey-Holton, E R; Globus, R K

1998-05-01

A model that uses hindlimb unloading of rats was developed to study the consequences of skeletal unloading and reloading as occurs during and following space flight. Studies using the model were initiated two decades ago and further developed at National Aeronautics and Space Administration (NASA)-Ames Research Center. The model mimics some aspects of exposure to microgravity by removing weightbearing loads from the hindquarters and producing a cephalic fluid shift. Unlike space flight, the forelimbs remain loaded in the model, providing a useful internal control to distinguish between the local and systemic effects of hindlimb unloading. Rats that are hindlimb unloaded by tail traction gain weight at the same rate as pairfed controls, and glucocorticoid levels are not different from controls, suggesting that systemic stress is minimal. Unloaded bones display reductions in cancellous osteoblast number, cancellous mineral apposition rate, trabecular bone volume, cortical periosteal mineralization rate, total bone mass, calcium content, and maturation of bone mineral relative to controls. Subsequent studies reveal that these changes also occur in rats exposed to space flight. In hindlimb unloaded rats, bone formation rates and masses of unloaded bones decline relative to controls, while loaded bones do not change despite a transient reduction in serum 1,25-dihydroxyvitamin D (1,25D) concentrations. Studies using the model to evaluate potential countermeasures show that 1,25D, growth hormone, dietary calcium, alendronate, and muscle stimulation modify, but do not completely correct, the suppression of bone growth caused by unloading, whereas continuous infusion of transforming growth factor-beta2 or insulin-like growth factor-1 appears to protect against some of the bone changes caused by unloading. These results emphasize the importance of local as opposed to systemic factors in the skeletal response to unloading, and reveal the pivotal role that osteoblasts play in the response to gravitational loading. The hindlimb unloading model provides a unique opportunity to evaluate in detail the physiological and cellular mechanisms of the skeletal response to weightbearing loads, and has proven to be an effective model for space flight.

Hindlimb unloading of growing rats: a model for predicting skeletal changes during space flight

NASA Technical Reports Server (NTRS)

Morey-Holton, E. R.; Globus, R. K.

1998-01-01

A model that uses hindlimb unloading of rats was developed to study the consequences of skeletal unloading and reloading as occurs during and following space flight. Studies using the model were initiated two decades ago and further developed at National Aeronautics and Space Administration (NASA)-Ames Research Center. The model mimics some aspects of exposure to microgravity by removing weightbearing loads from the hindquarters and producing a cephalic fluid shift. Unlike space flight, the forelimbs remain loaded in the model, providing a useful internal control to distinguish between the local and systemic effects of hindlimb unloading. Rats that are hindlimb unloaded by tail traction gain weight at the same rate as pairfed controls, and glucocorticoid levels are not different from controls, suggesting that systemic stress is minimal. Unloaded bones display reductions in cancellous osteoblast number, cancellous mineral apposition rate, trabecular bone volume, cortical periosteal mineralization rate, total bone mass, calcium content, and maturation of bone mineral relative to controls. Subsequent studies reveal that these changes also occur in rats exposed to space flight. In hindlimb unloaded rats, bone formation rates and masses of unloaded bones decline relative to controls, while loaded bones do not change despite a transient reduction in serum 1,25-dihydroxyvitamin D (1,25D) concentrations. Studies using the model to evaluate potential countermeasures show that 1,25D, growth hormone, dietary calcium, alendronate, and muscle stimulation modify, but do not completely correct, the suppression of bone growth caused by unloading, whereas continuous infusion of transforming growth factor-beta2 or insulin-like growth factor-1 appears to protect against some of the bone changes caused by unloading. These results emphasize the importance of local as opposed to systemic factors in the skeletal response to unloading, and reveal the pivotal role that osteoblasts play in the response to gravitational loading. The hindlimb unloading model provides a unique opportunity to evaluate in detail the physiological and cellular mechanisms of the skeletal response to weightbearing loads, and has proven to be an effective model for space flight.

8-Nitro-cGMP promotes bone growth through expansion of growth plate cartilage.

PubMed

Hoshino, Marie; Kaneko, Kotaro; Miyamoto, Yoichi; Yoshimura, Kentaro; Suzuki, Dai; Akaike, Takaaki; Sawa, Tomohiro; Ida, Tomoaki; Fujii, Shigemoto; Ihara, Hideshi; Tanaka, Junichi; Tsukuura, Risa; Chikazu, Daichi; Mishima, Kenji; Baba, Kazuyoshi; Kamijo, Ryutaro

2017-09-01

In endochondral ossification, growth of bones occurs at their growth plate cartilage. While it is known that nitric oxide (NO) synthases are required for proliferation of chondrocytes in growth plate cartilage and growth of bones, the precise mechanism by which NO facilitates these process has not been clarified yet. C-type natriuretic peptide (CNP) also positively regulate elongation of bones through expansion of the growth plate cartilage. Both NO and CNP are known to use cGMP as the second messenger. Recently, 8-nitro-cGMP was identified as a signaling molecule produced in the presence of NO in various types of cells. Here, we found that 8-nitro-cGMP is produced in proliferating chondrocytes in the growth plates, which was enhanced by CNP, in bones cultured ex vivo. In addition, 8-nitro-cGMP promoted bone growth with expansion of the proliferating zone as well as increase in the number of proliferating cells in the growth plates. 8-Nitro-cGMP also promoted the proliferation of chondrocytes in vitro. On the other hand, 8-bromo-cGMP enhanced the growth of bones with expansion of hypertrophic zone of the growth plates without affecting either the width of proliferating zone or proliferation of chondrocytes. These results indicate that 8-nitro-cGMP formed in growth plate cartilage accelerates chondrocyte proliferation and bone growth as a downstream molecule of NO. Copyright © 2017. Published by Elsevier Inc.

Cytokines and growth factors which regulate bone cell function

NASA Astrophysics Data System (ADS)

Seino, Yoshiki

Everybody knows that growth factors are most important in making bone. Hormones enhance bone formation from a long distance. Growth factors promote bone formation as an autocrine or paracrine factor in nearby bone. BMP-2 through BMP-8 are in the TGF-β family. BMP makes bone by enchondral ossification. In bone, IGF-II is most abundant, second, TGF-β, and third IGF-I. TGF-β enhances bone formation mainly by intramembranous ossification in vivo. TGF-β affects both cell proliferation and differentiation, however, TGF-β mainly enhances bone formation by intramembranous ossification. Interestingly, TGF-β is increased by estrogen(E 2), androgen, vitamin D, TGF-β and FGF. IGF-I and IGF-II also enhance bone formation. At present it remains unclear why IGF-I is more active in bone formation than IGF-II, although IGF-II is more abundant in bone compared to IGF-I. However, if only type I receptor signal transduction promotes bone formation, the strong activity of IGF-I in bone formation is understandable. GH, PTH and E 2 promotes IGF-I production. Recent data suggest that hormones containing vitamin D or E 2 enhance bone formation through growth factors. Therefore, growth factors are the key to clarifying the mechanism of bone formation.

Effect of chronic undernutrition on body mass and mechanical bone quality under normoxic and altitude hypoxic conditions.

PubMed

Lezon, Christian; Bozzini, Clarisa; Agûero Romero, Alan; Pinto, Patricia; Champin, Graciela; Alippi, Rosa M; Boyer, Patricia; Bozzini, Carlos E

2016-05-01

Both undernutrition and hypoxia exert a negative influence on both growth pattern and bone mechanical properties in developing rats. The present study explored the effects of chronic food restriction on both variables in growing rats exposed to simulated high-altitude hypoxia. Male rats (n 80) aged 28 d were divided into normoxic (Nx) and hypoxic (Hx) groups. Hx rats were exposed to hypobaric air (380 mmHg) in decompression chambers. At T0, Nx and Hx rats were subdivided into four equal subgroups: normoxic control and hypoxic controls, and normoxic growth-restricted and hypoxic growth-restricted received 80 % of the amount of food consumed freely by their respective controls for a 4-week period. Half of these animals were studied at the end of this period (T4). The remaining rats in each group continued under the same environmental conditions, but food was offered ad libitum to explore the type of catch-up growth during 8 weeks. Structural bone properties (strength and stiffness) were evaluated in the right femur midshaft by the mechanical three-point bending test; geometric properties (length, cross-sectional area, cortical mass, bending cross-sectional moment of inertia) and intrinsic properties of the bone tissue (elastic modulus) were measured or derived from appropriate equations. Bone mineralisation was assessed by ash measurement of the left femur. These data indicate that the growth-retarded effects of diminished food intake, induced either by food restriction or hypoxia-related inhibition of appetite, generated the formation of corresponding smaller bones in which subnormal structural and geometric properties were observed. However, they seemed to be appropriate to the body mass of the animals and suggest, therefore, that the bones were not osteopenic. When food restriction was imposed in Hx rats, the combined effects of both variables were additive, inducing a further reduction of bone mass and bone load-carrying capacity. In all cases, the mechanical properties of the mineralised tissue were unaffected. This and the capacity of the treated bones to undergone complete catch-up growth with full restoration of the biomechanical properties suggest that undernutrition, under either Nx or Hx conditions, does not affect bone behaviour because it remains appropriate to its mechanical functions.

Wnt-mediated reciprocal regulation between cartilage and bone development during endochondral ossification.

PubMed

Lu, Cheng; Wan, Yong; Cao, Jingjing; Zhu, Xuming; Yu, Jian; Zhou, Rujiang; Yao, Yiyun; Zhang, Lingling; Zhao, Haixia; Li, Hanjun; Zhao, Jianzhi; He, Lin; Ma, Gang; Yang, Xiao; Yao, Zhengju; Guo, Xizhi

2013-04-01

The role of Wnt signaling is extensively studied in skeletal development and postnatal bone remodeling, mostly based on the genetic approaches of β-catenin manipulation. However, given their independent function, a requirement for β-catenin is not the same as that for Wnt. Here, we investigated the effect of Wnt proteins in both tissues through generating cartilage- or bone-specific Wls null mice, respectively. Depletion of Wls by Col2-Cre, which would block Wnt secretion in the chondrocytes and perichondrium, delayed chondrocyte hypertrophy in the growth plate and impaired perichondrial osteogenesis. Loss of Wls in chondrocytes also disturbed the proliferating chondrocyte morphology and division orientation, which was similar to the defect observed in Wnt5a null mice. On the other hand, inactivation of Wls in osteoblasts by Col1-Cre resulted in a shorter hypertrophic zone and an increase of TRAP positive cell number in the chondro-osseous junction of growth plate, coupled with a decrease in bone mass. Taken together, our studies reveal that Wnt proteins not only modulate differentiation and cellular communication within populations of chondrocytes, but also mediate the cross regulation between the chondrocytes and osteoblasts in growth plate. Copyright © 2012 Elsevier Inc. All rights reserved.

Effects of the National School Lunch Program on Bone Growth in Japanese Elementary School Children.

PubMed

Kohri, Toshiyuki; Kaba, Naoko; Itoh, Tatsuki; Sasaki, Satoshi

2016-01-01

The Japanese school lunch program with milk was designed to supply 33-50% of the necessary nutrients per day and 50% of the recommended dietary allowance for calcium, which is difficult to obtain from Japanese meals. Although this program contributes to the mental and physical development of children, the effect of these meals on the bone growth in children remains unknown. Therefore, we compared the effect of school lunch with milk on bone growth between elementary school children attending schools that did not enforce the school lunch with milk program (box-lunch group) and those attending schools that did enforce the program (school-lunch group). The study subjects included fourth-grade children during the 2009-2013 school years, of whom 329 children were in the school-lunch group and 484 children in the box-lunch group. The bone area ratio of the right calcaneus was evaluated using quantitative ultrasound (Benus III). Dietary intakes were assessed using brief self-administered diet history questionnaires. The subjects were asked to record their activities for 3 d so that the mean physical activity intensity and the time spent sleeping could be estimated. The bone area ratios (%) were significantly higher in the school-lunch group than in the box-lunch group (males 31.0±0.3 vs. 30.3±0.2; females 30.6±0.2 vs. 29.7±0.2). This tendency did not change even after adjustment for confounding factors associated with bone growth. The results suggest that nutrients supplied by the Japanese school lunch program contributed to increased bone growth in elementary school children.

Bone growth and bone development in the presence of implants or after induced leg-lengthening studied using the Oxford Scanning Proton Microprobe

NASA Astrophysics Data System (ADS)

Pålsgård, Eva; Johansson, Carina; Li, Gang; Grime, Geoff W.; Triffitt, J. T.

1997-07-01

To respond to varying environmental demands the bone tissue in the body is under continual reconstruction throughout life. It is known that metallic elements are important for maintaining normal bone structure, but their roles are not well understood. More information about the effects of metal excess or deficiency is needed to help in the development of metallic bone implants and to improve the treatment of bone fractures and defects. The Oxford Scanning Proton Microprobe (SPM) is being applied in two studies involving metal ions in bone: (1) bone regrowth and bonding to titanium bone implants may be influenced by diffusion of Ti ions into the bone. We are using microPIXE to determine the metal ion content of bone developing in contact with implants of pure Nb, Ti and Ti alloys. (2) Bone lengthening as a surgical procedure is induced by fracturing the bone and allowing it to heal with a small gap between the fractured ends created by the use of external fixators. The gap can be slowly increased during the healing process to stimulate the production of new bone. The enzymes and other constituents of the developing bone need certain metals for their function. Using experimental animals we have studied the concentrations of the metals and whether a deficiency of trace metals limits the optimum rate of bone lengthening.

Hybrid use of combined and sequential delivery of growth factors and ultrasound stimulation in porous multilayer composite scaffolds to promote both vascularization and bone formation in bone tissue engineering.

PubMed

Yan, Haoran; Liu, Xia; Zhu, Minghua; Luo, Guilin; Sun, Tao; Peng, Qiang; Zeng, Yi; Chen, Taijun; Wang, Yingying; Liu, Keliang; Feng, Bo; Weng, Jie; Wang, Jianxin

2016-01-01

In this study, a multilayer coating technology would be adopted to prepare a porous composite scaffold and the growth factor release and ultrasound techniques were introduced into bone tissue engineering to finally solve the problems of vascularization and bone formation in the scaffold whilst the designed multilayer composite with gradient degradation characteristics in the space was used to match the new bone growth process better. The results of animal experiments showed that the use of low intensity pulsed ultrasound (LIPUS) combined with growth factors demonstrated excellent capabilities and advantages in both vascularization and new bone formation in bone tissue engineering. The degradation of the used scaffold materials could match new bone formation very well. The results also showed that only RGD-promoted cell adhesion was insufficient to satisfy the needs of new bone formation while growth factors and LIPUS stimulation were the key factors in new bone formation. © 2015 Wiley Periodicals, Inc.

ADAM10 is essential for cranial neural crest-derived maxillofacial bone development

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tan, Yu, E-mail: tanyu2048@163.com; Fu, Runqing, E-mail: furunqing@sjtu.edu.cn; Liu, Jiaqiang, E-mail: liujqmj@163.com

Growth disorders of the craniofacial bones may lead to craniofacial deformities. The majority of maxillofacial bones are derived from cranial neural crest cells via intramembranous bone formation. Any interruption of the craniofacial skeleton development process might lead to craniofacial malformation. A disintegrin and metalloprotease (ADAM)10 plays an essential role in organ development and tissue integrity in different organs. However, little is known about its function in craniofacial bone formation. Therefore, we investigated the role of ADAM10 in the developing craniofacial skeleton, particularly during typical mandibular bone development. First, we showed that ADAM10 was expressed in a specific area of themore » craniofacial bone and that the expression pattern dynamically changed during normal mouse craniofacial development. Then, we crossed wnt1-cre transgenic mice with adam10-flox mice to generate ADAM10 conditional knockout mice. The stereomicroscopic, radiographic, and von Kossa staining results showed that conditional knockout of ADAM10 in cranial neural crest cells led to embryonic death, craniofacial dysmorphia and bone defects. Furthermore, we demonstrated that impaired mineralization could be triggered by decreased osteoblast differentiation, increased cell death. Overall, these findings show that ADAM10 plays an essential role in craniofacial bone development. -- Highlights: •We firstly reported that ADAM10 was essentially involved in maxillofacial bone development. •ADAM10 cKO mice present craniofacial dysmorphia and bone defects. •Impaired osteoblast differentiation,proliferation and apoptosis underlie the bone deformity.« less

ADAM10 is essential for cranial neural crest-derived maxillofacial bone development.

PubMed

Tan, Yu; Fu, Runqing; Liu, Jiaqiang; Wu, Yong; Wang, Bo; Jiang, Ning; Nie, Ping; Cao, Haifeng; Yang, Zhi; Fang, Bing

2016-07-08

Growth disorders of the craniofacial bones may lead to craniofacial deformities. The majority of maxillofacial bones are derived from cranial neural crest cells via intramembranous bone formation. Any interruption of the craniofacial skeleton development process might lead to craniofacial malformation. A disintegrin and metalloprotease (ADAM)10 plays an essential role in organ development and tissue integrity in different organs. However, little is known about its function in craniofacial bone formation. Therefore, we investigated the role of ADAM10 in the developing craniofacial skeleton, particularly during typical mandibular bone development. First, we showed that ADAM10 was expressed in a specific area of the craniofacial bone and that the expression pattern dynamically changed during normal mouse craniofacial development. Then, we crossed wnt1-cre transgenic mice with adam10-flox mice to generate ADAM10 conditional knockout mice. The stereomicroscopic, radiographic, and von Kossa staining results showed that conditional knockout of ADAM10 in cranial neural crest cells led to embryonic death, craniofacial dysmorphia and bone defects. Furthermore, we demonstrated that impaired mineralization could be triggered by decreased osteoblast differentiation, increased cell death. Overall, these findings show that ADAM10 plays an essential role in craniofacial bone development. Copyright © 2016 Elsevier Inc. All rights reserved.

Expression of the genes for insulin-like growth factors and their receptors in bone during skeletal growth

NASA Technical Reports Server (NTRS)

Bikle, D. D.; Harris, J.; Halloran, B. P.; Roberts, C. T.; Leroith, D.; Morey-Holton, E.

1994-01-01

Insulin-like growth factors (IGF) are important regulators of skeletal growth. To determine whether the capacity to produce and respond to these growth factors changes during skeletal development, we measured the protein and mRNA levels for IGF-I, IGF-II, and their receptors (IGF-IR and IGF-IIR, respectively) in the tibia and femur of rats before and up to 28 mo after birth. The mRNA levels remained high during fetal development but fell after birth, reaching a nadir by 3-6 wk. This fall was most pronounced for IGF-II and IGF-IIR mRNA and least pronounced for IGF-I mRNA. However, after 6 wk, both IGF-I and IGF-IR mRNA levels recovered toward the levels observed at birth. In the prenatal bones, the signals for the mRNAs of IGF-II and IGF-IIR were stronger than the signals for the mRNAs of IGF-I and IGF-IR, although the content of IGF-I was three- to fivefold greater than that of IGF-II. IGF-II levels fell postnatally, whereas the IGF-I content rose after birth such that the ratio IGF-I/IGF-II continued to increase with age. We conclude that, during development, rat bone changes its capacity to produce and respond to IGFs with a progressive trend toward the dominance of IGF-I.

Losartan increases bone mass and accelerates chondrocyte hypertrophy in developing skeleton

PubMed Central

Rianon, Nahid; Rajagopal, Abbhirami; Munivez, Elda; Bertin, Terry; Dawson, Brian; Chen, Yuqing; Jiang, Ming-Ming; Lee, Brendan; Yang, Tao; Bae, Yangjin

2015-01-01

Angiotensin receptor blockers (ARBs) are a group of anti-hypertensive drugs that are widely used to treat pediatric hypertension. Recent application of ARBs to treat diseases such as Marfan syndrome or Alport syndrome has shown positive outcomes in animal and human studies, suggesting a broader therapeutic potential for this class of drugs. Multiple studies have reported a benefit of ARBs on adult bone homeostasis; however, its effect on the growing skeleton in children is unknown. We investigated the effect of Losartan, an ARB, in regulating bone mass and cartilage during development in mice. Wild type mice were treated with Losartan from birth until 6 weeks of age, after which bones were collected for microCT and histomorphometric analyses. Losartan increased trabecular bone volume vs. tissue volume (a 98% increase) and cortical thickness (a 9% increase) in 6-weeks old wild type mice. The bone changes were attributed to decreased osteoclastogenesis as demonstrated by reduced osteoclast number per bone surface in vivo and suppressed osteoclast differentiation in vitro. At the molecular level, Angiotensin II-induced ERK1/2 phosphorylation in RAW cells was attenuated by Losartan. Similarly, RANKL-induced ERK1/2 phosphorylation was suppressed by Losartan, suggesting a convergence of RANKL and angiotensin signaling at the level of ERK1/2 regulation. To assess the effect of Losartan on cartilage development, we examined the cartilage phenotype of wild type mice treated with Losartan in utero from conception to 1 day of age. Growth plates of these mice showed an elongated hypertrophic chondrocyte zone and increased Col10a1 expression level, with minimal changes in chondrocyte proliferation. Altogether, inhibition of the angiotensin pathway by Losartan increases bone mass and accelerates chondrocyte hypertrophy in growth plate during skeletal development. PMID:25779879

Losartan increases bone mass and accelerates chondrocyte hypertrophy in developing skeleton.

PubMed

Chen, Shan; Grover, Monica; Sibai, Tarek; Black, Jennifer; Rianon, Nahid; Rajagopal, Abbhirami; Munivez, Elda; Bertin, Terry; Dawson, Brian; Chen, Yuqing; Jiang, Ming-Ming; Lee, Brendan; Yang, Tao; Bae, Yangjin

2015-05-01

Angiotensin receptor blockers (ARBs) are a group of anti-hypertensive drugs that are widely used to treat pediatric hypertension. Recent application of ARBs to treat diseases such as Marfan syndrome or Alport syndrome has shown positive outcomes in animal and human studies, suggesting a broader therapeutic potential for this class of drugs. Multiple studies have reported a benefit of ARBs on adult bone homeostasis; however, its effect on the growing skeleton in children is unknown. We investigated the effect of Losartan, an ARB, in regulating bone mass and cartilage during development in mice. Wild type mice were treated with Losartan from birth until 6 weeks of age, after which bones were collected for microCT and histomorphometric analyses. Losartan increased trabecular bone volume vs. tissue volume (a 98% increase) and cortical thickness (a 9% increase) in 6-weeks old wild type mice. The bone changes were attributed to decreased osteoclastogenesis as demonstrated by reduced osteoclast number per bone surface in vivo and suppressed osteoclast differentiation in vitro. At the molecular level, Angiotensin II-induced ERK1/2 phosphorylation in RAW cells was attenuated by Losartan. Similarly, RANKL-induced ERK1/2 phosphorylation was suppressed by Losartan, suggesting a convergence of RANKL and angiotensin signaling at the level of ERK1/2 regulation. To assess the effect of Losartan on cartilage development, we examined the cartilage phenotype of wild type mice treated with Losartan in utero from conception to 1 day of age. Growth plates of these mice showed an elongated hypertrophic chondrocyte zone and increased Col10a1 expression level, with minimal changes in chondrocyte proliferation. Altogether, inhibition of the angiotensin pathway by Losartan increases bone mass and accelerates chondrocyte hypertrophy in growth plate during skeletal development. Copyright © 2015 Elsevier Inc. All rights reserved.

Potential effects of valproate and oxcarbazepine on growth velocity and bone metabolism in epileptic children- a medical center experience.

PubMed

Lin, Chien-Ming; Fan, Hueng-Chuen; Chao, Tsu-Yi; Chu, Der-Ming; Lai, Chi-Chieh; Wang, Chih-Chien; Chen, Shyi-Jou

2016-05-03

Children with longstanding use of antiepileptic drugs (AEDs) are susceptible to developing low bone mineral density and an increased fracture risk. However, the literature regarding the effects of AEDs on growth in epileptic children is limited. The aim of this study was to investigate the potential effects of valproate (VPA) and/or oxcarbazepine (OXC) therapy on growth velocity and bone metabolism. Seventy-three ambulatory children (40 boys and 33 girls) with epilepsy, aged between 1 and 18 years (mean age 9.8 ± 4.1 years), were evaluated for growth velocity before and for 1 year after VPA and/or OXC treatment. The bone resorption marker serum tartrate-resistant acid phosphatase 5b (TRAcP5b) and the bone formation marker serum bone-specific alkaline phosphatase (BAP) were measured post-AEDs therapy for 1 year. The difference in growth velocity (ΔHt) and body weight change (ΔWt) between pre- and post-AEDs treatment were -1.0 ± 2.8 cm/year (P < 0.05) and 0.1 ± 3.9 kg/year (P = 0.84), respectively. The study population had serum TRAcP5b-SDS of -1.6 ± 1.2 and BAP-SDS of 1.7 ± 3.7 compared with sex- and age-matched healthy children. Significant correlation between serum TRAcP 5b and BAP activities was noted (r = 0.60, p < 0.001). There was a positive correlation between growth velocity and serum TRAcP 5b activity after AED treatment (r = 0.42, p < 0.01). No correlation was found between ΔHt, ΔWt, serum TRAcP 5b, BAP activity and types of AEDs. Growth velocity was significantly decreased in epileptic children after 1 year of VPA and/or OXC treatment. The effect of VPA and/or OXC therapy on dysregulation of bone metabolism might play a crucial role in physical growth.

Cortical bone growth and maturational changes in dwarf rats induced by recombinant human growth hormone

NASA Technical Reports Server (NTRS)

Martinez, D. A.; Orth, M. W.; Carr, K. E.; Vanderby, R. Jr; Vailas, A. C.

1996-01-01

The growth hormone (GH)-deficient dwarf rat was used to investigate recombinant human (rh) GH-induced bone formation and to determine whether rhGH facilitates simultaneous increases in bone formation and bone maturation during rapid growth. Twenty dwarf rats, 37 days of age, were randomly assigned to dwarf plus rhGH (GH; n = 10) and dwarf plus vehicle (n = 10) groups. The GH group received 1.25 mg rhGH/kg body wt two times daily for 14 days. Biochemical, morphological, and X-ray diffraction measurements were performed on the femur middiaphysis. rhGH stimulated new bone growth in the GH group, as demonstrated by significant increases (P < 0.05) in longitudinal bone length (6%), middiaphyseal cross-sectional area (20%), and the amount of newly accreted bone collagen (28%) in the total pool of middiaphyseal bone collagen. Cortical bone density, mean hydroxyapatite crystal size, and the calcium and collagen contents (microgram/mm3) were significantly smaller in the GH group (P < 0.05). Our findings suggest that the processes regulating new collagen accretion, bone collagen maturation, and mean hydroxyapatite crystal size may be independently regulated during rapid growth.

Force-induced bone growth and adaptation: A system theoretical approach to understanding bone mechanotransduction

NASA Astrophysics Data System (ADS)

Maldonado, Solvey; Findeisen, Rolf

2010-06-01

The modeling, analysis, and design of treatment therapies for bone disorders based on the paradigm of force-induced bone growth and adaptation is a challenging task. Mathematical models provide, in comparison to clinical, medical and biological approaches an structured alternative framework to understand the concurrent effects of the multiple factors involved in bone remodeling. By now, there are few mathematical models describing the appearing complex interactions. However, the resulting models are complex and difficult to analyze, due to the strong nonlinearities appearing in the equations, the wide range of variability of the states, and the uncertainties in parameters. In this work, we focus on analyzing the effects of changes in model structure and parameters/inputs variations on the overall steady state behavior using systems theoretical methods. Based on an briefly reviewed existing model that describes force-induced bone adaptation, the main objective of this work is to analyze the stationary behavior and to identify plausible treatment targets for remodeling related bone disorders. Identifying plausible targets can help in the development of optimal treatments combining both physical activity and drug-medication. Such treatments help to improve/maintain/restore bone strength, which deteriorates under bone disorder conditions, such as estrogen deficiency.

Skeletal advance and arrest in giant non-metamorphosing African clawed frog tadpoles (Xenopus laevis: Daudin)

PubMed Central

Kerney, Ryan; Wassersug, Richard; Hall, Brian K

2010-01-01

This study examines the skeletons of giant non-metamorphosing (GNM) Xenopus laevis tadpoles, which arrest their development indefinitely before metamorphosis, and grow to excessively large sizes in the absence of detectable thyroid glands. Cartilage growth is isometric; however, chondrocyte size is smaller in GNM tadpoles than in controls. Most cartilages stain weakly with alcian blue, and several cartilages are calcified (unlike controls). However, cartilages subjacent to periosteum-derived bone retain strong affinities for alcian blue, indicating a role for periosteum-derived bone in the retention of glycosaminoglycans during protracted larval growth. Bone formation in the head, limb, and axial skeletons is advanced in comparison with stage-matched controls, but arrests at various mid-metamorphic states. Both dermal and periosteum-derived bones grow to disproportionately large sizes in comparison to controls. Additionally, mature monocuspid teeth form in several GNM tadpoles. Advances in skeletal development are attributable to the old ages and large sizes of these tadpoles, and reveal unexpected developmental potentials of the pre-metamorphic skeleton. PMID:20402828

PDGFBB promotes PDGFR{alpha}-positive cell migration into artificial bone in vivo

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yoshida, Shigeyuki; Center for Human Metabolomic Systems Biology, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582; Iwasaki, Ryotaro

2012-05-18

Highlights: Black-Right-Pointing-Pointer We examined effects of PDGFBB in PDGFR{alpha} positive cell migration in artificial bones. Black-Right-Pointing-Pointer PDGFBB was not expressed in osteoblastic cells but was expressed in peripheral blood cells. Black-Right-Pointing-Pointer PDGFBB promoted PDGFR{alpha} positive cell migration into artificial bones but not osteoblast proliferation. Black-Right-Pointing-Pointer PDGFBB did not inhibit osteoblastogenesis. -- Abstract: Bone defects caused by traumatic bone loss or tumor dissection are now treated with auto- or allo-bone graft, and also occasionally by artificial bone transplantation, particularly in the case of large bone defects. However, artificial bones often exhibit poor affinity to host bones followed by bony union failure.more » Thus therapies combining artificial bones with growth factors have been sought. Here we report that platelet derived growth factor bb (PDGFBB) promotes a significant increase in migration of PDGF receptor {alpha} (PDGFR{alpha})-positive mesenchymal stem cells/pre-osteoblastic cells into artificial bone in vivo. Growth factors such as transforming growth factor beta (TGF{beta}) and hepatocyte growth factor (HGF) reportedly inhibit osteoblast differentiation; however, PDGFBB did not exhibit such inhibitory effects and in fact stimulated osteoblast differentiation in vitro, suggesting that combining artificial bones with PDGFBB treatment could promote host cell migration into artificial bones without inhibiting osteoblastogenesis.« less

The Morphogenesis of Cranial Sutures in Zebrafish

PubMed Central

Topczewska, Jolanta M.; Shoela, Ramy A.; Tomaszewski, Joanna P.; Mirmira, Rupa B.; Gosain, Arun K.

2016-01-01

Using morphological, histological, and TEM analyses of the cranium, we provide a detailed description of bone and suture growth in zebrafish. Based on expression patterns and localization, we identified osteoblasts at different degrees of maturation. Our data confirm that, unlike in humans, zebrafish cranial sutures maintain lifelong patency to sustain skull growth. The cranial vault develops in a coordinated manner resulting in a structure that protects the brain. The zebrafish cranial roof parallels that of higher vertebrates and contains five major bones: one pair of frontal bones, one pair of parietal bones, and the supraoccipital bone. Parietal and frontal bones are formed by intramembranous ossification within a layer of mesenchyme positioned between the dermal mesenchyme and meninges surrounding the brain. The supraoccipital bone has an endochondral origin. Cranial bones are separated by connective tissue with a distinctive architecture of osteogenic cells and collagen fibrils. Here we show RNA in situ hybridization for col1a1a, col2a1a, col10a1, bglap/osteocalcin, fgfr1a, fgfr1b, fgfr2, fgfr3, foxq1, twist2, twist3, runx2a, runx2b, sp7/osterix, and spp1/ osteopontin, indicating that the expression of genes involved in suture development in mammals is preserved in zebrafish. We also present methods for examining the cranium and its sutures, which permit the study of the mechanisms involved in suture patency as well as their pathological obliteration. The model we develop has implications for the study of human disorders, including craniosynostosis, which affects 1 in 2,500 live births. PMID:27829009

Quantitative evaluation of bone development of the distal phalanx of the cow hind limb using computed tomography.

PubMed

Tsuka, T; Ooshita, K; Sugiyama, A; Osaki, T; Okamoto, Y; Minami, S; Imagawa, T

2012-01-01

Computed tomography (CT) was performed on 400 claws (200 inner and 200 outer claws) of 100 pairs of bovine hind limbs to investigate the etiological theory that an exacerbating factor for ulceration is exostosis of the tuberculum flexorium within the distal phalanx. A variety of morphological changes of the tuberculum flexorium of bovine hind limb claws was visualized by 3-dimensional CT, and the geometry of these claws suggested a growth pattern of bone development with respect to the assumed daily loading patterns. This growth occurs initially at the abaxial caudal aspect of the distal phalanx and is followed by horizontal progression toward the axial aspect. The length of downward bone development on the solar face of the distal phalanx was 2.73±1.32 mm in the outer claws, significantly greater than in the inner claws (2.38±0.96 mm). Ratios of downward (vertical) bone development to the thickness of the subcutis and the corium (VerBD ratios) did not differ between the outer and inner claws (36.7 vs. 38.3%, respectively). Ratios of horizontal bone development to the axial-to-abaxial line of the tuberculum flexorium (HorBD ratios) were approximately 60% for both outer and inner claws. These quantitative measures regarding horizontal and vertical bone development within the distal phalanx were positively correlated with age and VerBD ratios (r=0.53 and r=0.36 for the inner and outer claws, respectively). Correlations between claw width of the outer claw and length of vertical bone development (r=0.43), the HorBD ratio (r=0.51), and the VerBD ratio (r=0.42) suggested that the relative size difference between the inner and outer claws enhances bone development in the outer claw. Correlation coefficients between VerBD and HorBD ratios (r=0.52 and 0.63 for the inner and outer claws, respectively) suggested that horizontal and vertical bone development occurs as a synchronized process within the tuberculum flexorium. This age-related progress of bone development within the tuberculum flexorium is associated with increased exposure to several exacerbating factors and the laminitic process. Copyright © 2012 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Altered paracrine signaling from the injured knee joint impairs postnatal long bone growth.

PubMed

Roselló-Díez, Alberto; Stephen, Daniel; Joyner, Alexandra L

2017-07-25

Regulation of organ growth is a poorly understood process. In the long bones, the growth plates (GPs) drive elongation by generating a scaffold progressively replaced by bone. Although studies have focused on intrinsic GP regulation, classic and recent experiments suggest that local signals also modulate GP function. We devised a genetic mouse model to study extrinsic long bone growth modulation, in which injury is specifically induced in the left hindlimb, such that the right hindlimb serves as an internal control. Remarkably, when only mesenchyme cells surrounding postnatal GPs were killed, left bone growth was nevertheless reduced. GP signaling was impaired by altered paracrine signals from the knee joint, including activation of the injury response and, in neonates, dampened IGF1 production. Importantly, only the combined prevention of both responses rescued neonatal growth. Thus, we identified signals from the knee joint that modulate bone growth and could underlie establishment of body proportions.

Insulin- like Growth Factor-Binding Protein Action in Bone Tissue: A Key Role for Pregnancy- Associated Plasma Protein-A.

PubMed

Beattie, James; Al-Khafaji, Hasanain; Noer, Pernille R; Alkharobi, Hanaa Esa; Alhodhodi, Aishah; Meade, Josephine; El-Gendy, Reem; Oxvig, Claus

2018-01-01

The insulin-like growth factor (IGF) axis is required for the differentiation, development, and maintenance of bone tissue. Accordingly, dysregulation of this axis is associated with various skeletal pathologies including growth abnormalities and compromised bone structure. It is becoming increasingly apparent that the action of the IGF axis must be viewed holistically taking into account not just the actions of the growth factors and receptors, but also the influence of soluble high affinity IGF binding proteins (IGFBPs).There is a recognition that IGFBPs exert IGF-dependent and IGF-independent effects in bone and other tissues and that an understanding of the mechanisms of action of IGFBPs and their regulation in the pericellular environment impact critically on tissue physiology. In this respect, a group of IGFBP proteinases (which may be considered as ancillary members of the IGF axis) play a crucial role in regulating IGFBP function. In this model, cleavage of IGFBPs by specific proteinases into fragments with lower affinity for growth factor(s) regulates the partition of IGFs between IGFBPs and cell surface IGF receptors. In this review, we examine the importance of IGFBP function in bone tissue with special emphasis on the role of pregnancy associated plasma protein-A (PAPP-A). We examine the function of PAPP-A primarily as an IGFBP-4 proteinase and present evidence that PAPP-A induced cleavage of IGFBP-4 is potentially a key regulatory step in bone metabolism. We also highlight some recent findings with regard to IGFBP-2 and IGFBP-5 (also PAPP-A substrates) function in bone tissue and briefly discuss the actions of the other three IGFBPs (-1, -3, and -6) in this tissue. Although our main focus will be in bone we will allude to IGFBP activity in other cells and tissues where appropriate.

Increased FGF8 signaling promotes chondrogenic rather than osteogenic development in the embryonic skull.

PubMed

Schmidt, Linnea; Taiyab, Aftab; Melvin, Vida Senkus; Jones, Kenneth L; Williams, Trevor

2018-05-10

The bones of the cranial vault are formed directly from mesenchymal cells through intramembranous ossification rather than via a cartilage intermediate. Formation and growth of the skull bones involves the interaction of multiple cell:cell signaling pathways, with Fibroblast Growth Factors (FGFs) and their receptors exerting prominent influence. Mutations within this pathway are the most frequent cause of craniosynostosis, which is a common human craniofacial developmental abnormality characterized by the premature fusion of the cranial sutures. Here, we have developed new mouse models to investigate how different levels of increased Fgf signaling can impact the formation of the calvarial bones and associated sutures. While moderate Fgf8 overexpression resulted in delayed ossification followed by craniosynostosis of the coronal suture, higher Fgf8 levels promoted a loss of ossification and favored cartilage over bone formation across the skull. In contrast, endochondral bones were still able to form and ossify in the presence of increased Fgf8 , though the growth and mineralization of these bones were impacted to varying extents. Expression analysis demonstrated that abnormal skull chondrogenesis was accompanied by changes in genes required for Wnt signaling. Moreover, further analysis indicated that the pathology was associated with decreased Wnt signaling since the reduction in ossification could be partially rescued by halving Axin2 gene dosage. Taken together, these findings indicate that mesenchymal cells of the skull are not fated to form bone but can be forced into a chondrogenic fate via manipulation of FGF8 signaling. These results have implications for evolution of the different methods of ossification as well as for therapeutic intervention in craniosynostosis. © 2018. Published by The Company of Biologists Ltd.

Fibroblast growth factor signaling in skeletal development and disease.

PubMed

Ornitz, David M; Marie, Pierre J

2015-07-15

Fibroblast growth factor (FGF) signaling pathways are essential regulators of vertebrate skeletal development. FGF signaling regulates development of the limb bud and formation of the mesenchymal condensation and has key roles in regulating chondrogenesis, osteogenesis, and bone and mineral homeostasis. This review updates our review on FGFs in skeletal development published in Genes & Development in 2002, examines progress made on understanding the functions of the FGF signaling pathway during critical stages of skeletogenesis, and explores the mechanisms by which mutations in FGF signaling molecules cause skeletal malformations in humans. Links between FGF signaling pathways and other interacting pathways that are critical for skeletal development and could be exploited to treat genetic diseases and repair bone are also explored. © 2015 Ornitz and Marie; Published by Cold Spring Harbor Laboratory Press.

High resolution electron microscopy study of crystal growth mechanisms in chicken bone composites

NASA Astrophysics Data System (ADS)

Cuisinier, F. J. G.; Steuer, P.; Brisson, A.; Voegel, J. C.

1995-12-01

The present study describes the early stages of chicken bone crystal growth, followed by high resolution electron microscopy (HREM). We have developed an original analysis procedure to determine the crystal structure. Images were first digitalized and selected areas were fast Fourier transformed. Numerical masks were selected around the most intense spots and the filtered signal was retransformed back to real space. The filtered images were then compared to computer calculated images to identify the inorganic mineral phase. Nanometer-sized particles were observed on amorphous areas. These particles have a structure loosely related to hydroxyapatite (HA) and a specific orientation. In a more advanced situation, the nanoparticles appeared to grow in two dimensions and to form plate-like crystals. These crystals seem, in a last growth step, to fuse by their (100) faces. These experimental observations allowed us to propose a four-step model for the development and growth of chicken bone crystals. The two initial stages are the ionic adsorption onto the organic substrate followed by the nucleation of nanometer-sized particles. The two following steps, i.e. two-dimensional growth of the nanoparticles leading to the formation of needle-like crystals, and the lateral fusion of these crystals by their (100) faces, are controlled only by spatial constraints inside the extracellular organic matrix.

Botulinum Toxin Induces Muscle Paralysis and Inhibits Bone Regeneration in Zebrafish

PubMed Central

Recidoro, Anthony M.; Roof, Amanda C.; Schmitt, Michael; Worton, Leah E.; Petrie, Timothy; Strand, Nicholas; Ausk, Brandon J.; Srinivasan, Sundar; Moon, Randall T.; Gardiner, Edith M.; Kaminsky, Werner; Bain, Steven D.; Allan, Christopher H.; Gross, Ted S.; Kwon, Ronald Y.

2016-01-01

Intramuscular administration of Botulinum toxin (BTx) has been associated with impaired osteogenesis in diverse conditions of bone formation (e.g., development, growth, and healing), yet the mechanisms of neuromuscular-bone crosstalk underlying these deficits have yet to be identified. Motivated by the emerging utility of zebrafish (Danio rerio) as a rapid, genetically tractable, and optically transparent model for human pathologies (as well as the potential to interrogate neuromuscular-mediated bone disorders in a simple model that bridges in vitro and more complex in vivo model systems), in this study we developed a model of BTx-induced muscle paralysis in adult zebrafish, and examined its effects on intramembranous ossification during tail fin regeneration. BTx administration induced rapid muscle paralysis in adult zebrafish in a manner that was dose-dependent, transient, and focal, mirroring the paralytic phenotype observed in animal and human studies. During fin regeneration, BTx impaired continued bone ray outgrowth, morphology, and patterning, indicating defects in early osteogenesis. Further, BTx significantly decreased mineralizing activity and crystalline mineral accumulation, suggesting delayed late-stage osteoblast differentiation and/or altered secondary bone apposition. Bone ray transection proximal to the amputation site focally inhibited bone outgrowth in the affected ray, implicating intra- and/or inter-ray nerves in this process. Taken together, these studies demonstrate the potential to interrogate pathological features of BTx-induced osteoanabolic dysfunction in the regenerating zebrafish fin, define the technological toolbox for detecting bone growth and mineralization deficits in this process, and suggest that pathways mediating neuromuscular regulation of osteogenesis may be conserved beyond established mammalian models of bone anabolic disorders. PMID:24806738

Regulation of body growth by microRNAs.

PubMed

Lui, Julian C

2017-11-15

Regulation of body growth remains a fascinating and unresolved biological mystery. One key component of body growth is skeletal and longitudinal bone growth. Children grow taller because their bones grew longer, and the predominant driver of longitudinal bone growth is a cartilaginous structure found near the ends of long bone named the growth plate. Numerous recent studies have started to unveil the importance of microRNAs in regulation of growth plate functions, therefore contributing to regulation of linear growth. In addition to longitudinal growth, other organs in our body need to increase in size and cell number as we grow, and the regulation of organ growth involves both systemic factors like hormones; and other intrinsic mechanisms, which we are just beginning to understand. This review aims to summarize some recent important findings on how microRNAs are involved in both of these processes: the regulation of longitudinal bone growth, and the regulation of organs and overall body growth. Published by Elsevier B.V.

Influence of growth hormone therapy on selected dental and skeletal system parameters.

PubMed

Partyka, Małgorzata; Chałas, Renata; Dunin-Wilczyńska, Izabella; Drohomyretska, Myroslava; Klatka, Maria

2018-03-14

Growth hormone deficiency (GHD) is one of the main indications for growth hormone therapy. One characteristic of this disease is bone age delay in relation to the chronological age. Pituitary dysfunction negatively affects the growth and development of the jaws and teeth of the child. The secretion of endocrine glands regulates growth, development, and gender differentiation. It also controls the growth of bones and teeth, regulates metabolism of calcium and phosphate, proteins, lipids and carbohydrates. The primary role in the endocrine system is played by the pituitary gland which is responsible for the production of somatotropin [1]. Dysfunction of the pituitary gland has a negative effect on the growth and development of long bones in the body, and may have an adverse effect on the development of maxilla, mandible and dentition of a child. There is some information in the literature that dental age is delayed in short stature children; the replacement of deciduous teeth by permanent teeth is also delayed, and newly erupted permanent teeth often require orthodontic treatment. Applying hormonal therapy positively affects the process of replacement of dentition [2, 3, 4, 5, 6]. The aim of the study was to assess bone and dental age, as well as analyze the state of dentition in children diagnosed with GH deficiency treated with growth hormone, depending on the duration of treatment. The study material consisted of 110 children (27 males, 83 females), hospitalized for somatotropin hypopituitarism in the Department of Paediatric Endocrinology and Diabetology at the Medical University of Lublin, Poland. The mean birth age was 13 years (156 months) with a standard deviation of 2 years and 6 months (30 months). 47 children (43%) started treatment with the growth hormone (group starting treatment) and 63 children (57%) whose treatment was started 2-3 years previously (group in the course of treatment). The control group consisted of 41 generally healthy children (15males, 25 females) with ENT problems, such as hypoacusis and a condition after nasal injury, hospitalized in the Department of Paediatric Otolaryngology at the Medical University of Lublin, Poland. The mean age was 11 years and 5 months (137 months) with standard deviation of 2 years and 5 months (29 months). Informed consent was obtained from the parents. The study was approved by the Bioethical Committee at the Medical University of Lublin (Resolution No. KE-0254 /216 /2012).

Practical Modeling Concepts for Connective Tissue Stem Cell and Progenitor Compartment Kinetics

PubMed Central

2003-01-01

Stem cell activation and development is central to skeletal development, maintenance, and repair, as it is for all tissues. However, an integrated model of stem cell proliferation, differentiation, and transit between functional compartments has yet to evolve. In this paper, the authors review current concepts in stem cell biology and progenitor cell growth and differentiation kinetics in the context of bone formation. A cell-based modeling strategy is developed and offered as a tool for conceptual and quantitative exploration of the key kinetic variables and possible organizational hierarchies in bone tissue development and remodeling, as well as in tissue engineering strategies for bone repair. PMID:12975533

Signaling pathways effecting crosstalk between cartilage and adjacent tissues: Seminars in cell and developmental biology: The biology and pathology of cartilage.

PubMed

Maes, Christa

2017-02-01

Endochondral ossification, the mechanism responsible for the development of the long bones, is dependent on an extremely stringent coordination between the processes of chondrocyte maturation in the growth plate, vascular expansion in the surrounding tissues, and osteoblast differentiation and osteogenesis in the perichondrium and the developing bone center. The synchronization of these processes occurring in adjacent tissues is regulated through vigorous crosstalk between chondrocytes, endothelial cells and osteoblast lineage cells. Our knowledge about the molecular constituents of these bidirectional communications is undoubtedly incomplete, but certainly some signaling pathways effective in cartilage have been recognized to play key roles in steering vascularization and osteogenesis in the perichondrial tissues. These include hypoxia-driven signaling pathways, governed by the hypoxia-inducible factors (HIFs) and vascular endothelial growth factor (VEGF), which are absolutely essential for the survival and functioning of chondrocytes in the avascular growth plate, at least in part by regulating the oxygenation of developing cartilage through the stimulation of angiogenesis in the surrounding tissues. A second coordinating signal emanating from cartilage and regulating developmental processes in the adjacent perichondrium is Indian Hedgehog (IHH). IHH, produced by pre-hypertrophic and early hypertrophic chondrocytes in the growth plate, induces the differentiation of adjacent perichondrial progenitor cells into osteoblasts, thereby harmonizing the site and time of bone formation with the developmental progression of chondrogenesis. Both signaling pathways represent vital mediators of the tightly organized conversion of avascular cartilage into vascularized and mineralized bone during endochondral ossification. Copyright © 2016. Published by Elsevier Ltd.

Genetic effects on bone mass and turnover-relevance to black/white differences.

PubMed

Parfitt, A M

1997-08-01

The mass of a bone is given by its volume and its apparent density--mass per unit external volume. Most measurements of so-called density are of mass incompletely normalized by some index of bone size. Genes control about 60% to 75% of the variance of peak bone mass/density and a much smaller proportion of the variance in rate of loss. Genetic influence on bone mass/density are mediated in large part by body size, bone size, and muscle mass. Most of the fifty-fold increase in bone mass from birth to maturity is due to bone growth, which is linked to muscle growth and bodily growth. Three-D apparent bone density in the vertebrae increases about 15% during the pubertal growth spurt. The genetic potential for bone accumulation can be frustrated by insufficient calcium intake, disruption of the calendar of puberty and inadequate physical activity. The growing skeleton is much more responsive than the mature skeleton to the osteotrophic effect of exercise, which is mediated by the detection of deviations from a target value for strain, and orchestration of cellular responses that restore the target value, processes collectively termed the mechanostat. Production of metaphyseal cancellous bone and growth in length are both linked to endochondral ossification, which is driven by growth plate cartilage cell proliferation. Production of diaphyseal cortical bone and growth in width are both linked to periosteal apposition, which is driven by osteoblast precursor proliferation. During adolescence trabeculae and cortices become thicker by net endosteal apposition, which increases apparent density. Two lines of evidence support a genetic basis for black/white differences in bone mass. First, the magnitude (10% to 40%) is incommensurate with known nongenetic factors. Second, the difference is already evident in the fetus and increases progressively during growth, especially in adolescence; the difference in peak bone mass persists throughout life. The genetic determination of bone mass is mediated by two classes of gene. The first regulates growth of the body, including muscles and bones, under the control of a master gene or set of genes whose products function as the sizostat. The second regulates the increase in apparent bone density in response to load bearing, under the control of a master gene or set of genes whose products function as the mechanostat.

A novel approach for studying the temporal modulation of embryonic skeletal development using organotypic bone cultures and microcomputed tomography.

PubMed

Kanczler, Janos M; Smith, Emma L; Roberts, Carol A; Oreffo, Richard O C

2012-10-01

Understanding the structural development of embryonic bone in a three dimensional framework is fundamental to developing new strategies for the recapitulation of bone tissue in latter life. We present an innovative combined approach of an organotypic embryonic femur culture model, microcomputed tomography (μCT) and immunohistochemistry to examine the development and modulation of the three dimensional structures of the developing embryonic femur. Isolated embryonic chick femurs were organotypic (air/liquid interface) cultured for 10 days in either basal, chondrogenic, or osteogenic supplemented culture conditions. The growth development and modulating effects of basal, chondrogenic, or osteogenic culture media of the embryonic chick femurs was investigated using μCT, immunohistochemistry, and histology. The growth and development of noncultured embryonic chick femur stages E10, E11, E12, E13, E15, and E17 were very closely correlated with increased morphometric indices of bone formation as determined by μCT. After 10 days in the organotpyic culture set up, the early aged femurs (E10 and E11) demonstrated a dramatic response to the chondrogenic or osteogenic culture conditions compared to the basal cultured femurs as determined by a change in μCT morphometric indices and modified expression of chondrogenic and osteogenic markers. Although the later aged femurs (E12 and E13) increased in size and structure after 10 days organotpypic culture, the effects of the osteogenic and chondrogenic organotypic cultures on these femurs were not significantly altered compared to basal conditions. We have demonstrated that the embryonic chick femur organotpyic culture model combined with the μCT and immunohistochemical analysis can provide an integral methodology for investigating the modulation of bone development in an ex vivo culture setting. Hence, these interdisciplinary techniques of μCT and whole organ bone cultures will enable us to delineate some of the temporal, structural developmental paradigms and modulation of bone tissue formation to underpin innovative skeletal regenerative technology for clinical therapeutic strategies in musculoskeletal trauma and diseases.

In vitro differentiation of embryonic stem cells into hepatocytes induced by fibroblast growth factors and bone morphological protein-4.

PubMed

Zhou, Qing-Jun; Huang, Yan-Dan; Xiang, Li-Xin; Shao, Jian-Zhong; Zhou, Guo-Shun; Yao, Hang; Dai, Li-Cheng; Lu, Yong-Liang

2007-01-01

The feasibility of transforming embryonic endoderm into different cell types is tightly controlled by mesodermal and septum transversumal signalings during early embryonic development. Here, an induction protocol tracing embryonic liver development was designed, in which, three growth factors, acid fibroblast growth factor, basic fibroblast growth factor and bone morphological protein-4 that secreted from pre-cardiac mesoderm and septum transversum mesenchyme, respectively, were employed to investigate their specific potency of modulating the mature hepatocyte proportion during the differentiation process. Results showed that hepatic differentiation took place spontaneously at a low level, however, supplements of the three growth factors gave rise to a significant up-regulation of mature hepatocytes. Bone morphological protein-4 highlighted the differentiation ratio to 40-55%, showing the most effective promotion, and also exhibited a synergistic effect with the other two fibroblast factors, whereas no similar phenomenon was observed between the other two factors, which was reported for the first time. Our study not only provides a high-performance system of embryonic stem cells differentiating into hepatocytes, which would supply a sufficient hepatic population for related studies, but also make it clear of the inductive effects of three important growth factors, which could support for further investigation on the mechanisms of mesodermal and septumal derived signalings that regulate hepatic differentiation.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Martino, Mikaël M.; Briquez, Priscilla S.; Maruyama, Kenta

Growth factors are very promising molecules to enhance bone regeneration. However, their translation to clinical use has been seriously limited, facing issues related to safety and cost-effectiveness. These problems derive from the vastly supra-physiological doses of growth factor used without optimized delivery systems. Therefore, these issues have motivated the development of new delivery systems allowing better control of the spatio-temporal release and signaling of growth factors. Because the extracellular matrix (ECM) naturally plays a fundamental role in coordinating growth factor activity in vivo, a number of novel delivery systems have been inspired by the growth factor regulatory function of themore » ECM. After introducing the role of growth factors during the bone regeneration process, this review exposes different issues that growth factor-based therapies have encountered in the clinic and highlights recent delivery approaches based on the natural interaction between growth factor and the ECM.« less

Regional variations in growth plate chondrocyte deformation as predicted by three-dimensional multi-scale simulations.

PubMed

Gao, Jie; Roan, Esra; Williams, John L

2015-01-01

The physis, or growth plate, is a complex disc-shaped cartilage structure that is responsible for longitudinal bone growth. In this study, a multi-scale computational approach was undertaken to better understand how physiological loads are experienced by chondrocytes embedded inside chondrons when subjected to moderate strain under instantaneous compressive loading of the growth plate. Models of representative samples of compressed bone/growth-plate/bone from a 0.67 mm thick 4-month old bovine proximal tibial physis were subjected to a prescribed displacement equal to 20% of the growth plate thickness. At the macroscale level, the applied compressive deformation resulted in an overall compressive strain across the proliferative-hypertrophic zone of 17%. The microscale model predicted that chondrocytes sustained compressive height strains of 12% and 6% in the proliferative and hypertrophic zones, respectively, in the interior regions of the plate. This pattern was reversed within the outer 300 μm region at the free surface where cells were compressed by 10% in the proliferative and 26% in the hypertrophic zones, in agreement with experimental observations. This work provides a new approach to study growth plate behavior under compression and illustrates the need for combining computational and experimental methods to better understand the chondrocyte mechanics in the growth plate cartilage. While the current model is relevant to fast dynamic events, such as heel strike in walking, we believe this approach provides new insight into the mechanical factors that regulate bone growth at the cell level and provides a basis for developing models to help interpret experimental results at varying time scales.

Regional Variations in Growth Plate Chondrocyte Deformation as Predicted By Three-Dimensional Multi-Scale Simulations

PubMed Central

Gao, Jie; Roan, Esra; Williams, John L.

2015-01-01

The physis, or growth plate, is a complex disc-shaped cartilage structure that is responsible for longitudinal bone growth. In this study, a multi-scale computational approach was undertaken to better understand how physiological loads are experienced by chondrocytes embedded inside chondrons when subjected to moderate strain under instantaneous compressive loading of the growth plate. Models of representative samples of compressed bone/growth-plate/bone from a 0.67 mm thick 4-month old bovine proximal tibial physis were subjected to a prescribed displacement equal to 20% of the growth plate thickness. At the macroscale level, the applied compressive deformation resulted in an overall compressive strain across the proliferative-hypertrophic zone of 17%. The microscale model predicted that chondrocytes sustained compressive height strains of 12% and 6% in the proliferative and hypertrophic zones, respectively, in the interior regions of the plate. This pattern was reversed within the outer 300 μm region at the free surface where cells were compressed by 10% in the proliferative and 26% in the hypertrophic zones, in agreement with experimental observations. This work provides a new approach to study growth plate behavior under compression and illustrates the need for combining computational and experimental methods to better understand the chondrocyte mechanics in the growth plate cartilage. While the current model is relevant to fast dynamic events, such as heel strike in walking, we believe this approach provides new insight into the mechanical factors that regulate bone growth at the cell level and provides a basis for developing models to help interpret experimental results at varying time scales. PMID:25885547

Autogenous cultured growth plate chondrocyte transplantation in the treatment of physeal injury in rabbits.

PubMed

Tomaszewski, R; Bohosiewicz, J; Gap, A; Bursig, H; Wysocka, A

2014-11-01

The aim of this experimental study on New Zealand's white rabbits was to investigate the transplantation of autogenous growth plate cells in order to treat the injured growth plate. They were assessed in terms of measurements of radiological tibial varus and histological characteristics. An experimental model of plate growth medial partial resection of the tibia in 14 New Zealand white rabbits was created. During this surgical procedure the plate growth cells were collected and cultured. While the second surgery was being performed, the autologous cultured growth plate cells were grafted at the right tibia, whereas the left tibia was used as a control group. Histological examinations showed that the grafted right tibia presented the regular shape of the plate growth with hypertrophic maturation, chondrocyte columniation and endochondral calcification. Radiological study shows that the mean tibial deformity at the left angle was 20.29° (6.25 to 33) and 7.21° (5 to 10) in the right angle. This study has demonstrated that grafting of autogenous cultured growth plate cells into a defect of the medial aspect of the proximal tibial physis can prevent bone bridge formation, growth arrest and the development of varus deformity. Cite this article: Bone Joint Res 2014;3:310-16. ©2014 The British Editorial Society of Bone & Joint Surgery.

The consequences of pediatric renal transplantation on bone metabolism and growth.

PubMed

Bacchetta, Justine; Ranchin, Bruno; Demède, Delphine; Allard, Lise

2013-10-01

During childhood, growth retardation, decreased final height and renal osteodystrophy are common complications of chronic kidney disease (CKD). These problems remain present in patients undergoing renal transplantation, even though steroid-sparing strategies are more widely used. In this context, achieving normal height and growth in children after transplantation is a crucial issue for both quality of life and self-esteem. The aim of this review is to provide an overview of pathophysiology of CKD-mineral bone disorder (MBD) in children undergoing renal transplantation and to propose keypoints for its daily management. In adults, calcimimetics are effective for posttransplant hyperparathyroidism, but data are missing in the pediatric population. Fibroblast growth factor 23 levels are associated with increased risk of rejection, but the underlying mechanisms remain unclear. A recent meta-analysis also demonstrated the effectiveness of rhGH therapy in short transplanted children. In 2013, the daily clinical management of CKD-MBD in transplanted children should still focus on simple objectives: to optimize renal function, to develop and promote steroid-sparing strategies, to provide optimal nutritional support to maximize final height and avoid bone deformations, to equilibrate calcium/phosphate metabolism so as to provide acceptable bone quality and cardiovascular status, to correct all metabolic and clinical abnormalities that can worsen both bone and growth (mainly metabolic acidosis, anemia and malnutrition), promote good lifestyle habits (adequate calcium intake, regular physical activity, no sodas consumption, no tobacco exposure) and eventually to correct native vitamin D deficiency (target of 25-vitamin D >75 nmol/l).

Comparative osteohistology of Hesperornis with reference to pygoscelid penguins: the effects of climate and behaviour on avian bone microstructure

PubMed Central

Wilson, Laura E.; Chin, Karen

2014-01-01

The broad biogeographic distribution of Hesperornis fossils in Late Cretaceous Western Interior Seaway deposits has prompted questions about whether they endured polar winters or migrated between mid- and high latitudes. Here, we compare microstructures of hesperornithiform long bones from Kansas and the Arctic to investigate whether migration or Late Cretaceous polar climate affected bone growth. We also examine modern penguin bones to determine how migration and climate may influence bone growth in birds with known behaviours. Histological analysis of hesperornithiform samples reveals continuous bone deposition throughout the cortex, plus an outer circumferential layer in adults. No cyclic growth marks, zonation or differences in vasculature are apparent in the Hesperornis specimens. Comparatively, migratory Adélie and chinstrap penguin bones show no zonation or changes in microstructure, suggesting that migration is not necessarily recorded in avian bone microstructure. Non-migratory gentoos show evidence of rapid bone growth possibly associated with increased chick growth rates in high-latitude populations and large body size. The absence of histological evidence for migration in extinct Hesperornis and extant pygoscelid penguins may reflect that these birds reached skeletal maturity before migration or overwintering. This underscores the challenges of using bone microstructure to infer the effects of behaviour and climate on avian growth. PMID:26064560

Sequential growth factor application in bone marrow stromal cell ligament engineering.

PubMed

Moreau, Jodie E; Chen, Jingsong; Horan, Rebecca L; Kaplan, David L; Altman, Gregory H

2005-01-01

In vitro bone marrow stromal cell (BMSC) growth may be enhanced through culture medium supplementation, mimicking the biochemical environment in which cells optimally proliferate and differentiate. We hypothesize that the sequential administration of growth factors to first proliferate and then differentiate BMSCs cultured on silk fiber matrices will support the enhanced development of ligament tissue in vitro. Confluent second passage (P2) BMSCs obtained from purified bone marrow aspirates were seeded on RGD-modified silk matrices. Seeded matrices were divided into three groups for 5 days of static culture, with medium supplement of basic fibroblast growth factor (B) (1 ng/mL), epidermal growth factor (E; 1 ng/mL), or growth factor-free control (C). After day 5, medium supplementation was changed to transforming growth factor-beta1 (T; 5 ng/mL) or C for an additional 9 days of culture. Real-time RT-PCR, SEM, MTT, histology, and ELISA for collagen type I of all sample groups were performed. Results indicated that BT supported the greatest cell ingrowth after 14 days of culture in addition to the greatest cumulative collagen type I expression measured by ELISA. Sequential growth factor application promoted significant increases in collagen type I transcript expression from day 5 of culture to day 14, for five of six groups tested. All T-supplemented samples surpassed their respective control samples in both cell ingrowth and collagen deposition. All samples supported spindle-shaped, fibroblast cell morphology, aligning with the direction of silk fibers. These findings indicate significant in vitro ligament development after only 14 days of culture when using a sequential growth factor approach.

[New therapies for children affected by bone diseases].

PubMed

Ballhausen, Diana; Dépraz, Nuria Garcia; Kern, Ilse; Unger, Sheila; Bonafé, Luisa

2012-02-22

Considerable progress has been achieved in recent years in treating children affected by bone diseases. Advances in the understanding of the molecular pathophysiology of genetic bone diseases have led to the development of enzyme replacement therapies for various lysosomal storage diseases, following the breakthrough initiated in treating Gaucher disease. Clinical studies are underway with tailored molecules correcting bone fragility and alleviating chronic bone pain and other manifestations of hypophosphatasia, or promoting growth of long bones in achondroplasia patients. We further report our very encouraging experience with intravenous bisphosphonate treatment in children suffering from secondary osteopenia and the high prevalence of calcium and vitamin D deficits in these severely disabled children.

Biomaterial delivery of morphogens to mimic the natural healing cascade in bone

PubMed Central

Mehta, Manav; Schmidt-Bleek, Katharina; Duda, Georg N; Mooney, David J

2012-01-01

Complications in treatment of large bone defects using bone grafting still remain. Our understanding of the endogenous bone regeneration cascade has inspired the exploration of a wide variety of growth factors (GFs) in an effort to mimic the natural signaling that controls bone healing. Biomaterial-based delivery of single exogenous GFs has shown therapeutic efficacy, and this likely relates to its ability to recruit and promote replication of cells involved in tissue development and the healing process. However, as the natural bone healing cascade involves the action of multiple factors, each acting in a specific spatiotemporal pattern, strategies aiming to mimic the critical aspects of this process will likely benefit from the usage of multiple therapeutic agents. This article reviews the current status of approaches to deliver single GFs, as well as ongoing efforts to develop sophisticated delivery platforms to deliver multiple lineage-directing morphogens (multiple GFs) during bone healing. PMID:22626978

Effects of lead and cadmium exposure from electronic waste on child physical growth.

PubMed

Yang, Hui; Huo, Xia; Yekeen, Taofeek Akangbe; Zheng, Qiujian; Zheng, Minghao; Xu, Xijin

2013-07-01

Many studies indicate that lead (Pb) and cadmium (Cd) exposure may alter bone development through both direct and indirect mechanisms, increasing the risk of osteoporosis later in life. The aim of this study was to investigate the association between Pb and Cd exposure, physical growth, and bone and calcium metabolism in children of an electronic waste (e-waste) processing area. We recruited 246 children (3-8 years) in a kindergarten located in Guiyu, China. Blood lead levels (BLLs) and blood cadmium levels (BCLs) of recruited children were measured as biomarkers for exposure. Serum calcium, osteocalcin, bone alkaline phosphatase, and urinary deoxypyridinoline were used as biomarkers for bone and calcium metabolism. Physical indexes such as height, weight, and head and chest circumference were also measured. The mean values of BLLs and BCLs obtained were 7.30 μg/dL and 0.69 μg/L, respectively. The average of BCLs increased with age. In multiple linear regression analysis, BLLs were negatively correlated with both height and weight, and positively correlated with bone resorption biomarkers. Neither bone nor calcium metabolic biomarkers showed significant correlation with cadmium. Childhood lead exposure affected both physical development and increased bone resorption of children in Guiyu. Primitive e-waste recycling may threaten the health of children with elevated BLL which may eventually cause adult osteoporosis.

Development of bioactive porous α-TCP/HAp beads for bone tissue engineering.

PubMed

Asaoka, Teruo; Ohtake, Shoji; Furukawa, Katsuko S; Tamura, Akito; Ushida, Takashi

2013-11-01

Porous beads of bioactive ceramics such as hydroxyapatite (HAp) and tribasic calcium phosphate (TCP) are considered a promising scaffold for cultivating bone cells. To realize this, α-TCP/HAp functionally graded porous beads are fabricated with two main purposes: to maintain the function of the scaffold with sufficient strength up to the growth of new bone, and is absorbed completely after the growth. HAp is a bioactive material that has both high strength and strong tissue-adhesive properties, but is not readily absorbed by the human body. On the contrary, α-TCP is highly bioabsorbable, resulting in a scaffold that is absorbed before it is completely replaced by bone. In this study, we produced porous, bead-shaped carriers as scaffolds for osteoblast culture. To control the solubility in vivo, the fabricated beads contained α-TCP at the center and HAp at the surface. Cell adaptability of these beads for bone tissue engineering was confirmed in vitro. It was found that α-TCP/HAp bead carriers exhibit low toxicity in the initial stages of cell seeding and cell adhesion. The presence of HAp in the composite bead form effectively increased ALP activity. In conclusion, it is suggested that these newly developed α-TCP/HAp beads are a promising tool for bone tissue engineering. Copyright © 2013 Wiley Periodicals, Inc.

Soluble VEGF isoforms are essential for establishingepiphyseal vascularization and regulating chondrocyte development and survival

PubMed Central

Maes, Christa; Stockmans, Ingrid; Moermans, Karen; Van Looveren, Riet; Smets, Nico; Carmeliet, Peter; Bouillon, Roger; Carmeliet, Geert

2004-01-01

VEGF is crucial for metaphyseal bone vascularization. In contrast, the angiogenic factors required for vascularization of epiphyseal cartilage are unknown, although this represents a developmentally and clinically important aspect of bone growth. The VEGF gene is alternatively transcribed into VEGF120, VEGF164, and VEGF188 isoforms that differ in matrix association and receptor binding. Their role in bone development was studied in mice expressing single isoforms. Here we report that expression of only VEGF164 or only VEGF188 (in VEGF188/188 mice) was sufficient for metaphyseal development. VEGF188/188 mice, however, showed dwarfism, disrupted development of growth plates and secondary ossification centers, and knee joint dysplasia. This phenotype was at least partly due to impaired vascularization surrounding the epiphysis, resulting in ectopically increased hypoxia and massive chondrocyte apoptosis in the interior of the epiphyseal cartilage. In addition to the vascular defect, we provide in vitro evidence that the VEGF188 isoform alone is also insufficient to regulate chondrocyte proliferation and survival responses to hypoxia. Consistent herewith, chondrocytes in or close to the hypoxic zone in VEGF188/188 mice showed increased proliferation and decreased differentiation. These findings indicate that the insoluble VEGF188 isoform is insufficient for establishing epiphyseal vascularization and regulating cartilage development during endochondral bone formation. PMID:14722611

Soluble VEGF isoforms are essential for establishing epiphyseal vascularization and regulating chondrocyte development and survival.

PubMed

Maes, Christa; Stockmans, Ingrid; Moermans, Karen; Van Looveren, Riet; Smets, Nico; Carmeliet, Peter; Bouillon, Roger; Carmeliet, Geert

2004-01-01

VEGF is crucial for metaphyseal bone vascularization. In contrast, the angiogenic factors required for vascularization of epiphyseal cartilage are unknown, although this represents a developmentally and clinically important aspect of bone growth. The VEGF gene is alternatively transcribed into VEGF(120), VEGF(164), and VEGF(188) isoforms that differ in matrix association and receptor binding. Their role in bone development was studied in mice expressing single isoforms. Here we report that expression of only VEGF(164) or only VEGF(188) (in VEGF(188/188) mice) was sufficient for metaphyseal development. VEGF(188/188) mice, however, showed dwarfism, disrupted development of growth plates and secondary ossification centers, and knee joint dysplasia. This phenotype was at least partly due to impaired vascularization surrounding the epiphysis, resulting in ectopically increased hypoxia and massive chondrocyte apoptosis in the interior of the epiphyseal cartilage. In addition to the vascular defect, we provide in vitro evidence that the VEGF(188) isoform alone is also insufficient to regulate chondrocyte proliferation and survival responses to hypoxia. Consistent herewith, chondrocytes in or close to the hypoxic zone in VEGF(188/188) mice showed increased proliferation and decreased differentiation. These findings indicate that the insoluble VEGF(188) isoform is insufficient for establishing epiphyseal vascularization and regulating cartilage development during endochondral bone formation.

Lack of hepcidin ameliorates anemia and improves growth in an adenine-induced mouse model of chronic kidney disease

PubMed Central

Sureshbabu, Angara; Doty, Steve B.; Zhu, Yuan-Shan; Patino, Edwin; Cunningham-Rundles, Susanna; Choi, Mary E.; Boskey, Adele; Rivella, Stefano

2016-01-01

Growth delay is common in children with chronic kidney disease (CKD), often associated with poor quality of life. The role of anemia in uremic growth delay is poorly understood. Here we describe an induction of uremic growth retardation by a 0.2% adenine diet in wild-type (WT) and hepcidin gene (Hamp) knockout (KO) mice, compared with their respective littermates fed a regular diet. Experiments were started at weaning (3 wk). After 8 wk, blood was collected and mice were euthanized. Adenine-fed WT mice developed CKD (blood urea nitrogen 82.8 ± 11.6 mg/dl and creatinine 0.57 ± 0.07 mg/dl) and were 2.1 cm shorter compared with WT controls. WT adenine-fed mice were anemic and had low serum iron, elevated Hamp, and elevated IL6 and TNF-α. WT adenine-fed mice had advanced mineral bone disease (serum phosphorus 16.9 ± 3.1 mg/dl and FGF23 204.0 ± 115.0 ng/ml) with loss of cortical and trabecular bone volume seen on microcomputed tomography. Hamp disruption rescued the anemia phenotype resulting in improved growth rate in mice with CKD, thus providing direct experimental evidence of the relationship between Hamp pathway and growth impairment in CKD. Hamp disruption ameliorated CKD-induced growth hormone-insulin-like growth factor 1 axis derangements and growth plate alterations. Disruption of Hamp did not mitigate the development of uremia, inflammation, and mineral and bone disease in this model. Taken together, these results indicate that an adenine diet can be successfully used to study growth in mice with CKD. Hepcidin appears to be related to pathways of growth retardation in CKD suggesting that investigation of hepcidin-lowering therapies in juvenile CKD is warranted. PMID:27440777

The effect of bone growth onto massive prostheses collars in protecting the implant from fracture.

PubMed

Fromme, Paul; Blunn, Gordon W; Aston, William J; Abdoola, Tasneem; Koris, Jacob; Coathup, Melanie J

2017-03-01

Limb-sparing distal femoral endoprotheses used in cancer patients have a high risk of aseptic loosening. It had been reported that young adolescent patients have a higher rate of loosening and fatigue fracture of intramedullary stems because the implant becomes undersized as patients grow. Extracortical bone growth into the grooved hydroxyapatite-coated collar had been shown to reduce failure rates. The stresses in the implant and femur have been calculated from Finite Element models for different stages of bone growth onto the collar. For a small diameter stem without any bone growth, a large stress concentration at the implant shoulder was found, leading to a significant fracture risk under normal walking loads. Bone growth and osseointergration onto the implant collar reduced the stress level in the implant to safe levels. For small bone bridges a risk of bone fracture was observed. Copyright © 2016 IPEM. Published by Elsevier Ltd. All rights reserved.

The effects of 1α, 25-dihydroxyvitamin D3 and transforming growth factor-β3 on bone development in an ex vivo organotypic culture system of embryonic chick femora.

PubMed

Smith, Emma L; Rashidi, Hassan; Kanczler, Janos M; Shakesheff, Kevin M; Oreffo, Richard O C

2015-01-01

Transforming growth factor-beta3 (TGF-β3) and 1α,25-dihydroxyvitamin D3 (1α,25 (OH) 2D3) are essential factors in chondrogenesis and osteogenesis respectively. These factors also play a fundamental role in the developmental processes and the maintenance of skeletal integrity, but their respective direct effects on these processes are not fully understood. Using an organotypic bone rudiment culture system the current study has examined the direct roles the osteotropic factors 1α,25 (OH)2D3 and TGF-β3 exert on the development and modulation of the three dimensional structure of the embryonic femur. Isolated embryonic chick femurs (E11) were organotypically cultured for 10 days in basal media, or basal media supplemented with either 1α,25 (OH) 2D3 (25 nM) or TGF-β3 (5 ng/mL & 15 ng/mL). Analyses of the femurs were undertaken using micro-computed tomography (μCT), histology and immunohistochemistry. 1α,25 (OH)2D3 supplemented cultures enhanced osteogenesis directly in the developing femurs with elevated levels of osteogenic markers such as type 1 collagen. In marked contrast organotypic femur cultures supplemented with TGF-β3 (5 ng/mL & 15 ng/mL) demonstrated enhanced chondrogenesis with a reduction in osteogenesis. These studies demonstrate the efficacy of the ex vivo organotypic embryonic femur culture employed to elucidate the direct roles of these molecules, 1α,25 (OH) 2D3 and TGF-β3 on the structural development of embryonic bone within a three dimensional framework. We conclude that 1α,25(OH)2D and TGF-β3 modify directly the various cell populations in bone rudiment organotypic cultures effecting tissue metabolism resulting in significant changes in embryonic bone growth and modulation. Understanding the roles of osteotropic agents in the process of skeletal development is integral to developing new strategies for the recapitulation of bone tissue in later life.

Modeling of time dependent localized flow shear stress and its impact on cellular growth within additive manufactured titanium implants

PubMed Central

Zhang, Ziyu; Yuan, Lang; Lee, Peter D; Jones, Eric; Jones, Julian R

2014-01-01

Bone augmentation implants are porous to allow cellular growth, bone formation and fixation. However, the design of the pores is currently based on simple empirical rules, such as minimum pore and interconnects sizes. We present a three-dimensional (3D) transient model of cellular growth based on the Navier–Stokes equations that simulates the body fluid flow and stimulation of bone precursor cellular growth, attachment, and proliferation as a function of local flow shear stress. The model's effectiveness is demonstrated for two additive manufactured (AM) titanium scaffold architectures. The results demonstrate that there is a complex interaction of flow rate and strut architecture, resulting in partially randomized structures having a preferential impact on stimulating cell migration in 3D porous structures for higher flow rates. This novel result demonstrates the potential new insights that can be gained via the modeling tool developed, and how the model can be used to perform what-if simulations to design AM structures to specific functional requirements. PMID:24664988

Rac1 Dosage Is Crucial for Normal Endochondral Bone Growth.

PubMed

Suzuki, Dai; Bush, Jason R; Bryce, Dawn-Marie; Kamijo, Ryutaro; Beier, Frank

2017-10-01

Rac1, a member of the small Rho GTPase family, plays multiple cellular roles. Studies of mice conditionally lacking Rac1 have revealed essential roles for Rac1 in various tissues, including cartilage and limb mesenchyme, where Rac1 loss produces dwarfism and long bone shortening. To gain further insight into the role of Rac1 in skeletal development, we have used transgenic mouse lines to express a constitutively active (ca) Rac1 mutant protein in a Cre recombinase-dependent manner. Overexpression of caRac1 in limb bud mesenchyme or chondrocytes leads to reduced body weight and shorter bones compared with control mice. Histological analysis of growth plates showed that caRac1;Col2-Cre mice displayed ectopic hypertrophic chondrocytes in the proliferative zone and enlarged hypertrophic zones. These mice also displayed a reduced proportion of proliferating cell nuclear antigen-positive cells in the proliferative zone and nuclear β-catenin localization in the ectopic hypertrophic chondrocytes. Importantly, overexpression of caRac1 partially rescued the phenotypes of Rac1fl/fl;Col2-Cre and Rac1fl/fl;Prx1-Cre conditional knockout mice, including body weight, bone length, and growth plate disorganization. These results suggest that tight regulation of Rac1 activity is necessary for normal cartilage development. Copyright © 2017 Endocrine Society.

Automated bone age assessment of older children using the radius

NASA Astrophysics Data System (ADS)

Tsao, Sinchai; Gertych, Arkadiusz; Zhang, Aifeng; Liu, Brent J.; Huang, Han K.

2008-03-01

The Digital Hand Atlas in Assessment of Skeletal Development is a large-scale Computer Aided Diagnosis (CAD) project for automating the process of grading Skeletal Development of children from 0-18 years of age. It includes a complete collection of 1,400 normal hand X-rays of children between the ages of 0-18 years of age. Bone Age Assessment is used as an index of skeletal development for detection of growth pathologies that can be related to endocrine, malnutrition and other disease types. Previous work at the Image Processing and Informatics Lab (IPILab) allowed the bone age CAD algorithm to accurately assess bone age of children from 1 to 16 (male) or 14 (female) years of age using the Phalanges as well as the Carpal Bones. At the older ages (16(male) or 14(female) -19 years of age) the Phalanges as well as the Carpal Bones are fully developed and do not provide well-defined features for accurate bone age assessment. Therefore integration of the Radius Bone as a region of interest (ROI) is greatly needed and will significantly improve the ability to accurately assess the bone age of older children. Preliminary studies show that an integrated Bone Age CAD that utilizes the Phalanges, Carpal Bones and Radius forms a robust method for automatic bone age assessment throughout the entire age range (1-19 years of age).

Altered paracrine signaling from the injured knee joint impairs postnatal long bone growth

PubMed Central

Roselló-Díez, Alberto; Stephen, Daniel; Joyner, Alexandra L

2017-01-01

Regulation of organ growth is a poorly understood process. In the long bones, the growth plates (GPs) drive elongation by generating a scaffold progressively replaced by bone. Although studies have focused on intrinsic GP regulation, classic and recent experiments suggest that local signals also modulate GP function. We devised a genetic mouse model to study extrinsic long bone growth modulation, in which injury is specifically induced in the left hindlimb, such that the right hindlimb serves as an internal control. Remarkably, when only mesenchyme cells surrounding postnatal GPs were killed, left bone growth was nevertheless reduced. GP signaling was impaired by altered paracrine signals from the knee joint, including activation of the injury response and, in neonates, dampened IGF1 production. Importantly, only the combined prevention of both responses rescued neonatal growth. Thus, we identified signals from the knee joint that modulate bone growth and could underlie establishment of body proportions. DOI: http://dx.doi.org/10.7554/eLife.27210.001 PMID:28741471

A comparison of skeletal maturity and growth.

PubMed

Molinari, Luciano; Gasser, Theo; Largo, Remo

2013-07-01

Somatic and bone development have each been studied in detail, but rarely in conjunction. The aim of this study was to determine what somatic and bone development have in common and how they differ. A second aim was to check for a pubertal spurt in bone age (BA) and to quantify it in a similar way as has been done for height. The Preece-Baines model is used to fit longitudinal data for BA. The data analysed are from the 1st Zurich Longitudinal Growth Study comprising 120 boys and 112 girls with almost complete data from birth to adulthood. Variability of somatic milestones was reduced in terms of BA and there was an aftergrowth after reaching adult RUS score 1000. A strong increase in the RUS score was seen at a late stage of the pubertal spurt (PS). Somatic milestones correlated with the RUS score attained at these ages and more so at an early stage of the PS. A PS for BA was clearly identified with a location at 14.2 years for boys and 12.2 years for girls. Age of peak bone development correlated highly with age of peak velocity of somatic variables. BA can be successfully modelled as a semi-quantitative entity. Bone development shows marked associations with somatic development, despite the fact that the latter reflects changes in size, while the former is essentially a maturity index and reflects changes in biochemical composition of tissues.

VEGF-incorporated biomimetic poly(lactide-co-glycolide) sintered microsphere scaffolds for bone tissue engineering.

PubMed

Jabbarzadeh, Ehsan; Deng, Meng; Lv, Qing; Jiang, Tao; Khan, Yusuf M; Nair, Lakshmi S; Laurencin, Cato T

2012-11-01

Regenerative engineering approaches utilizing biomimetic synthetic scaffolds provide alternative strategies to repair and restore damaged bone. The efficacy of the scaffolds for functional bone regeneration critically depends on their ability to induce and support vascular infiltration. In the present study, three-dimensional (3D) biomimetic poly(lactide-co-glycolide) (PLAGA) sintered microsphere scaffolds were developed by sintering together PLAGA microspheres followed by nucleation of minerals in a simulated body fluid. Further, the angiogenic potential of vascular endothelial growth factor (VEGF)-incorporated mineralized PLAGA scaffolds were examined by monitoring the growth and phenotypic expression of endothelial cells on scaffolds. Scanning electron microscopy micrographs confirmed the growth of bone-like mineral layers on the surface of microspheres. The mineralized PLAGA scaffolds possessed interconnectivity and a compressive modulus of 402 ± 61 MPa and compressive strength of 14.6 ± 2.9 MPa. Mineralized scaffolds supported the attachment and growth and normal phenotypic expression of endothelial cells. Further, precipitation of apatite layer on PLAGA scaffolds resulted in an enhanced VEGF adsorption and prolonged release compared to nonmineralized PLAGA and, thus, a significant increase in endothelial cell proliferation. Together, these results demonstrated the potential of VEGF-incorporated biomimetic PLAGA sintered microsphere scaffolds for bone tissue engineering as they possess the combined effects of osteointegrativity and angiogenesis. Copyright © 2012 Wiley Periodicals, Inc.

Loss of ephrinB1 in osteogenic progenitor cells impedes endochondral ossification and compromises bone strength integrity during skeletal development.

PubMed

Nguyen, Thao M; Arthur, Agnieszka; Paton, Sharon; Hemming, Sarah; Panagopoulos, Romana; Codrington, John; Walkley, Carl R; Zannettino, Andrew C W; Gronthos, Stan

2016-12-01

The EphB receptor tyrosine kinase family and their ephrinB ligands have been implicated as mediators of skeletal development and bone homeostasis in humans, where mutations in ephrinB1 contribute to frontonasal dysplasia and coronal craniosynostosis. In mouse models, ephrinB1 has been shown to be a critical factor mediating osteoblast function. The present study examined the functional importance of ephrinB1 during endochondral ossification using the Cre recombination system with targeted deletion of ephrinB1 (EfnB1 fl/fl ) in osteogenic progenitor cells, under the control of the osterix (Osx:Cre) promoter. The Osx:EfnB1 -/- mice displayed aberrant bone growth during embryonic and postnatal skeletal development up to 4weeks of age, when compared to the Osx:Cre controls. Furthermore, compared to the Osx:Cre control mice, the Osx:EfnB1 -/- mice exhibited significantly weaker and less rigid bones, with a reduction in trabecular/ cortical bone formation, reduced trabecular architecture and a reduction in the size of the growth plates at the distal end of the femora from newborn through to 4weeks of age. The aberrant bone formation correlated with increased numbers of tartrate resistant acid phosphatase positive osteoclasts and decreased numbers of bone lining osteoblasts in 4week old Osx:EfnB1 -/- mice, compared to Osx:Cre control mice. Taken together, these observations demonstrate the importance of ephrinB1 signalling between cells of the skeleton required for endochondral ossification. Copyright © 2016 Elsevier Inc. All rights reserved.

Growth and development of male "little" mice assessed with Parks' theory of feeding and growth.

PubMed

Puche, Rodolfo C; Alloatti, Rosa; Chapo, Gustavo

2002-01-01

This work was designed to characterize the appetite kinetics and growth of male C57BL/6J (lit) mice. Those variables were assessed with Parks' function of ad libitum feeding and growth. Heterozygous mice (lit/+) attained their mature weight at 12-15 weeks of age, peak growth rate (3.5 g/week) at 5 weeks and displayed the normal decay of food conversion efficiency as a function of age. The homozygous genotype has a chronic defect in the synthesis and secretion of growth hormone (GH). Homozygous mice could not be assessed with Park's function. From the 4th to the 15th week of age, body weight increased linearly and exhibited constant food conversion efficiency. Food intake of both genotypes was commensurate with their body weights. Lit/lit mice became progressively obese. At 40 weeks of age, body fat of lit/lit mice was fivefold that of lit/+ and their body weight was similar to their heterozygous controls. The chronic deficiency of growth hormone produced a lower bone mass (compared to heterozygous controls). Bone mass of both genotypes attained maturity at 12-15 weeks with a maximum growth rate at 5 weeks. Body weight and bone mass grow harmoniously in lit/+ but not in lit/lit mice.

Widespread differential maternal and paternal genome effects on fetal bone phenotype at mid-gestation.

PubMed

Xiang, Ruidong; Lee, Alice M C; Eindorf, Tanja; Javadmanesh, Ali; Ghanipoor-Samami, Mani; Gugger, Madeleine; Fitzsimmons, Carolyn J; Kruk, Zbigniew A; Pitchford, Wayne S; Leviton, Alison J; Thomsen, Dana A; Beckman, Ian; Anderson, Gail I; Burns, Brian M; Rutley, David L; Xian, Cory J; Hiendleder, Stefan

2014-11-01

Parent-of-origin-dependent (epi)genetic factors are important determinants of prenatal development that program adult phenotype. However, data on magnitude and specificity of maternal and paternal genome effects on fetal bone are lacking. We used an outbred bovine model to dissect and quantify effects of parental genomes, fetal sex, and nongenetic maternal effects on the fetal skeleton and analyzed phenotypic and molecular relationships between fetal muscle and bone. Analysis of 51 bone morphometric and weight parameters from 72 fetuses recovered at day 153 gestation (54% term) identified six principal components (PC1-6) that explained 80% of the variation in skeletal parameters. Parental genomes accounted for most of the variation in bone wet weight (PC1, 72.1%), limb ossification (PC2, 99.8%), flat bone size (PC4, 99.7%), and axial skeletal growth (PC5, 96.9%). Limb length showed lesser effects of parental genomes (PC3, 40.8%) and a significant nongenetic maternal effect (gestational weight gain, 29%). Fetal sex affected bone wet weight (PC1, p < 0.0001) and limb length (PC3, p < 0.05). Partitioning of variation explained by parental genomes revealed strong maternal genome effects on bone wet weight (74.1%, p < 0.0001) and axial skeletal growth (93.5%, p < 0.001), whereas paternal genome controlled limb ossification (95.1%, p < 0.0001). Histomorphometric data revealed strong maternal genome effects on growth plate height (98.6%, p < 0.0001) and trabecular thickness (85.5%, p < 0.0001) in distal femur. Parental genome effects on fetal bone were mirrored by maternal genome effects on fetal serum 25-hydroxyvitamin D (96.9%, p < 0.001) and paternal genome effects on alkaline phosphatase (90.0%, p < 0.001) and their correlations with maternally controlled bone wet weight and paternally controlled limb ossification, respectively. Bone wet weight and flat bone size correlated positively with muscle weight (r = 0.84 and 0.77, p < 0.0001) and negatively with muscle H19 expression (r = -0.34 and -0.31, p < 0.01). Because imprinted maternally expressed H19 regulates growth factors by miRNA interference, this suggests muscle-bone interaction via epigenetic factors. © 2014 American Society for Bone and Mineral Research.

Enhanced bioactive scaffolds for bone tissue regeneration

NASA Astrophysics Data System (ADS)

Karnik, Sonali

Bone injuries are commonly termed as fractures and they vary in their severity and causes. If the fracture is severe and there is loss of bone, implant surgery is prescribed. The response to the implant depends on the patient's physiology and implant material. Sometimes, the compromised physiology and undesired implant reactions lead to post-surgical complications. [4, 5, 20, 28] Efforts have been directed towards the development of efficient implant materials to tackle the problem of post-surgical implant failure. [ 15, 19, 24, 28, 32]. The field of tissue engineering and regenerative medicine involves the use of cells to form a new tissue on bio-absorbable or inert scaffolds. [2, 32] One of the applications of this field is to regenerate the damaged or lost bone by using stem cells or osteoprogenitor cells on scaffolds that can integrate in the host tissue without causing any harmful side effects. [2, 32] A variety of natural, synthetic materials and their combinations have been used to regenerate the damaged bone tissue. [2, 19, 30, 32, 43]. Growth factors have been supplied to progenitor cells to trigger a sequence of metabolic pathways leading to cellular proliferation, differentiation and to enhance their functionality. [56, 57] The challenge persists to supply these proteins, in the range of nano or even picograms, and in a sustained fashion over a period of time. A delivery system has yet to be developed that would mimic the body's inherent mechanism of delivering the growth factor molecules in the required amount to the target organ or tissue. Titanium is the most preferred metal for orthopedic and orthodontic implants. [28, 46, 48] Even though it has better osteogenic properties as compared to other metals and alloys, it still has drawbacks like poor integration into the surrounding host tissue leading to bone resorption and implant failure. [20, 28, 35] It also faces the problem of postsurgical infections that contributes to the implant failure. [26, 37]. The focus of this dissertation was to design and develop novel implant materials for coating titanium to improve its biological properties. These natural and/or semi-synthetic materials improved cellular adhesion, biological response to the scaffolds and prevented growth of bacteria when they were enhanced with growth factor and anti-infective loaded nanotubes. The implant materials showed promise when tested in vitro for cell proliferation, differentiation and bacterial growth inhibition.

Role of FGFs/FGFRs in skeletal development and bone regeneration.

PubMed

Du, Xiaolan; Xie, Yangli; Xian, Cory J; Chen, Lin

2012-12-01

Fibroblast growth factor (FGF)/FGF (FGFR) signaling is an important pathway involved in skeletal development. Missense mutations in FGFs and FGFRs were found clinically to cause multiple congenital skeleton diseases including chondrodysplasia, craniosynostosis, syndromes with dysregulated phosphate metabolism. FGFs/FGFRs also have crucial roles in bone fracture repair and bone regeneration. Understanding the molecular mechanisms for the role of FGFs/FGFRs in the regulation of skeletal development, genetic skeletal diseases, and fracture healing will ultimately lead to better treatment of skeleton diseases caused by mutations of FGFs/FGFRs and fracture. This review summarizes the major findings on the role of FGF signaling in skeletal development, genetic skeletal diseases and bone healing, and discusses issues that remain to be resolved in applying FGF signaling-related measures to promote bone healing. This review has also provided a perspective view on future work for exploring the roles and action mechanisms of FGF signaling in skeletal development, genetic skeletal diseases, and fracture healing. Copyright © 2012 Wiley Periodicals, Inc.

Cyp26b1 within the growth plate regulates bone growth in juvenile mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Minegishi, Yoshiki; Department of Plastic and Reconstructive Surgery, University of Fukui Hospital, 23-3 Matsuokashimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui 910-1193; Department of Plastic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871

Highlights: • Retinoic acid and Cyp26b1 were oppositely localized in growth plate cartilage. • Cyp26b1 deletion in chondrocytes decreased bone growth in juvenile mice. • Cyp26b1 deletion reduced chondrocyte proliferation and growth plate height. • Vitamin A-depletion partially reversed growth plate abnormalities caused by Cyp26b1 deficiency. • Cyp26b1 regulates bone growth by controlling chondrocyte proliferation. - Abstract: Retinoic acid (RA) is an active metabolite of vitamin A and plays important roles in embryonic development. CYP26 enzymes degrade RA and have specific expression patterns that produce a RA gradient, which regulates the patterning of various structures in the embryo. However, itmore » has not been addressed whether a RA gradient also exists and functions in organs after birth. We found localized RA activities in the diaphyseal portion of the growth plate cartilage were associated with the specific expression of Cyp26b1 in the epiphyseal portion in juvenile mice. To disturb the distribution of RA, we generated mice lacking Cyp26b1 specifically in chondrocytes (Cyp26b1{sup Δchon} cKO). These mice showed reduced skeletal growth in the juvenile stage. Additionally, their growth plate cartilage showed decreased proliferation rates of proliferative chondrocytes, which was associated with a reduced height in the zone of proliferative chondrocytes, and closed focally by four weeks of age, while wild-type mouse growth plates never closed. Feeding the Cyp26b1 cKO mice a vitamin A-deficient diet partially reversed these abnormalities of the growth plate cartilage. These results collectively suggest that Cyp26b1 in the growth plate regulates the proliferation rates of chondrocytes and is responsible for the normal function of the growth plate and growing bones in juvenile mice, probably by limiting the RA distribution in the growth plate proliferating zone.« less

Diagnostic workstation for digital hand atlas in bone age assessment

NASA Astrophysics Data System (ADS)

Cao, Fei; Huang, H. K.; Pietka, Ewa; Gilsanz, Vicente; Ominsky, Steven

1998-06-01

Bone age assessment by a radiological examination of a hand and wrist image is a procedure frequently performed in pediatric patients to evaluate growth disorders, determine growth potential in children and monitor therapy effects. The assessment method currently used in radiological diagnosis is based on atlas matching of the diagnosed hand image with the reference set of atlas patterns, which was developed in 1950s and is not fully applicable for children of today. We intent to implement a diagnostic workstation for creating a new reference set of clinically normal images which will serve as a digital atlas and can be used for a computer-assisted bone age assessment. In this paper, we present the initial data- collection and system setup phase of this five-year research program. We describe the system design, user interface implementation and software tool development for collection, visualization, management and processing of clinically normal hand and wrist images.

Effects of Recombinant Human Growth Hormone for Osteoporosis: Systematic Review and Meta-Analysis.

PubMed

Atkinson, Hayden F; Moyer, Rebecca F; Yacoub, Daniel; Coughlin, Dexter; Birmingham, Trevor B

2017-03-01

Our objective was to evaluate the efficacy of recombinant human growth hormone (GH) on bone mineral density (BMD) in persons age 50 and older, with normal pituitary function, with or at risk for developing osteoporosis. We systematically reviewed randomized clinical trials (RCTs), searching six databases, and conducted meta-analyses to examine GH effects on BMD of the lumbar spine and femoral neck. Data for fracture incidence, bone metabolism biomarkers, and adverse events were also extracted and analysed. Thirteen RCTs met the eligibility criteria. Pooled effect sizes suggested no significant GH effect on BMD. Pooled effect sizes were largest, but nonsignificant, when compared to placebo. GH had a significant effect on several bone metabolism biomarkers. A significantly higher rate of adverse events was observed in the GH groups. Meta-analysis of RCTs suggests that GH treatment for persons with or at risk for developing osteoporosis results in very small, nonsignificant increases in BMD.

Ontogeny of the maxilla in Neanderthals and their ancestors

PubMed Central

Lacruz, Rodrigo S.; Bromage, Timothy G.; O'Higgins, Paul; Arsuaga, Juan-Luis; Stringer, Chris; Godinho, Ricardo Miguel; Warshaw, Johanna; Martínez, Ignacio; Gracia-Tellez, Ana; de Castro, José María Bermúdez; Carbonell, Eudald

2015-01-01

Neanderthals had large and projecting (prognathic) faces similar to those of their putative ancestors from Sima de los Huesos (SH) and different from the retracted modern human face. When such differences arose during development and the morphogenetic modifications involved are unknown. We show that maxillary growth remodelling (bone formation and resorption) of the Devil's Tower (Gibraltar 2) and La Quina 18 Neanderthals and four SH hominins, all sub-adults, show extensive bone deposition, whereas in modern humans extensive osteoclastic bone resorption is found in the same regions. This morphogenetic difference is evident by ∼5 years of age. Modern human faces are distinct from those of the Neanderthal and SH fossils in part because their postnatal growth processes differ markedly. The growth remodelling identified in these fossil hominins is shared with Australopithecus and early Homo but not with modern humans suggesting that the modern human face is developmentally derived. PMID:26639346

Ontogeny of the maxilla in Neanderthals and their ancestors.

PubMed

Lacruz, Rodrigo S; Bromage, Timothy G; O'Higgins, Paul; Arsuaga, Juan-Luis; Stringer, Chris; Godinho, Ricardo Miguel; Warshaw, Johanna; Martínez, Ignacio; Gracia-Tellez, Ana; de Castro, José María Bermúdez; Carbonell, Eudald

2015-12-07

Neanderthals had large and projecting (prognathic) faces similar to those of their putative ancestors from Sima de los Huesos (SH) and different from the retracted modern human face. When such differences arose during development and the morphogenetic modifications involved are unknown. We show that maxillary growth remodelling (bone formation and resorption) of the Devil's Tower (Gibraltar 2) and La Quina 18 Neanderthals and four SH hominins, all sub-adults, show extensive bone deposition, whereas in modern humans extensive osteoclastic bone resorption is found in the same regions. This morphogenetic difference is evident by ∼5 years of age. Modern human faces are distinct from those of the Neanderthal and SH fossils in part because their postnatal growth processes differ markedly. The growth remodelling identified in these fossil hominins is shared with Australopithecus and early Homo but not with modern humans suggesting that the modern human face is developmentally derived.

In vitro comparison of the efficacy of TGF-β1 and PDGF-BB in combination with freeze-dried bone allografts for induction of osteogenic differentiation in MG-63 osteoblast-like cells.

PubMed

Vahabi, Surena; Torshabi, Maryam; Esmaeil Nejad, Azadeh

2016-12-01

Predictable regeneration of alveolar bone defects has always been a challenge in implant dentistry. Bone allografts are widely used bone substitutes with controversial osteoinductive activity. This in vitro study aimed to assess the osteogenic potential of some commercially available freeze-dried bone allografts supplemented with human recombinant platelet-derived growth factor-BB and transforming growth factor beta-1. Cell viability, mineralization, and osteogenic gene expression of MG-63 osteoblast-like cells were compared among the allograft alone, allograft/platelet-derived growth factor-BB, allograft/transforming growth factor beta-1, and allograft/platelet-derived growth factor-BB/transforming growth factor beta-1 groups. The methyl thiazol tetrazolium assay, real-time quantitative reverse transcription polymerase chain reaction and alizarin red staining were performed, respectively, for assessment of cell viability, differentiation, and mineralization at 24-72 h post treatment. The allograft with greater cytotoxic effect on MG-63 cells caused the lowest differentiation among the groups. In comparison with allograft alone, allograft/transforming growth factor beta-1, and allograft/transforming growth factor beta-1/platelet-derived growth factor-BB caused significant upregulation of bone sialoprotein and osteocalcin osteogenic mid-late marker genes, and resulted in significantly higher amounts of calcified nodules especially in mineralized non-cytotoxic allograft group. Supplementation of platelet-derived growth factor-BB alone in 5 ng/mL concentration had no significant effect on differentiation or mineralization markers. According to the results, transforming growth factor beta-1 acts synergistically with bone allografts to enhance the osteogenic differentiation potential. Therefore, this combination may be useful for rapid transformation of undifferentiated cells into bone-forming cells for bone regeneration. However, platelet-derived growth factor-BB supplementation did not support this synergistic ability to enhance osteogenic differentiation and thus, further investigations are required.

Comparative morphology, histology and growth of the dental plates of the Devonian dipnoan Chirodipterus.

PubMed

Smith, M M; Campbell, K S

1987-10-14

The dental plates of the Devonian lungfish Chirodipterus australis Miles (Osteichthyes; Dipnoi) are shown to have achieved their characteristic morphology by a growth process different from that assumed for the plates of genera such as Dipterus. Each plate was thickened by the addition of layers of bone that also extended the plate labially, thus providing the base on which and into which dentine grew. Distinctive features of the dentition are: (a) labial increase of the dentine mass by the addition of blister-like denticles of simple enamel-covered dentine, which is initially ingrown by pleromic dentine and subsequently resorbed and replaced by petrodentine; (b) increase in the midline by a similar process that results in the addition of one (or possibly two) new ridges; (c) resorption of the posterior edge of the pterygoid plates and the posterior and posteromedial edges of the prearticular plates, with subsequent development over the resorbed surfaces of several generations of simple regenerative dentine; (d) resorption and redeposition of pleromic dentine and bone in a triangular region posteromedially on the pterygoid plates; (e) the formation of tuberosities that simulate teeth at a short distance in from the labial edge, by four processes: formation of an undulating plate margin, differential growth of petrodentine (hard compact dentine) within the pulp cavity, differential wear of the petrodentine and the adjacent bone plus pleromic dentine, and slightly greater growth of the petrodentine towards the occlusal surface relative to the adjacent bone and dentine; (f) expansion of the large flat surfaces of the plates by gradual replacement of the bone and dentine at the proximal ends of the furrows and also by the development of linkages of petrodentine across the furrows; (g) development of isolated tuberosities on the flat posterolateral parts of the plates. The petrodentine of the ridges, tuberosities and plateaus of the plates is indistinguishable structurally and in its mode of growth from the petrodentine in extant species of dipnoans. Plates similar to those of C. australis have been observed in Stomiahykus, Archaeonectes, Conchodus, Palaedaphus and Sunwapta, as well as several species usually referred to as Dipterus. Sunwapta may be congeneric with C. australis.(ABSTRACT TRUNCATED AT 400 WORDS)

Insulin-like growth factor 1, glycation and bone fragility: implications for fracture resistance of bone.

PubMed

Sroga, Grażyna E; Wu, Ping-Cheng; Vashishth, Deepak

2015-01-01

Despite our extensive knowledge of insulin-like growth factor 1 (IGF1) action on the growing skeleton, its role in skeletal homeostasis during aging and age-related development of certain diseases is still unclear. Advanced glycation end products (AGEs) derived from glucose are implicated in osteoporosis and a number of diabetic complications. We hypothesized that because in humans and rodents IGF1 stimulates uptake of glucose (a glycation substrate) from the bloodstream in a dose-dependent manner, the decline of IGF1 could be associated with the accumulation of glycation products and the decreasing resistance of bone to fracture. To test the aforementioned hypotheses, we used human tibial posterior cortex bone samples to perform biochemical (measurement of IGF1, fluorescent AGEs and pentosidine (PEN) contents) and mechanical tests (crack initiation and propagation using compact tension specimens). Our results for the first time show a significant, age-independent association between the levels of IGF1 and AGEs. Furthermore, AGEs (fAGEs, PEN) predict propensity of bone to fracture (initiation and propagation) independently of age in human cortical bone. Based on these results we propose a model of IGF1-based regulation of bone fracture. Because IGF1 level increases postnatally up to the juvenile developmental phase and decreases thereafter with aging, we propose that IGF1 may play a protective role in young skeleton and its age-related decline leads to bone fragility and an increased fracture risk. Our results may also have important implications for current understanding of osteoporosis- and diabetes-related bone fragility as well as in the development of new diagnostic tools to screen for fragile bones.

Insulin-Like Growth Factor 1, Glycation and Bone Fragility: Implications for Fracture Resistance of Bone

PubMed Central

Sroga, Grażyna E.; Wu, Ping-Cheng; Vashishth, Deepak

2015-01-01

Despite our extensive knowledge of insulin-like growth factor 1 (IGF1) action on the growing skeleton, its role in skeletal homeostasis during aging and age-related development of certain diseases is still unclear. Advanced glycation end products (AGEs) derived from glucose are implicated in osteoporosis and a number of diabetic complications. We hypothesized that because in humans and rodents IGF1 stimulates uptake of glucose (a glycation substrate) from the bloodstream in a dose-dependent manner, the decline of IGF1 could be associated with the accumulation of glycation products and the decreasing resistance of bone to fracture. To test the aforementioned hypotheses, we used human tibial posterior cortex bone samples to perform biochemical (measurement of IGF1, fluorescent AGEs and pentosidine (PEN) contents) and mechanical tests (crack initiation and propagation using compact tension specimens). Our results for the first time show a significant, age-independent association between the levels of IGF1 and AGEs. Furthermore, AGEs (fAGEs, PEN) predict propensity of bone to fracture (initiation and propagation) independently of age in human cortical bone. Based on these results we propose a model of IGF1-based regulation of bone fracture. Because IGF1 level increases postnatally up to the juvenile developmental phase and decreases thereafter with aging, we propose that IGF1 may play a protective role in young skeleton and its age-related decline leads to bone fragility and an increased fracture risk. Our results may also have important implications for current understanding of osteoporosis- and diabetes-related bone fragility as well as in the development of new diagnostic tools to screen for fragile bones. PMID:25629402

Osteoclast inhibition impairs chondrosarcoma growth and bone destruction.

PubMed

Otero, Jesse E; Stevens, Jeff W; Malandra, Allison E; Fredericks, Douglas C; Odgren, Paul R; Buckwalter, Joseph A; Morcuende, Jose

2014-12-01

Because Chondrosarcoma is resistant to available chemotherapy and radiation regimens, wide resection is the mainstay in treatment, which frequently results in high morbidity and which may not prevent local recurrence. There is a clear need for improved adjuvant treatment of this malignancy. We have observed the presence of osteoclasts in the microenvironment of chondrosarcoma in human pathological specimens. We utilized the Swarm rat chondrosarcoma (SRC) model to test the hypothesis that osteoclasts affect chondrosarcoma pathogenesis. We implanted SRC tumors in tibia of Sprague-Dawley rats and analyzed bone histologically and radiographically for bone destruction and tumor growth. At three weeks, tumors invaded local bone causing cortical disruption and trabecular resorption. Bone destruction was accompanied by increased osteoclast number and resorbed bone surface. Treatment of rats with the zoledronic acid prevented cortical destruction, inhibited trabecular resorption, and resulted in decreased tumor volume in bone. To confirm that inhibition of osteoclasts per se, and not off-target effects of drug, was responsible for the prevention of tumor growth and bone destruction, we implanted SRC into osteopetrotic rat tibia. SRC-induced bone destruction and tumor growth were impaired in osteopetrotic bone compared with control bone. The results from our animal model demonstrate that osteoclasts contribute to chondrosarcoma-mediated bone destruction and tumor growth and may represent a therapeutic target in particular chondrosarcoma patients. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Effects of combined maternal administration with alpha-ketoglutarate (AKG) and β-hydroxy-β-methylbutyrate (HMB) on prenatal programming of skeletal properties in the offspring.

PubMed

Tatara, Marcin R; Krupski, Witold; Tymczyna, Barbara; Studziński, Tadeusz

2012-05-11

Nutritional manipulations during fetal growth may induce long-term metabolic effects in postnatal life. The aim of the study was to test whether combined treatment of pregnant sows with alpha-ketoglutarate and β-hydroxy-β-methylbutyrate induces additive long-term effects on skeletal system properties in the offspring. The study was performed on 290 pigs obtained from 24 sows divided into 4 equal groups and subjected to experimental treatment during two weeks before delivery. The first group consisted of control sows, while the second group received alpha-ketoglutarate. The third group was treated with β-hydroxy-β-methylbutyrate and the fourth group underwent combined administration of alpha-ketoglutarate and β-hydroxy-β-methylbutyrate. Piglets obtained from sows were reared until slaughter age to perform morphometric, densitometric and mechanical analyses of femur. Serum evaluations of growth hormone, insulin-like growth factor-1, bone-specific alkaline phosphatase and osteocalcin were performed in newborns and 90-day old piglets; additionally, plasma amino acid concentration was measured in newborns. Maternal treatment with alpha-ketoglutarate and β-hydroxy-β-methylbutyrate significantly reduced fattening time and increased birth body weight, daily body weight gain, bone weight, volumetric bone mineral density, geometrical parameters and mechanical endurance of femur. These effects were associated with increased serum concentrations of growth hormone, insulin-like growth factor-1, bone-specific alkaline phosphatase and osteocalcin. Furthermore, alpha-ketoglutarate and β-hydroxy-β-methylbutyrate administered solely or in combination significantly increased plasma level of 19 amino acids. Hormonal and amino acid evaluations in pigs indicate additive effects of AKG and HMB on systemic growth and development; however, determination of bone properties has not shown such phenomenon.

Effects of combined maternal administration with alpha-ketoglutarate (AKG) and β-hydroxy-β-methylbutyrate (HMB) on prenatal programming of skeletal properties in the offspring

PubMed Central

2012-01-01

Background Nutritional manipulations during fetal growth may induce long-term metabolic effects in postnatal life. The aim of the study was to test whether combined treatment of pregnant sows with alpha-ketoglutarate and β-hydroxy-β-methylbutyrate induces additive long-term effects on skeletal system properties in the offspring. Methods The study was performed on 290 pigs obtained from 24 sows divided into 4 equal groups and subjected to experimental treatment during two weeks before delivery. The first group consisted of control sows, while the second group received alpha-ketoglutarate. The third group was treated with β-hydroxy-β-methylbutyrate and the fourth group underwent combined administration of alpha-ketoglutarate and β-hydroxy-β-methylbutyrate. Piglets obtained from sows were reared until slaughter age to perform morphometric, densitometric and mechanical analyses of femur. Serum evaluations of growth hormone, insulin-like growth factor-1, bone-specific alkaline phosphatase and osteocalcin were performed in newborns and 90-day old piglets; additionally, plasma amino acid concentration was measured in newborns. Results Maternal treatment with alpha-ketoglutarate and β-hydroxy-β-methylbutyrate significantly reduced fattening time and increased birth body weight, daily body weight gain, bone weight, volumetric bone mineral density, geometrical parameters and mechanical endurance of femur. These effects were associated with increased serum concentrations of growth hormone, insulin-like growth factor-1, bone-specific alkaline phosphatase and osteocalcin. Furthermore, alpha-ketoglutarate and β-hydroxy-β-methylbutyrate administered solely or in combination significantly increased plasma level of 19 amino acids. Conclusions Hormonal and amino acid evaluations in pigs indicate additive effects of AKG and HMB on systemic growth and development; however, determination of bone properties has not shown such phenomenon. PMID:22578071

Phosphate homeostasis and its role in bone health.

PubMed

Penido, Maria Goretti M G; Alon, Uri S

2012-11-01

Phosphate is one of the most abundant minerals in the body, and its serum levels are regulated by a complex set of processes occurring in the intestine, skeleton, and kidneys. The currently known main regulators of phosphate homeostasis include parathyroid hormone (PTH), calcitriol, and a number of peptides collectively known as the "phosphatonins" of which fibroblast growth factor-23 (FGF-23) has been best defined. Maintenance of extracellular and intracellular phosphate levels within a narrow range is important for many biological processes, including energy metabolism, cell signaling, regulation of protein synthesis, skeletal development, and bone integrity. The presence of adequate amounts of phosphate is critical for the process of apoptosis of mature chondrocytes in the growth plate. Without the presence of this mineral in high enough quantities, chondrocytes will not go into apoptosis, and the normal physiological chain of events that includes invasion of blood vessels and the generation of new bone will be blocked, resulting in rickets and delayed growth. In the rest of the skeleton, hypophosphatemia will result in osteomalacia due to an insufficient formation of hydroxyapatite. This review will address phosphate metabolism and its role in bone health.

Influence of growth hormone replacement on neurological and psychomotor development. Case report.

PubMed

Motta, Felipe; Eisencraft, Adriana Pasmanik; Crisostomo, Lindiane Gomes

2018-05-14

The height response to the use of growth hormone in short height cases has already been confirmed in the literature. The influence of the insulin-like growth factor 1 (GH-IGF1) axis components on development, function, regeneration, neuroprotection, cognition, and motor functions has been evaluated in experimental studies and in adults with central nervous system lesions. However, there is still little research on the clinical impact of hormone replacement on neurological and psychomotor development. This report presents the case of a patient with excellent weight-height recovery and, even more surprisingly, neurological and psychomotor development in response to use of growth hormone. The result strengthens the correlation between experimental and clinical findings related to cerebral plasticity response to growth hormone in children. A preterm male patient with multiple health problems during the neonatal and young infancy period, who for six years presented with a relevant deficit in growth, bone maturation, and neurological and psychomotor development. At six years of age, he had low stature (z-score -6.89), low growth rate, and low weight (z-score -7.91). He was incapable of sustaining his axial weight, had not developed fine motor skills or sphincter control, and presented with dysfunctional swallowing and language. Supplementary tests showed low IGF-11 levels, with no changes on the image of the hypothalamus-pituitary region, and bone age consistent with three-year-old children - for a chronological age of six years and one month. Growth hormone replacement therapy had a strong impact on the weight-height recovery as well as on the neurological and psychomotor development of this child.

Phenotypic characterization of Grm1crv4 mice reveals a functional role for the type 1 metabotropic glutamate receptor in bone mineralization.

PubMed

Musante, Ilaria; Mattinzoli, Deborah; Otescu, Lavinia Alexandra; Bossi, Simone; Ikehata, Masami; Gentili, Chiara; Cangemi, Giuliana; Gatti, Cinzia; Emionite, Laura; Messa, Piergiorgio; Ravazzolo, Roberto; Rastaldi, Maria Pia; Riccardi, Daniela; Puliti, Aldamaria

2017-01-01

Recent increasing evidence supports a role for neuronal type signaling in bone. Specifically glutamate receptors have been found in cells responsible for bone remodeling, namely the osteoblasts and the osteoclasts. While most studies have focused on ionotropic glutamate receptors, the relevance of the metabotropic glutamate signaling in bone is poorly understood. Specifically type 1 metabotropic glutamate (mGlu1) receptors are expressed in bone, but the effect of its ablation on skeletal development has never been investigated. Here we report that Grm1 crv4/crv4 mice, homozygous for an inactivating mutation of the mGlu1 receptor, and mainly characterized by ataxia and renal dysfunction, exhibit decreased body weight, bone length and bone mineral density compared to wild type (WT) animals. Blood analyses of the affected mice demonstrate the absence of changes in circulating factors, such as vitamin D and PTH, suggesting renal damage is not the main culprit of the skeletal phenotype. Cultures of osteoblasts lacking functional mGlu1 receptors exhibit less homogeneous collagen deposition than WT cells, and present increased expression of osteocalcin, a marker of osteoblast maturation. These data suggest that the skeletal damage is directly linked to the absence of the receptor, which in turn leads to osteoblasts dysfunction and earlier maturation. Accordingly, skeletal histomorphology suggests that Grm1 crv4/crv4 mice exhibit enhanced bone maturation, resulting in premature fusion of the growth plate and shortened long bones, and further slowdown of bone apposition rate compared to the WT animals. In summary, this work reveals novel functions of mGlu1 receptors in the bone and indicates that in osteoblasts mGlu1 receptors are necessary for production of normal bone matrix, longitudinal bone growth, and normal skeletal development. Copyright © 2016 Elsevier Inc. All rights reserved.

Effect of transforming growth factor beta (TGF-β) receptor I kinase inhibitor on prostate cancer bone growth.

PubMed

Wan, Xinhai; Li, Zhi-Gang; Yingling, Jonathan M; Yang, Jun; Starbuck, Michael W; Ravoori, Murali K; Kundra, Vikas; Vazquez, Elba; Navone, Nora M

2012-03-01

Transforming growth factor beta 1 (TGF-β1) has been implicated in the pathogenesis of prostate cancer (PCa) bone metastasis. In this study, we tested the antitumor efficacy of a selective TGF-β receptor I kinase inhibitor, LY2109761, in preclinical models. The effect of LY2109761 on the growth of MDA PCa 2b and PC-3 human PCa cells and primary mouse osteoblasts (PMOs) was assessed in vitro by measuring radiolabeled thymidine incorporation into DNA. In vivo, the right femurs of male SCID mice were injected with PCa cells. We monitored the tumor burden in control- and LY2109761-treated mice with MRI analysis and the PCa-induced bone response with X-ray and micro-CT analyses. Histologic changes in bone were studied by performing bone histomorphometric evaluations. PCa cells and PMOs expressed TGF-β receptor I. TGF-β1 induced pathway activation (as assessed by induced expression of p-Smad2) and inhibited cell growth in PC-3 cells and PMOs but not in MDA PCa 2b cells. LY2109761 had no effect on PCa cells but induced PMO proliferation in vitro. As expected, LY2109761 reversed the TGF-β1-induced pathway activation and growth inhibition in PC-3 cells and PMOs. In vivo, LY2109761 treatment for 6weeks resulted in increased volume in normal bone and increased osteoblast and osteoclast parameters. In addition, LY2109761 treatment significantly inhibited the growth of MDA PCa 2b and PC-3 in the bone of SCID mice (p<0.05); moreover, it resulted in significantly less bone loss and change in osteoclast-associated parameters in the PC-3 tumor-bearing bones than in the untreated mice. In summary, we report for the first time that targeting TGF-β receptors with LY2109761 can control PCa bone growth while increasing the mass of normal bone. This increased bone mass in nontumorous bone may be a desirable side effect of LY2109761 treatment for men with osteopenia or osteoporosis secondary to androgen-ablation therapy, reinforcing the benefit of effectively controlling PCa growth in bone. Thus, targeting TGF-β receptor I is a valuable intervention in men with advanced PCa. Copyright © 2011 Elsevier Inc. All rights reserved.

Effect of transforming growth factor beta (TGF-β) receptor I kinase inhibitor on prostate cancer bone growth

PubMed Central

Wan, Xinhai; Li, Zhi-Gang; Yingling, Jonathan M.; Yang, Jun; Starbuck, Michael W.; Ravoori, Murali K.; Kundra, Vikas; Vazquez, Elba; Navone, Nora M.

2012-01-01

Transforming growth factor beta 1 (TGF-β1) has been implicated in the pathogenesis of prostate cancer (PCa) bone metastasis. In this study, we tested the antitumor efficacy of a selective TGF-β receptor I kinase inhibitor, LY2109761, in preclinical models. The effect of LY2109761 on the growth of MDA PCa 2b and PC-3 human PCa cells and primary mouse osteoblasts (PMOs) was assessed in vitro by measuring radiolabeled thymidine incorporation into DNA. In vivo, the right femurs of male SCID mice were injected with PCa cells. We monitored the tumor burden in control- and LY2109761-treated mice with MRI analysis and the PCa-induced bone response with x-ray and micro-CT analyses. Histologic changes in bone were studied by performing bone histomorphometric evaluations. PCa cells and PMOs expressed TGF-β receptor I. TGF-β1 induced pathway activation (as assessed by induced expression of p-Smad2) and inhibited cell growth in PC-3 cells and PMOs but not in MDA PCa 2b cells. LY2109761 had no effect on PCa cells but induced PMO proliferation in vitro. As expected, LY2109761 reversed the TGF-β1–induced pathway activation and growth inhibition in PC-3 cells and PMOs. In vivo, LY2109761 treatment for 6 weeks resulted in increased volume in normal bone and increased osteoblast and osteoclast parameters. In addition, LY2109761 treatment significantly inhibited the growth of MDA PCa 2b and PC-3 in the bone of SCID mice (p < 0.05); moreover, it resulted in significantly less bone loss and change in osteoclast-associated parameters in the PC-3 tumor–bearing bones than in the untreated mice. In summary, we report for the first time that targeting TGF-β receptors with LY2109761 can control PCa bone growth while increasing the mass of normal bone. This increased bone mass in nontumorous bone may be a desirable side effect of LY2109761 treatment for men with osteopenia or osteoporosis secondary to androgen-ablation therapy, reinforcing the benefit of effectively controlling PCa growth in bone. Thus, targeting TGF-β receptor I is a valuable intervention in men with advanced PCa. PMID:22173053

Bone Geometry as a Predictor of Tissue Fragility and Stress Fracture Risk

DTIC Science & Technology

2005-10-01

sectional growth. Bone 14:635–642. 23. Duan Y, Beck TJ, Wang XF, Seeman E 2003 Structural and biomechanical basis of sexual dimorphism in femoral neck...orientation in primary bone? An evaluation in the turkey ulna diaphysis. J Anat 205:121–134. 48. Jepsen KJ, Davy DT, Akkus O 2001 Observations of damage in bone...significantly alter their growth patterns after puberty and predispose them to dras- tically increased bone growth in association with sexual

Adaptive growth factor delivery from a polyelectrolyte coating promotes synergistic bone tissue repair and reconstruction

PubMed Central

Shah, Nisarg J.; Hyder, Md. Nasim; Quadir, Mohiuddin A.; Dorval Courchesne, Noémie-Manuelle; Seeherman, Howard J.; Nevins, Myron; Spector, Myron; Hammond, Paula T.

2014-01-01

Traumatic wounds and congenital defects that require large-scale bone tissue repair have few successful clinical therapies, particularly for craniomaxillofacial defects. Although bioactive materials have demonstrated alternative approaches to tissue repair, an optimized materials system for reproducible, safe, and targeted repair remains elusive. We hypothesized that controlled, rapid bone formation in large, critical-size defects could be induced by simultaneously delivering multiple biological growth factors to the site of the wound. Here, we report an approach for bone repair using a polyelectrolye multilayer coating carrying as little as 200 ng of bone morphogenetic protein-2 and platelet-derived growth factor-BB that were eluted over readily adapted time scales to induce rapid bone repair. Based on electrostatic interactions between the polymer multilayers and growth factors alone, we sustained mitogenic and osteogenic signals with these growth factors in an easily tunable and controlled manner to direct endogenous cell function. To prove the role of this adaptive release system, we applied the polyelectrolyte coating on a well-studied biodegradable poly(lactic-co-glycolic acid) support membrane. The released growth factors directed cellular processes to induce bone repair in a critical-size rat calvaria model. The released growth factors promoted local bone formation that bridged a critical-size defect in the calvaria as early as 2 wk after implantation. Mature, mechanically competent bone regenerated the native calvaria form. Such an approach could be clinically useful and has significant benefits as a synthetic, off-the-shelf, cell-free option for bone tissue repair and restoration. PMID:25136093

Dmp1-deficient Mice Display Severe Defects in Cartilage Formation Responsible for a Chondrodysplasia-like Phenotype*

PubMed Central

Ye, Ling; Mishina, Yuji; Chen, Di; Huang, Haiyang; Dallas, Sarah L.; Dallas, Mark R.; Sivakumar, Pitchumani; Kunieda, Tetsuo; Tsutsui, Takeo W.; Boskey, Adele; Bonewald, Lynda F.; Feng, Jian Q.

2009-01-01

Understanding the molecular mechanisms by which cartilage formation is regulated is essential toward understanding the physiology of both embryonic bone development and postnatal bone growth. Although much is known about growth factor signaling in cartilage formation, the regulatory role of noncollagenous matrix proteins in this process are still largely unknown. In the present studies, we present evidence for a critical role of DMP1 (dentin matrix protein 1) in postnatal chondrogenesis. The Dmp1 gene was originally identified from a rat incisor cDNA library and has been shown to play an important role in late stage dentinogenesis. Whereas no apparent abnormalities were observed in prenatal bone development, Dmp1-deficient (Dmp1−/−) mice unexpectedly develop a severe defect in cartilage formation during postnatal chondrogenesis. Vertebrae and long bones in Dmp1-deficient (Dmp1−/−) mice are shorter and wider with delayed and malformed secondary ossification centers and an irregular and highly expanded growth plate, results of both a highly expanded proliferation and a highly expanded hypertrophic zone creating a phenotype resembling dwarfism with chondrodysplasia. This phenotype appears to be due to increased cell proliferation in the proliferating zone and reduced apoptosis in the hypertrophic zone. In addition, blood vessel invasion is impaired in the epiphyses of Dmp1−/− mice. These findings show that DMP1 is essential for normal postnatal chondrogenesis and subsequent osteogenesis. PMID:15590631

A study of stress-free living bone and its application to space flight

NASA Technical Reports Server (NTRS)

Leblanc, A.; Spira, M.

1983-01-01

Observations of animals and human subjects in weightless space flight (Skylab and COSMOS) document altered bone metabolism. Bone metabolism is affected by a number of local and systemic factors. The calcification and growth of transplanted bone is independent of local muscle, nervous, and mechanical forces; therefore, transplanted bone would provide data on the role of local vs. systematic factors. Bone metabolism in living transplanted bone, devoid of stress, was investigated as a possible tool for the investigation of countermeasures against disuse bone loss. An animal model using Sprague-Dawley rats was developed for transplantation of femur bone tissue on a nutrient vascular pedicel. The long term course of these implants was assessed through the measure of regional and total bone mineral, blood flow, and methylene diphosphonate (MDP) uptake. Clomid, an estrogen agonist/antagonist, was shown to protect bone from disuse loss of minerals by retarding trabecular and cortical resorption.

Consensus and controversy regarding osteoporosis in the pediatric population.

PubMed

Bachrach, Laura Keyes

2007-09-01

To review current consensus and controversy surrounding the diagnosis and treatment of osteoporosis in childhood and adolescence. The medical literature was reviewed with emphasis on the importance of early skeletal health, risk factors for bone fragility, and the diagnosis and management of children at risk for osteoporosis. Childhood and adolescence are critical periods for optimizing bone growth and mineral accrual. Bone strength is determined by bone size, geometry, quality, and mass-variables that are influenced by genetic factors, activity, nutrition, and hormones. For children with genetic skeletal disorders or chronic disease, bone growth and mineral accrual may be compromised, increasing the lifetime risk of osteoporosis. The goal for the clinician is to identify children at greatest risk for future fragility fracture. Bone densitometry and turnover markers are challenging to interpret in children. Prevention and treatment of bone fragility in children are less well established than in adults. Optimizing nutrition and activity may not restore bone health, but the drug armamentarium is limited. Sex steroid replacement has not proven effective in restoring bone mass in patients with anorexia nervosa or exercise-associated amenorrhea. Bisphosphonates can increase bone mass and may reduce bone pain and fractures, most convincingly in patients with osteogenesis imperfecta. Further studies are needed to establish the safety, efficacy, and optimal drug, duration, and dosage in pediatric patients. Bone health during the first 2 decades contributes to the lifetime risk of osteoporosis. Further research is needed to develop evidence-based recommendations for the diagnosis and treatment of osteoporosis in childhood.

Tissue Nonspecific Alkaline Phosphatase (TNAP) Regulates Cranial Base Growth and Synchondrosis Maturation

PubMed Central

Nam, Hwa K.; Sharma, Monika; Liu, Jin; Hatch, Nan E.

2017-01-01

Hypophosphatasia is a rare heritable disorder caused by inactivating mutations in the gene (Alpl) that encodes tissue nonspecific alkaline phosphatase (TNAP). Hypophosphatasia with onset in infants and children can manifest as rickets. How TNAP deficiency leads to bone hypomineralization is well explained by TNAP's primary function of pyrophosphate hydrolysis when expressed in differentiated bone forming cells. How TNAP deficiency leads to abnormalities within endochondral growth plates is not yet known. Previous studies in hypophosphatemic mice showed that phosphate promotes chondrocyte maturation and apoptosis via MAPK signaling. Alpl−/− mice are not hypophosphatemic but TNAP activity does increase local levels of inorganic phosphate. Therefore, we hypothesize that TNAP influences endochondral bone development via MAPK. In support of this premise, here we demonstrate cranial base bone growth deficiency in Alpl−/− mice, utilize primary rib chondrocytes to show that TNAP influences chondrocyte maturation, apoptosis, and MAPK signaling in a cell autonomous manner; and demonstrate that similar chondrocyte signaling and apoptosis abnormalities are present in the cranial base synchondroses of Alpl−/− mice. Micro CT studies revealed diminished anterior cranial base bone and total cranial base lengths in Alpl−/− mice, that were prevented upon injection with mineral-targeted recombinant TNAP (strensiq). Histomorphometry of the inter-sphenoidal synchondrosis (cranial base growth plate) demonstrated significant expansion of the hypertrophic chondrocyte zone in Alpl−/− mice that was minimized upon treatment with recombinant TNAP. Alpl−/− primary rib chondrocytes exhibited diminished chondrocyte proliferation, aberrant mRNA expression, diminished hypertrophic chondrocyte apoptosis and diminished MAPK signaling. Diminished apoptosis and VEGF expression were also seen in 15 day-old cranial base synchondroses of Alpl−/− mice. MAPK signaling was significantly diminished in 5 day-old cranial base synchondroses of Alpl−/− mice. Together, our data suggests that TNAP is essential for the later stages of endochondral bone development including hypertrophic chondrocyte apoptosis and VEGF mediated recruitment of blood vessels for replacement of cartilage with bone. These changes may be mediated by diminished MAPK signaling in TNAP deficient chondrocytes due to diminished local inorganic phosphate production. PMID:28377728

Proportionate Dwarfism in Mice Lacking Heterochromatin Protein 1 Binding Protein 3 (HP1BP3) Is Associated With Alterations in the Endocrine IGF-1 Pathway

PubMed Central

Arad, Shiri; Le, Phuong T.; Bustin, Michael; Rosen, Clifford J.; Gabet, Yankel

2015-01-01

Heterochromatin protein 1 binding protein 3 (HP1BP3) is a recently described histone H1-related protein with roles in chromatin structure and transcriptional regulation. To explore the potential physiological role of HP1BP3, we have previously described an Hp1bp3−/− mouse model with reduced postnatal viability and growth. We now find that these mice are proportionate dwarfs, with reduction in body weight, body length, and organ weight. In addition to their small size, microcomputed tomography analysis showed that Hp1bp3−/− mice present a dramatic impairment of their bone development and structure. By 3 weeks of age, mice of both sexes have severely impaired cortical and trabecular bone, and these defects persist into adulthood and beyond. Primary cultures of both osteoblasts and osteoclasts from Hp1bp3−/− bone marrow and splenocytes, respectively, showed normal differentiation and function, strongly suggesting that the impaired bone accrual is due to noncell autonomous systemic cues in vivo. One major endocrine pathway regulating both body growth and bone acquisition is the IGF regulatory system, composed of IGF-1, the IGF receptors, and the IGF-binding proteins (IGFBPs). At 3 weeks of age, Hp1bp3−/− mice exhibited a 60% reduction in circulating IGF-1 and a 4-fold increase in the levels of IGFBP-1 and IGFBP-2. These alterations were reflected in similar changes in the hepatic transcripts of the Igf1, Igfbp1, and Igfbp2 genes. Collectively, these results suggest that HP1BP3 plays a key role in normal growth and bone development by regulating transcription of endocrine IGF-1 components. PMID:26402843

Proportionate Dwarfism in Mice Lacking Heterochromatin Protein 1 Binding Protein 3 (HP1BP3) Is Associated With Alterations in the Endocrine IGF-1 Pathway.

PubMed

Garfinkel, Benjamin P; Arad, Shiri; Le, Phuong T; Bustin, Michael; Rosen, Clifford J; Gabet, Yankel; Orly, Joseph

2015-12-01

Heterochromatin protein 1 binding protein 3 (HP1BP3) is a recently described histone H1-related protein with roles in chromatin structure and transcriptional regulation. To explore the potential physiological role of HP1BP3, we have previously described an Hp1bp3(-/-) mouse model with reduced postnatal viability and growth. We now find that these mice are proportionate dwarfs, with reduction in body weight, body length, and organ weight. In addition to their small size, microcomputed tomography analysis showed that Hp1bp3(-/-) mice present a dramatic impairment of their bone development and structure. By 3 weeks of age, mice of both sexes have severely impaired cortical and trabecular bone, and these defects persist into adulthood and beyond. Primary cultures of both osteoblasts and osteoclasts from Hp1bp3(-/-) bone marrow and splenocytes, respectively, showed normal differentiation and function, strongly suggesting that the impaired bone accrual is due to noncell autonomous systemic cues in vivo. One major endocrine pathway regulating both body growth and bone acquisition is the IGF regulatory system, composed of IGF-1, the IGF receptors, and the IGF-binding proteins (IGFBPs). At 3 weeks of age, Hp1bp3(-/-) mice exhibited a 60% reduction in circulating IGF-1 and a 4-fold increase in the levels of IGFBP-1 and IGFBP-2. These alterations were reflected in similar changes in the hepatic transcripts of the Igf1, Igfbp1, and Igfbp2 genes. Collectively, these results suggest that HP1BP3 plays a key role in normal growth and bone development by regulating transcription of endocrine IGF-1 components.

Gut microbiota induce IGF-1 and promote bone formation and growth.

PubMed

Yan, Jing; Herzog, Jeremy W; Tsang, Kelly; Brennan, Caitlin A; Bower, Maureen A; Garrett, Wendy S; Sartor, Balfour R; Aliprantis, Antonios O; Charles, Julia F

2016-11-22

Appreciation of the role of the gut microbiome in regulating vertebrate metabolism has exploded recently. However, the effects of gut microbiota on skeletal growth and homeostasis have only recently begun to be explored. Here, we report that colonization of sexually mature germ-free (GF) mice with conventional specific pathogen-free (SPF) gut microbiota increases both bone formation and resorption, with the net effect of colonization varying with the duration of colonization. Although colonization of adult mice acutely reduces bone mass, in long-term colonized mice, an increase in bone formation and growth plate activity predominates, resulting in equalization of bone mass and increased longitudinal and radial bone growth. Serum levels of insulin-like growth factor 1 (IGF-1), a hormone with known actions on skeletal growth, are substantially increased in response to microbial colonization, with significant increases in liver and adipose tissue IGF-1 production. Antibiotic treatment of conventional mice, in contrast, decreases serum IGF-1 and inhibits bone formation. Supplementation of antibiotic-treated mice with short-chain fatty acids (SCFAs), products of microbial metabolism, restores IGF-1 and bone mass to levels seen in nonantibiotic-treated mice. Thus, SCFA production may be one mechanism by which microbiota increase serum IGF-1. Our study demonstrates that gut microbiota provide a net anabolic stimulus to the skeleton, which is likely mediated by IGF-1. Manipulation of the microbiome or its metabolites may afford opportunities to optimize bone health and growth.

Gut microbiota induce IGF-1 and promote bone formation and growth

PubMed Central

Yan, Jing; Herzog, Jeremy W.; Tsang, Kelly; Brennan, Caitlin A.; Bower, Maureen A.; Garrett, Wendy S.; Sartor, Balfour R.; Charles, Julia F.

2016-01-01

Appreciation of the role of the gut microbiome in regulating vertebrate metabolism has exploded recently. However, the effects of gut microbiota on skeletal growth and homeostasis have only recently begun to be explored. Here, we report that colonization of sexually mature germ-free (GF) mice with conventional specific pathogen-free (SPF) gut microbiota increases both bone formation and resorption, with the net effect of colonization varying with the duration of colonization. Although colonization of adult mice acutely reduces bone mass, in long-term colonized mice, an increase in bone formation and growth plate activity predominates, resulting in equalization of bone mass and increased longitudinal and radial bone growth. Serum levels of insulin-like growth factor 1 (IGF-1), a hormone with known actions on skeletal growth, are substantially increased in response to microbial colonization, with significant increases in liver and adipose tissue IGF-1 production. Antibiotic treatment of conventional mice, in contrast, decreases serum IGF-1 and inhibits bone formation. Supplementation of antibiotic-treated mice with short-chain fatty acids (SCFAs), products of microbial metabolism, restores IGF-1 and bone mass to levels seen in nonantibiotic-treated mice. Thus, SCFA production may be one mechanism by which microbiota increase serum IGF-1. Our study demonstrates that gut microbiota provide a net anabolic stimulus to the skeleton, which is likely mediated by IGF-1. Manipulation of the microbiome or its metabolites may afford opportunities to optimize bone health and growth. PMID:27821775

Bone Histology of a Kannemeyeriid Dicynodont Wadiasaurus: Palaeobiological Implications

NASA Astrophysics Data System (ADS)

Ray, Sanghamitra; Bandyopadhyay, Saswati; Appana, Ravi

Examination of the bone microstructure of several skeletal elements shows that the cortex comprises fibrolamellar bone tissue suggesting rapid osteogenesis and overall fast growth for Wadiasaurus, a kannemeyeriid dicynodont from India. Three distinct stages have been identified in the ontogeny of Wadiasaurus. In the juvenile stage, when up to 30% of adult size is attained, growth was fast and sustained, whereas in the sub-adult stage when up to 60% of adult size is attained, growth was fast but periodically interrupted as evident from the presence of growth marks. During the adult stage the bone microstructure is characterized by the presence of peripheral parallel-fibred bone that suggested considerable slowing down of growth, possibly with the onset of sexual maturity. A flexible and indeterminate growth strategy is proposed for Wadiasaurus. The cortical thickness (RBT) and the correspondingly low optimal k values of the various limb bones of Wadiasaurus were comparable with that of the land vertebrates such as Ceratotherium, suggesting that the limbs were selected for impact loading.

Maxillary growth after the use of protraction head gear in conjunction with presurgical orthopedics and gingivoperiosteoplasty for complete bilateral cleft lip and alveolus patients.

PubMed

Kobayashi, Shinji; Hirakawa, Takashi; Fukawa, Toshihiko; Maegawa, Jiro

2013-09-01

Maxillary development is often inadequate in bilateral cleft patients. The use of presurgical orthopedics (PSO) and gingivoperiosteoplasty (GPP) may promote bone formation at the alveolar cleft, but can also have detrimental effects on maxillary development. Our objective was to investigate the effect of PSO and GPP on maxillary development in bilateral cleft lip and alveolus (BCLA) patients. We had 3 complete BCLA patients who had received PSO. All patients underwent cheiloplasty and GPP simultaneously. At 4 years, maxillary protraction head gear was used as part of the protocol. They were evaluated by cephalometric analysis at 4 and 8 years of age, and by CT imaging at 5 years of age. At 4 years of age, patients with all BCLA had anterior crossbite of deciduous central incisors. As a result of maxillary protraction, jaw development at 8 years was good. Among all patients, only one showed bone formation at the alveolar cleft sufficient to avoid alveolar bone grafting (ABG). All patients presented anterior crossbite in the premaxillary region, but had good maxillary growth at 8 years old as a result of maxillary protraction. The combination of PSO and GPP can potentially eliminate the need for ABG and does not significantly retard maxillary development. PSO with GPP and protraction head gear may be an option, but long-term growth is not known.

Digital electronic bone growth stimulator

DOEpatents

Kronberg, James W.

1995-01-01

A device for stimulating bone tissue by applying a low level alternating current signal directly to the patient's skin. A crystal oscillator, a binary divider chain and digital logic gates are used to generate the desired waveforms that reproduce the natural electrical characteristics found in bone tissue needed for stimulating bone growth and treating osteoporosis. The device, powered by a battery, contains a switch allowing selection of the correct waveform for bone growth stimulation or osteoporosis treatment so that, when attached to the skin of the patient using standard skin contact electrodes, the correct signal is communicated to the underlying bone structures.

Numerical modeling of the traction process in the treatment for Pierre-Robin Sequence.

PubMed

Słowiński, Jakub J; Czarnecka, Aleksandra

2016-10-01

The goal of this numerical study was to identify the results of modulated growth simulation of the mandibular bone during traction in Pierre-Robin Sequence (PRS) treatment. Numerical simulation was conducted in the Ansys 16.2 environment. Two FEM (finite elements method) models of a newborn's mandible (a spatial and a flat model) were developed. The procedure simulated a 20-week traction period. The adopted growth measure was mandibular length increase, defined as the distance between the Co-Pog anatomic points used in cephalometric analysis. The simulation calculations conducted on the developed models showed that modulation had a significant influence on the pace of bone growth. In each of the analyzed cases, growth modulation resulted in an increase in pace. The largest value of increase was 6.91 mm. The modulated growth with the most beneficial load variant increased the basic value of the growth by as much as 24.6%, and growth with the least beneficial variant increased by 7.4%. Traction is a simple, minimally invasive and inexpensive procedure. The proposed algorithm may enable the development of a helpful forecasting tool, which could be of real use to doctors working on Pierre-Robin Sequence and other mandibular deformations in children. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Bioactive factors for tissue regeneration: state of the art.

PubMed

Ohba, Shinsuke; Hojo, Hironori; Chung, Ung-Il

2012-07-01

THERE ARE THREE COMPONENTS FOR THE CREATION OF NEW TISSUES: cell sources, scaffolds, and bioactive factors. Unlike conventional medical strategies, regenerative medicine requires not only analytical approaches but also integrative ones. Basic research has identified a number of bioactive factors that are necessary, but not sufficient, for organogenesis. In skeletal development, these factors include bone morphogenetic proteins (BMPs), transforming growth factor β TGF-β, Wnts, hedgehogs (Hh), fibroblast growth factors (FGFs), insulin-like growth factors (IGFs), SRY box-containing gene (Sox) 9, Sp7, and runt-related transcription factors (Runx). Clinical and preclinical studies have been extensively performed to apply the knowledge to bone and cartilage regeneration. Given the large number of findings obtained so far, it would be a good time for a multi-disciplinary, collaborative effort to optimize these known factors and develop appropriate drug delivery systems for delivering them.

Proposed equations and reference values for calculating bone health in children and adolescent based on age and sex

PubMed Central

Gómez-Campos, Rossana; Andruske, Cynthia Lee; de Arruda, Miguel; Urra Albornoz, Camilo; Cossio-Bolaños, Marco

2017-01-01

Background The Dual Energy X-Ray Absorptiometry (DXA) is the gold standard for measuring BMD and bone mineral content (BMC). In general, DXA is ideal for pediatric use. However, the development of specific standards for particular geographic regions limits its use and application for certain socio-cultural contexts. Additionally, the anthropometry may be a low cost and easy to use alternative method in epidemiological contexts. The goal of our study was to develop regression equations for predicting bone health of children and adolescents based on anthropometric indicators to propose reference values based on age and sex. Methods 3020 students (1567 males and 1453 females) ranging in ages 4.0 to 18.9 were studied from the Maule Region (Chile). Anthropometric variables evaluated included: weight, standing height, sitting height, forearm length, and femur diameter. A total body scan (without the head) was conducted by means of the Dual Energy X-Ray Absorptiometry. Bone mineral density (BMD) and the bone mineral content (BMC) were also determined. Calcium consumption was controlled for by recording the intake of the three last days prior to the evaluation. Body Mass Index (BMI) was calculated, and somatic maturation was determined by using the years of peak growth rate (APHV). Results Four regression models were generated to calculate bone health: for males BMD = (R2 = 0.79) and BMC = (R2 = 0.84) and for the females BMD = (R2 = 0.76) and BMC = (R2 = 0.83). Percentiles were developed by using the LMS method (p3, p5, p15, p25, p50, p75, p85, p95 and p97). Conclusions Regression equations and reference curves were developed to assess the bone health of Chilean children and adolescents. These instruments help identify children with potential underlying problems in bone mineralization during the growth stage and biological maturation. PMID:28759569

Proposed equations and reference values for calculating bone health in children and adolescent based on age and sex.

PubMed

Gómez-Campos, Rossana; Andruske, Cynthia Lee; Arruda, Miguel de; Urra Albornoz, Camilo; Cossio-Bolaños, Marco

2017-01-01

The Dual Energy X-Ray Absorptiometry (DXA) is the gold standard for measuring BMD and bone mineral content (BMC). In general, DXA is ideal for pediatric use. However, the development of specific standards for particular geographic regions limits its use and application for certain socio-cultural contexts. Additionally, the anthropometry may be a low cost and easy to use alternative method in epidemiological contexts. The goal of our study was to develop regression equations for predicting bone health of children and adolescents based on anthropometric indicators to propose reference values based on age and sex. 3020 students (1567 males and 1453 females) ranging in ages 4.0 to 18.9 were studied from the Maule Region (Chile). Anthropometric variables evaluated included: weight, standing height, sitting height, forearm length, and femur diameter. A total body scan (without the head) was conducted by means of the Dual Energy X-Ray Absorptiometry. Bone mineral density (BMD) and the bone mineral content (BMC) were also determined. Calcium consumption was controlled for by recording the intake of the three last days prior to the evaluation. Body Mass Index (BMI) was calculated, and somatic maturation was determined by using the years of peak growth rate (APHV). Four regression models were generated to calculate bone health: for males BMD = (R2 = 0.79) and BMC = (R2 = 0.84) and for the females BMD = (R2 = 0.76) and BMC = (R2 = 0.83). Percentiles were developed by using the LMS method (p3, p5, p15, p25, p50, p75, p85, p95 and p97). Regression equations and reference curves were developed to assess the bone health of Chilean children and adolescents. These instruments help identify children with potential underlying problems in bone mineralization during the growth stage and biological maturation.

The development and morphogenesis of the tendon-to-bone insertion What development can teach us about healing

PubMed Central

Thomopoulos, Stavros; Genin, Guy M.; Galatz, Leesa M.

2013-01-01

The attachment of dissimilar materials is a major challenge because of the high levels of stress that develop at such interfaces. An effective solution to this problem develops at the attachment of tendon (a compliant “soft tissue”) to bone (a stiff “hard tissue”). This tissue, the “enthesis”, transitions from tendon to bone through gradations in structure, composition, and mechanical properties. These gradations are not regenerated during tendon-to-bone healing, leading to a high incidence of failure after surgical repair. Understanding the development of the enthesis may allow scientists to develop treatments that regenerate the natural tendon-to-bone insertion. Recent work has demonstrated that both biologic and mechanical factors drive the development and morphogenesis of the enthesis. A cascade of biologic signals similar to those seen in the growth plate promotes mineralization of cartilage on the bony end of the enthesis and the formation of fibrocartilage on the tendon end of the enthesis. Mechanical loading is also necessary for the development of the enthesis. Removal of muscle load impairs the formation of bone, fibrocartilage, and tendon at the developing enthesis. This paper reviews recent work on the development of the enthesis, with an emphasis on the roles of biologic and mechanical factors. PMID:20190378

Femoral bone perfusion through the nutrient foramen during growth and locomotor development of western grey kangaroos (Macropus fuliginosus).

PubMed

Hu, Qiaohui; Nelson, Thomas J; Snelling, Edward P; Seymour, Roger S

2018-02-20

The nutrient artery passes through the nutrient foramen on the shaft of the femur and supplies more than half of the total blood flow to the bone. Assuming that the size of the nutrient foramen correlates with the size of the nutrient artery, an index of blood flow rate ( Q i ) can be calculated from nutrient foramen dimensions. Interspecific Q i is proportional to locomotor activity levels in adult mammals, birds and reptiles. However, no studies have yet estimated intraspecific Q i to test for the effects of growth and locomotor development on bone blood flow requirements. In this study, we used micro-CT and medical CT scanning to measure femoral dimensions and foramen radius to calculate femoral Q i during the in-pouch and post-pouch life stages of western grey kangaroos ( Macropus fuliginosus ) weighing 5.7 g to 70.5 kg and representing a 12,350-fold range in body mass. A biphasic scaling relationship between Q i and body mass was observed (breakpoint at ca. 1-5 kg body mass right before permanent pouch exit), with a steep exponent of 0.96±0.09 (95% CI) during the in-pouch life stage and a statistically independent exponent of -0.59±0.90 during the post-pouch life stage. In-pouch joeys showed Q i values that were 50-100 times higher than those of adult diprotodont marsupials of the same body mass, but gradually converged with them as post-pouch adults. Bone modelling during growth appears to be the main determinant of femoral bone blood flow during in-pouch development, whereas bone remodelling for micro-fracture repair due to locomotion gradually becomes the main determinant when kangaroos leave the pouch and become more active. © 2018. Published by The Company of Biologists Ltd.

Segmenting Bone Parts for Bone Age Assessment using Point Distribution Model and Contour Modelling

NASA Astrophysics Data System (ADS)

Kaur, Amandeep; Singh Mann, Kulwinder, Dr.

2018-01-01

Bone age assessment (BAA) is a task performed on radiographs by the pediatricians in hospitals to predict the final adult height, to diagnose growth disorders by monitoring skeletal development. For building an automatic bone age assessment system the step in routine is to do image pre-processing of the bone X-rays so that features row can be constructed. In this research paper, an enhanced point distribution algorithm using contours has been implemented for segmenting bone parts as per well-established procedure of bone age assessment that would be helpful in building feature row and later on; it would be helpful in construction of automatic bone age assessment system. Implementation of the segmentation algorithm shows high degree of accuracy in terms of recall and precision in segmenting bone parts from left hand X-Rays.

Laser Sintered Porous Ti-6Al-4V Implants Stimulate Vertical Bone Growth.

PubMed

Cheng, Alice; Cohen, David J; Kahn, Adrian; Clohessy, Ryan M; Sahingur, Kaan; Newton, Joseph B; Hyzy, Sharon L; Boyan, Barbara D; Schwartz, Zvi

2017-08-01

The objective of this study was to examine the ability of 3D implants with trabecular-bone-inspired porosity and micro-/nano-rough surfaces to enhance vertical bone ingrowth. Porous Ti-6Al-4V constructs were fabricated via laser-sintering and processed to obtain micro-/nano-rough surfaces. Male and female human osteoblasts were seeded on constructs to analyze cell morphology and response. Implants were then placed on rat calvaria for 10 weeks to assess vertical bone ingrowth, mechanical stability and osseointegration. All osteoblasts showed higher levels of osteocalcin, osteoprotegerin, vascular endothelial growth factor and bone morphogenetic protein 2 on porous constructs compared to solid laser-sintered controls. Porous implants placed in vivo resulted in an average of 3.1 ± 0.6 mm 3 vertical bone growth and osseointegration within implant pores and had significantly higher pull-out strength values than solid implants. New bone formation and pull-out strength was not improved with the addition of demineralized bone matrix putty. Scanning electron images and histological results corroborated vertical bone growth. This study indicates that Ti-6Al-4V implants fabricated by additive manufacturing to have porosity based on trabecular bone and post-build processing to have micro-/nano-surface roughness can support vertical bone growth in vivo, and suggests that these implants may be used clinically to increase osseointegration in challenging patient cases.

Bone growth and composition in weanling and mature rats exposed to chronic centrifugation

NASA Technical Reports Server (NTRS)

Keil, L. C.; Evans, J. W.

1982-01-01

The primary objective of the study is to determine the effect of continuous exposure to hypergravity on the development and composition of weight-bearing bone. The experimental results are seen to suggest that many, if not all, of the changes observed in bone growth and composition derive from the retarded growth rate of the centrifuged rats. Both centrifuged weanling and mature rats exhibit a significant reduction in femur length and mass. The changes in femur size are more apparent in the weanlings since they are exposed to hypergravity during their most rapid phase of skeletal development. In addition to a slower growth rate, the body mass of the mature and weanling animals is reduced even further by the depletion of body fat. The rapid loss of body fat observed in rats and mice during centrifugation, it is found, can produce a prompt and significant rise in relative femur mass after two weeks of exposure. After adaptation to centrifugation, however, relative femur mass is similar to that of controls at four and eight weeks. At 18 weeks, the centrifuged rats again exhibit an increase in relative femur mass. It is thought that this increase in relative femur mass may be generated by the difference in fat deposition between the 1-G controls and the high-G rats.

[THE IMPORTANCE OF "MILK BONES" TO "WISDOM BONES" - COW MILK AND BONE HEALTH - LESSONS FROM MILK ALLERGY PATIENTS].

PubMed

Nachshon, Liat; Katz, Yitzhak

2016-03-01

The necessity of milk consumption in the western diet is a subject of intense controversy. One of the main benefits of milk is that it is the main source of dietary calcium. Calcium is a major bone mineral, mandatory for bone health. Its supply is derived exclusively from external dietary sources. During the growth period, an increased calcium supply is needed for the process of bone mass accumulation. An optimal bone mass achieved by the end of the growth period may be protective later in life against the bone mass loss that commonly occurs. This in turn, can be preventative against the occurrence of osteoporosis and the development of spontaneous bone fractures. Over the past several decades, an increased incidence of osteoporosis has been documented in western countries, leading to high rates of morbidity and mortality in the middle-aged and geriatric population. Many studies have investigated the dietary calcium requirements for different ages, to achieve and maintain proper bone health. Based on their results, guidelines concerning calcium intake in every stage of life have been published by national and international organizations. In the western diet, it is difficult to achieve the recommended calcium intake without milk consumption. Moreover, calcium bioavailability for intestinal absorption is high. Several studies have recently raised doubts concerning the amounts of calcium intake in the western diet and its effectiveness in preventing osteoporosis. The main disadvantage of these studies is their being based on the patient's past memory recall of milk consumption. Patients with IgE-mediated cow's milk protein allergy are a unique population. Their lifetime negligible milk consumption is undisputed. A recent study investigated for the first time, the bone density of young adults with milk allergy at the end of their growth period. Their severe reduction in bone mineral density and dietary calcium intake defines them as a high risk group for the development of early osteoporosis. Another finding of this study was that normal bone density was found in milk allergic patients who started to consume milk after a successful desensitization program. Interestingly, these patients had consumed milk for a period of only 12-36 months and had only partially achieved the recommended dietary intake for calcium. It appears that dietary milk is essential for optimal peak bone mass. The required amounts of calcium and the preferred form for consumption, however, requires further investigation.

Molecular genetics of craniosynostosis

NASA Astrophysics Data System (ADS)

Caterine; Auerkari, Elza Ibrahim

2018-03-01

Tight regulation process and complex interplay occur along the osteogenic interfaces of the cranial sutures in normal growth and development of the skull. Cranial sutures serve as sites of bone growth while maintaining a state of patency to accommodate the developing brain. Cranial sutures are fibro-cellular structures that separate the rigid plates of the skull bones. Premature fusion of one or more cranial sutures leads to a condition known as craniosynostosis. Craniosynostosis is one of the most common craniofacial anomalies with a prevalence of 1 in 2,500 newborns. Several genes have been identified in the pathogenesis of craniosynostosis. Molecular signaling events and the intracellular signal transduction pathways implicated in the suture pathobiology will provide a useful approach for therapeutic targeting.

Interaction of tumor and host cells with adhesion and extracellular matrix molecules in the development of multiple myeloma.

PubMed

Teoh, G; Anderson, K C

1997-02-01

Adhesion molecules play an important role in the growth regulation and migration of multiple myeloma (MM) cells. They mediate homing of MM cells to the bone marrow and MM cell to bone marrow stromal cell adhesion, with resultant interleukin-6 related autocrine and paracine growth and antiapoptotic affects. Their pattern of expression on tumor cells correlates with the development of plasma cell leukemia or extramedullary disease. Clinically, expression of adhesion molecules on tumor cells or in the serum has already shown prognostic utility. Finally, since adhesion molecules are involved at multiple steps in the pathogenesis of MM, therapeutic studies may target these molecules.

Contrasting skeletal phenotypes in mice with an identical mutation targeted to thyroid hormone receptor alpha1 or beta.

PubMed

O'Shea, Patrick J; Bassett, J H Duncan; Sriskantharajah, Srividya; Ying, Hao; Cheng, Sheue-yann; Williams, Graham R

2005-12-01

Thyroid hormone (T(3)) regulates bone turnover and mineralization in adults and is essential for skeletal development. Surprisingly, we identified a phenotype of skeletal thyrotoxicosis in T(3) receptor beta(PV) (TRbeta(PV)) mice in which a targeted frameshift mutation in TRbeta results in resistance to thyroid hormone. To characterize mechanisms underlying thyroid hormone action in bone, we analyzed skeletal development in TRalpha1(PV) mice in which the same PV mutation was targeted to TRalpha1. In contrast to TRbeta(PV) mice, TRalpha1(PV) mutants exhibited skeletal hypothyroidism with delayed endochondral and intramembranous ossification, severe postnatal growth retardation, diminished trabecular bone mineralization, reduced cortical bone deposition, and delayed closure of the skull sutures. Skeletal hypothyroidism in TRalpha1(PV) mutants was accompanied by impaired GH receptor and IGF-I receptor expression and signaling in the growth plate, whereas GH receptor and IGF-I receptor expression and signaling were increased in TRbeta(PV) mice. These data indicate that GH receptor and IGF-I receptor are physiological targets for T(3) action in bone in vivo. The divergent phenotypes observed in TRalpha1(PV) and TRbeta(PV) mice arise because the pituitary gland is a TRbeta-responsive tissue, whereas bone is TRalpha responsive. These studies provide a new understanding of the complex relationship between central and peripheral thyroid status.

Expression of the growth factor pleiotrophin and its receptor protein tyrosine phosphatase beta/zeta in the serum, cartilage and subchondral bone of patients with osteoarthritis.

PubMed

Kaspiris, Angelos; Mikelis, Constantinos; Heroult, Melanie; Khaldi, Lubna; Grivas, Theodoros B; Kouvaras, Ioannis; Dangas, Spyridon; Vasiliadis, Elias; Lioté, Frédéric; Courty, José; Papadimitriou, Evangelia

2013-07-01

Pleiotrophin is a heparin-binding growth factor expressed in embryonic but not mature cartilage, suggesting a role in cartilage development. Elucidation of the molecular changes observed during the remodelling process in osteoarthritis is of paramount importance. This study aimed to investigate serum pleiotrophin levels and expression of pleiotrophin and its receptor protein tyrosine phosphatase beta/zeta in the cartilage and subchondral bone of osteoarthritis patients. Serum samples derived from 16 osteoarthritis patients and 18 healthy donors. Pleiotrophin and receptor protein tyrosine phosphatase beta/zeta in the cartilage and subchondral bone were studied in 29 patients who had undergone total knee or hip replacement for primary osteoarthritis and in 10 control patients without macroscopic osteoarthritis changes. Serum pleiotrophin levels and expression of pleiotrophin in chondrocytes and subchondral bone osteocytes significantly increased in osteoarthritis patients graded Ahlback II to III. Receptor protein tyrosine phosphatase beta/zeta was mainly detected in the subchondral bone osteocytes of patients with moderate osteoarthritis and as disease severity increased, in the osteocytes and bone lining cells of the distant trabeculae. These data render pleiotrophin and receptor protein tyrosine phosphatase beta/zeta promising candidates for further studies towards developing targeted therapeutic schemes for osteoarthritis. Copyright © 2012 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.

The Effect of a Histone Deacetylase Inhibitor (AR-42) on Canine Prostate Cancer Growth and Metastasis.

PubMed

Elshafae, Said M; Kohart, Nicole A; Altstadt, Lucas A; Dirksen, Wessel P; Rosol, Thomas J

2017-05-01

Canine prostate cancer (PCa) is an excellent preclinical model for human PCa. AR-42 is a histone deacetylase inhibitor (HDACi) developed at The Ohio State University that inhibits the proliferation of several cancers, including multiple myeloma, lung, and hepatocellular cancer. In this study, we investigated whether AR-42 would prevent or decrease. The growth and metastasis of a canine PCa (Ace-1 cells) to bone in vitro and in vivo. Proliferation, cell viability, invasion, and metastasis of a canine prostate cancer cell line (Ace-1) were measured following treatment with AR-42. Expression of anoikis resistance, epithelial-to-mesenchymal transition (EMT), and stem cell-related markers were also evaluated. To assess the efficacy of AR-42 on prevention of PCa metastasis to bone, Ace-1 cells were injected in the left cardiac ventricle of nude mice, mice were treated with AR-42, and the incidence and growth of bone metastasis were measured. Bioluminescence was performed to monitor the bone metastases in nude mice. AR-42 inhibited the in vitro proliferation of Ace-1 cells in a time- and dose-dependent manner. The IC 50 concentration of AR-42 for Ace-1 cells was 0.42 μM after 24 hr of treatment. AR-42 induced apoptosis, decreased cell migration, and increased the stem cell properties of Ace-1 cells in vitro. AR-42 downregulated E-cadherin, N-cadherin, TWIST, MYOF, anoikis resistance, and osteomimicry genes, while it upregulated SNAIL, PTEN, FAK, and ZEB1 gene expression in Ace-1 cells. Importantly, AR-42 decreased the bioluminescence and incidence of bone metastasis in nude mice. In addition, AR-42 induced apoptosis and altered the tumor cell morphology to an irregular cell phenotype with condensed chromatin in the bone metastases. AR-42 decreased PCa growth and bone metastasis, induced apoptosis, and downregulated osteomimicry genes in PCa cells in the bone microenvironment. Prostate 77:776-793, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Micropore-induced capillarity enhances bone distribution in vivo in biphasic calcium phosphate scaffolds.

PubMed

Rustom, Laurence E; Boudou, Thomas; Lou, Siyu; Pignot-Paintrand, Isabelle; Nemke, Brett W; Lu, Yan; Markel, Mark D; Picart, Catherine; Wagoner Johnson, Amy J

2016-10-15

The increasing demand for bone repair solutions calls for the development of efficacious bone scaffolds. Biphasic calcium phosphate (BCP) scaffolds with both macropores and micropores (MP) have improved healing compared to those with macropores and no micropores (NMP), but the role of micropores is unclear. Here, we evaluate capillarity induced by micropores as a mechanism that can affect bone growth in vivo. Three groups of cylindrical scaffolds were implanted in pig mandibles for three weeks: MP were implanted either dry (MP-Dry), or after submersion in phosphate buffered saline, which fills pores with fluid and therefore suppresses micropore-induced capillarity (MP-Wet); NMP were implanted dry. The amount and distribution of bone in the scaffolds were quantified using micro-computed tomography. MP-Dry had a more homogeneous bone distribution than MP-Wet, although the average bone volume fraction, BVF‾, was not significantly different for these two groups (0.45±0.03 and 0.37±0.03, respectively). There was no significant difference in the radial bone distribution of NMP and MP-Wet, but the BVF‾, of NMP was significantly lower among the three groups (0.25±0.02). These results suggest that micropore-induced capillarity enhances bone regeneration by improving the homogeneity of bone distribution in BCP scaffolds. The explicit design and use of capillarity in bone scaffolds may lead to more effective treatments of large and complex bone defects. The increasing demand for bone repair calls for more efficacious bone scaffolds and calcium phosphate-based materials are considered suitable for this application. Macropores (>100μm) are necessary for bone ingrowth and vascularization. However, studies have shown that microporosity (<20μm) also enhances growth, but there is no consensus on the controlling mechanisms. In previous in vitro work, we suggested that micropore-induced capillarity had the potential to enhance bone growth in vivo. This work illustrates the positive effects of capillarity on bone regeneration in vivo; it demonstrates that micropore-induced capillarity significantly enhances the bone distribution in the scaffold. The results will impact the design of scaffolds to better exploit capillarity and improve treatments for large and load-bearing bone defects. Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Facial Morphogenesis of the Earliest Europeans

PubMed Central

Lacruz, Rodrigo S.; de Castro, José María Bermúdez; Martinón-Torres, María; O’Higgins, Paul; Paine, Michael L.; Carbonell, Eudald; Arsuaga, Juan Luis; Bromage, Timothy G.

2013-01-01

The modern human face differs from that of our early ancestors in that the facial profile is relatively retracted (orthognathic). This change in facial profile is associated with a characteristic spatial distribution of bone deposition and resorption: growth remodeling. For humans, surface resorption commonly dominates on anteriorly-facing areas of the subnasal region of the maxilla and mandible during development. We mapped the distribution of facial growth remodeling activities on the 900–800 ky maxilla ATD6-69 assigned to H. antecessor, and on the 1.5 My cranium KNM-WT 15000, part of an associated skeleton assigned to African H. erectus. We show that, as in H. sapiens, H. antecessor shows bone resorption over most of the subnasal region. This pattern contrasts with that seen in KNM-WT 15000 where evidence of bone deposition, not resorption, was identified. KNM-WT 15000 is similar to Australopithecus and the extant African apes in this localized area of bone deposition. These new data point to diversity of patterns of facial growth in fossil Homo. The similarities in facial growth in H. antecessor and H. sapiens suggest that one key developmental change responsible for the characteristic facial morphology of modern humans can be traced back at least to H. antecessor. PMID:23762314

Social networking between cells of the foetal skeleton: the importance of thyroid hormones.

PubMed

Farquharson, Colin

2011-08-01

In this issue of Journal of Endocrinology, Lanham et al. investigated the effects of hypothyroidism on the developing skeleton of the ovine foetus in utero. Their analyses indicated that, following thyroidectomy, bone growth, structure and mechanical properties were all altered at late gestation or at term. Adrenalectomy, whilst preventing the prepartum rise in triiodothyronine, did not modify skeletal development. The hypothyroid-mediated skeletal defects of the developing foetus described in this study may have clinical implications for bone health in later life.

BMP-2/PLGA delayed-release microspheres composite graft, selection of bone particulate diameters, and prevention of aseptic inflammation for bone tissue engineering.

PubMed

Ji, Ye; Xu, Gong Ping; Zhang, Zhi Peng; Xia, Jing Jun; Yan, Jing Long; Pan, Shang Ha

2010-03-01

Autogenous bone grafts are widely used in the repair of bone defects. Growth factors such as bone morphogenetic protein 2 (BMP-2) can induce bone regeneration and enhance bone growth. The combination of an autogenous bone graft and BMP-2 may provide a better osteogenic effect than either treatment alone, but BMP-2 is easily inactivated in body fluid. The objective of this study was to develop a technique that can better preserve the in vivo activity of BMP-2 incorporated in bone grafts. In this study, we first prepared BMP-2/poly(lactic-co-glycolic acid) (PLGA) delayed-release microspheres, and then combined collagen, the delayed-release microspheres, and rat autologous bone particulates to form four groups of composite grafts with different combinations: collagen in group A; collagen combined with bone particulates in group B; collagen combined with BMP-2/PLGA delayed-release microspheres in group C; and collagen combined with both bone particulates and BMP-2/PLGA delayed-release microspheres in group D. The four groups of composite grafts were implanted into the gluteus maximus pockets in rats. The ectopic osteogenesis and ALP level in group D (experimental group) were compared with those in groups A, B, and C (control groups) to study whether it had higher osteogenic capability. Results showed that the composite graft design increased the utility of BMP-2 and reduced the required dose of BMP-2 and volume of autologous bone. The selection of bone particulate diameter had an impact on the osteogenetic potential of bone grafts. Collagen prevented the occurrence of aseptic inflammation and improved the osteoinductivity of BMP-2. These results showed that this composite graft design is effective and feasible for use in bone repair.

Effect of early nutritional intake on long-term growth and bone mineralization of former very low birth weight infants.

PubMed

Christmann, V; van der Putten, M E; Rodwell, L; Steiner, K; Gotthardt, M; van Goudoever, J B; van Heijst, A F J

2018-03-01

Preterm infants are at risk for impaired bone mineralization and growth in length later in life due to inadequate nutritional intake in the early postnatal period. To investigate whether increased nutritional supplementation of calcium, phosphate and protein in Very Low Birth Weight (VLBW) infants during the first 14days after birth was associated with improvement in length and bone development until 9-10years of age. Observational follow-up study of VLBW infants (birth weight<1500g or gestational age<32weeks) born in two consecutive years (eligible infants: 2004 n: 63 and 2005: n: 66). Cohort 2005 received higher intake of calcium, phosphate and protein with parenteral nutrition compared to Cohort 2004. Anthropometric data were collected during standard follow-up visits until five years, and additionally at 9-10years of age including measurements of bone mineral content, bone mineral density of the whole body and lumbar spine determined by dual-energy X-ray absorptiometry. Long-term growth trajectories of both cohorts were evaluated separately for participants born appropriate (AGA) and small for gestational age (SGA), stratified by gender. Multivariate linear regression was used to examine the effect of nutritional intake and clinical covariates on length and bone mineralization. Both cohorts achieved a catch-up in length to SDS within the normal range by 6months (length SDS: estimated mean (95% confidence interval (CI): 6months: Cohort 2004: -0.7 (-1.1, -0.3) Cohort 2005: -0.5 (-0.8, -0.2)). Bone mineral content and density were within the normal range and not different between the cohorts. SGA children achieved a catch-up in length at 5years with bone mineralization comparable to AGA children. Only for girls birth weight was significantly associated with length SDS (per gram: β 0.001; 95% CI (0.000, 0.003); p=0.03) There was no evidence of an association between early nutritional intake and bone mineralization. Children born as appropriate or small for gestational age preterm infants are able to catch up in length after the postnatal period, and achieve a normal length and bone mineralization at age nine-ten years. An improvement of calcium and phosphate intake during the first 14days after birth was not associated with improvement in length and bone development. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Recent biological trends in management of fracture non-union

PubMed Central

Emara, Khaled M; Diab, Ramy Ahmed; Emara, Ahmed Khaled

2015-01-01

Bone regeneration is a complex, well-orchestrated physiological process of bone formation, which can be seen during normal fracture healing, and is involved in continuous remodelling throughout adult life. Currently, there is a plethora of different strategies to augment the impaired or “insufficient” bone-regeneration process, including the “gold standard” autologous bone graft, free fibula vascularised graft, allograft implantation, and use of growth factors, osteoconductive scaffolds, osteoprogenitor cells and distraction osteogenesis. Improved “local” strategies in terms of tissue engineering and gene therapy, or even “systemic” enhancement of bone repair, are under intense investigation, in an effort to overcome the limitations of the current methods, to produce bone-graft substitutes with biomechanical properties that are as identical to normal bone as possible, to accelerate the overall regeneration process, or even to address systemic conditions, such as skeletal disorders and osteoporosis. An improved understanding of the molecular and cellular events that occur during bone repair and remodeling has led to the development of biologic agents that can augment the biological microenvironment and enhance bone repair. Orthobiologics, including stem cells, osteoinductive growth factors, osteoconductive matrices, and anabolic agents, are available clinically for accelerating fracture repair and treatment of compromised bone repair situations like delayed unions and nonunions. A lack of standardized outcome measures for comparison of biologic agents in clinical fracture repair trials, frequent off-label use, and a limited understanding of the biological activity of these agents at the bone repair site have limited their efficacy in clinical applications. PMID:26396938

Biomaterial delivery of morphogens to mimic the natural healing cascade in bone.

PubMed

Mehta, Manav; Schmidt-Bleek, Katharina; Duda, Georg N; Mooney, David J

2012-09-01

Complications in treatment of large bone defects using bone grafting still remain. Our understanding of the endogenous bone regeneration cascade has inspired the exploration of a wide variety of growth factors (GFs) in an effort to mimic the natural signaling that controls bone healing. Biomaterial-based delivery of single exogenous GFs has shown therapeutic efficacy, and this likely relates to its ability to recruit and promote replication of cells involved in tissue development and the healing process. However, as the natural bone healing cascade involves the action of multiple factors, each acting in a specific spatiotemporal pattern, strategies aiming to mimic the critical aspects of this process will likely benefit from the usage of multiple therapeutic agents. This article reviews the current status of approaches to deliver single GFs, as well as ongoing efforts to develop sophisticated delivery platforms to deliver multiple lineage-directing morphogens (multiple GFs) during bone healing. Copyright © 2012 Elsevier B.V. All rights reserved.

Interactions between bone cells and biomaterials: An update.

PubMed

Beauvais, Sabrina; Drevelle, Olivier; Jann, Jessica; Lauzon, Marc-Antoine; Foruzanmehr, Mohammadreza; Grenier, Guillaume; Roux, Sophie; Faucheux, Nathalie

2016-06-01

As the populations of the Western world become older, they will suffer more and more from bone defects related to osteoporosis (non-union fractures, vertebral damages), cancers (malignant osteolysis) and infections (osteomyelitis). Autografts are usually used to fill these defects, but they have several drawbacks such as morbidity at the donor site and the amount and quality of bone that can be harvested. Recent scientific milestones made in biomaterials development were shown to be promising to overcome these limitations. Cell interactions with biomaterials can be improved by adding at their surface functional groups such as adhesive peptides and/or growth factors. The development of such biomimetic materials able to control bone cell responses can only proceed if it is based on a sound understanding of bone cell behavior and regulation. This review focuses on bone physiology and the regulation of bone cell differentiation and function, and how the latest advances in biomimetic materials can be translated within promising clinical outcomes.

The in vitro viability and growth of fibroblasts cultured in the presence of different bone grafting materials (NanoBone and Straumann Bone Ceramic).

PubMed

Kauschke, E; Rumpel, E; Fanghänel, J; Bayerlein, T; Gedrange, T; Proff, P

2006-02-01

Different clinical applications, including dentistry, are making increasing demands on bone grafting material. In the present study we have analysed the viability, proliferation and growth characteristics of fibroblasts cultured in vitro together with two different bone grafting materials, NanoBone and Straumann Bone Ceramic, over a period of 24 and 28 days respectively. Viability was measured at least every 72 hours by using the alamarBlue assay, a test that measures quantitatively cell proliferation and viability but does not require cell fixation or extraction. After one week of culture fibroblast viability was as high as in controls for both grafting materials and remained high (> 90%) for the duration of the experiment. Cell growth was evaluated microscopically. Scanning electron microscopy revealed a dense fibroblast growth at the surface of both bone grafting materials after three weeks of in vitro culture. Generally, our in vitro analyses contribute to further insights into cell - scaffold interactions.

In vivo loss of function study reveals the short stature homeobox-containing (shox) gene plays indispensable roles in early embryonic growth and bone formation in zebrafish.

PubMed

Sawada, Rie; Kamei, Hiroyasu; Hakuno, Fumihiko; Takahashi, Shin-Ichiro; Shimizu, Toshiaki

2015-02-01

Congenital loss of the SHOX gene is considered to be a genetic cause of short stature phenotype in Turner syndrome and Leri-Weill dyschondrosteosis patients. Though SHOX expression initiates during early fetal development, little is known about the embryonic roles of SHOX. The evolutionary conservation of the zebrafish shox gene and the convenience of the early developmental stages for analyses make zebrafish a preferred model. Here, we characterized structure, expression, and developmental roles of zebrafish shox through a loss-of-function approach. We found a previously undiscovered Shox protein that has both a homeodomain and an OAR-domain in zebrafish. The shox transcript emerged during the segmentation period and it increased in later stages. The predominant domains of shox expression were mandibular arch, pectoral fin, anterior notochord, rhombencephalon, and mesencephalon, suggesting that Shox is involved in bone and neural development. Translational blockade of Shox mRNA by an antisense morpholino oligo delayed embryonic growth, which was restored by the co-overexpression of morpholino-resistant Shox mRNA. At later stages, impaired Shox expression markedly delayed the calcification process in the anterior vertebral column and craniofacial bones. Our data demonstrate evolutionarily conserved Shox plays roles in early embryonic growth and in later bone formation. © 2014 Wiley Periodicals, Inc.

Development of controlled drug delivery systems for bone fracture-targeted therapeutic delivery: A review.

PubMed

Wang, Yuchen; Newman, Maureen R; Benoit, Danielle S W

2018-06-01

Impaired fracture healing is a major clinical problem that can lead to patient disability, prolonged hospitalization, and significant financial burden. Although the majority of fractures heal using standard clinical practices, approximately 10% suffer from delayed unions or non-unions. A wide range of factors contribute to the risk for nonunions including internal factors, such as patient age, gender, and comorbidities, and external factors, such as the location and extent of injury. Current clinical approaches to treat nonunions include bone grafts and low-intensity pulsed ultrasound (LIPUS), which realizes clinical success only to select patients due to limitations including donor morbidities (grafts) and necessity of fracture reduction (LIPUS), respectively. To date, therapeutic approaches for bone regeneration rely heavily on protein-based growth factors such as INFUSE, an FDA-approved scaffold for delivery of bone morphogenetic protein 2 (BMP-2). Small molecule modulators and RNAi therapeutics are under development to circumvent challenges associated with traditional growth factors. While preclinical studies has shown promise, drug delivery has become a major hurdle stalling clinical translation. Therefore, this review overviews current therapies employed to stimulate fracture healing pre-clinically and clinically, including a focus on drug delivery systems for growth factors, parathyroid hormone (PTH), small molecules, and RNAi therapeutics, as well as recent advances and future promise of fracture-targeted drug delivery. Copyright © 2018 Elsevier B.V. All rights reserved.

Effect of parathyroidectomy on bone growth and composition in the young rat

NASA Technical Reports Server (NTRS)

Keil, L. C.; Prinz, J. A.; Evans, J. W.

1974-01-01

In an effort to determine the influence of the parathyroids on bone growth and composition, 28-day-old male Sprague-Dawley rats were sacrificed 28, 56, and 84 days after parathyroidectomy or sham parathyroidectomy. Body growth as well as femur growth were retarded following parathyroidectomy. Hypocalcemia and hyperphosphatemia occurred in all parathyroidectomized rats; no alterations in plasma magnesium levels were noted. Femur magnesium was increased by 22-30% in the parathyroidectomized rats whereas femur calcium remained unchanged. Bone phosphorus was increased 56 and 84 days following parathyroidectomy. Results of this study indicate that parathyroidectomy retards growth while increasing bone magnesium and phosphorus content.

A Novel Approach for Studying the Temporal Modulation of Embryonic Skeletal Development Using Organotypic Bone Cultures and Microcomputed Tomography

PubMed Central

Smith, Emma L.; Roberts, Carol A.

2012-01-01

Understanding the structural development of embryonic bone in a three dimensional framework is fundamental to developing new strategies for the recapitulation of bone tissue in latter life. We present an innovative combined approach of an organotypic embryonic femur culture model, microcomputed tomography (μCT) and immunohistochemistry to examine the development and modulation of the three dimensional structures of the developing embryonic femur. Isolated embryonic chick femurs were organotypic (air/liquid interface) cultured for 10 days in either basal, chondrogenic, or osteogenic supplemented culture conditions. The growth development and modulating effects of basal, chondrogenic, or osteogenic culture media of the embryonic chick femurs was investigated using μCT, immunohistochemistry, and histology. The growth and development of noncultured embryonic chick femur stages E10, E11, E12, E13, E15, and E17 were very closely correlated with increased morphometric indices of bone formation as determined by μCT. After 10 days in the organotpyic culture set up, the early aged femurs (E10 and E11) demonstrated a dramatic response to the chondrogenic or osteogenic culture conditions compared to the basal cultured femurs as determined by a change in μCT morphometric indices and modified expression of chondrogenic and osteogenic markers. Although the later aged femurs (E12 and E13) increased in size and structure after 10 days organotpypic culture, the effects of the osteogenic and chondrogenic organotypic cultures on these femurs were not significantly altered compared to basal conditions. We have demonstrated that the embryonic chick femur organotpyic culture model combined with the μCT and immunohistochemical analysis can provide an integral methodology for investigating the modulation of bone development in an ex vivo culture setting. Hence, these interdisciplinary techniques of μCT and whole organ bone cultures will enable us to delineate some of the temporal, structural developmental paradigms and modulation of bone tissue formation to underpin innovative skeletal regenerative technology for clinical therapeutic strategies in musculoskeletal trauma and diseases. PMID:22472170

Neurotrophin-3 Induces BMP-2 and VEGF Activities and Promotes the Bony Repair of Injured Growth Plate Cartilage and Bone in Rats.

PubMed

Su, Yu-Wen; Chung, Rosa; Ruan, Chun-Sheng; Chim, Shek Man; Kuek, Vincent; Dwivedi, Prem P; Hassanshahi, Mohammadhossein; Chen, Ke-Ming; Xie, Yangli; Chen, Lin; Foster, Bruce K; Rosen, Vicki; Zhou, Xin-Fu; Xu, Jiake; Xian, Cory J

2016-06-01

Injured growth plate is often repaired by bony tissue causing bone growth defects, for which the mechanisms remain unclear. Because neurotrophins have been implicated in bone fracture repair, here we investigated their potential roles in growth plate bony repair in rats. After a drill-hole injury was made in the tibial growth plate and bone, increased injury site mRNA expression was observed for neurotrophins NGF, BDNF, NT-3, and NT-4 and their Trk receptors. NT-3 and its receptor TrkC showed the highest induction. NT-3 was localized to repairing cells, whereas TrkC was observed in stromal cells, osteoblasts, and blood vessel cells at the injury site. Moreover, systemic NT-3 immunoneutralization reduced bone volume at injury sites and also reduced vascularization at the injured growth plate, whereas recombinant NT-3 treatment promoted bony repair with elevated levels of mRNA for osteogenic markers and bone morphogenetic protein (BMP-2) and increased vascularization and mRNA for vascular endothelial growth factor (VEGF) and endothelial cell marker CD31 at the injured growth plate. When examined in vitro, NT-3 promoted osteogenesis in rat bone marrow stromal cells, induced Erk1/2 and Akt phosphorylation, and enhanced expression of BMPs (particularly BMP-2) and VEGF in the mineralizing cells. It also induced CD31 and VEGF mRNA in rat primary endothelial cell culture. BMP activity appears critical for NT-3 osteogenic effect in vitro because it can be almost completely abrogated by co-addition of the BMP inhibitor noggin. Consistent with its angiogenic effect in vivo, NT-3 promoted angiogenesis in metatarsal bone explants, an effect abolished by co-treatment with anti-VEGF. This study suggests that NT-3 may be an osteogenic and angiogenic factor upstream of BMP-2 and VEGF in bony repair, and further studies are required to investigate whether NT-3 may be a potential target for preventing growth plate faulty bony repair or for promoting bone fracture healing. © 2016 American Society for Bone and Mineral Research. © 2016 American Society for Bone and Mineral Research.

Controlled Release Strategies for Bone, Cartilage, and Osteochondral Engineering—Part II: Challenges on the Evolution from Single to Multiple Bioactive Factor Delivery

PubMed Central

Santo, Vítor E.; Mano, João F.; Reis, Rui L.

2013-01-01

The development of controlled release systems for the regeneration of bone, cartilage, and osteochondral interface is one of the hot topics in the field of tissue engineering and regenerative medicine. However, the majority of the developed systems consider only the release of a single growth factor, which is a limiting step for the success of the therapy. More recent studies have been focused on the design and tailoring of appropriate combinations of bioactive factors to match the desired goals regarding tissue regeneration. In fact, considering the complexity of extracellular matrix and the diversity of growth factors and cytokines involved in each biological response, it is expected that an appropriate combination of bioactive factors could lead to more successful outcomes in tissue regeneration. In this review, the evolution on the development of dual and multiple bioactive factor release systems for bone, cartilage, and osteochondral interface is overviewed, specifically the relevance of parameters such as dosage and spatiotemporal distribution of bioactive factors. A comprehensive collection of studies focused on the delivery of bioactive factors is also presented while highlighting the increasing impact of platelet-rich plasma as an autologous source of multiple growth factors. PMID:23249320

Effects of Monoclonal Antibodies against Nerve Growth Factor on Healthy Bone and Joint Tissues in Mice, Rats, and Monkeys: Histopathologic, Biomarker, and Microcomputed Tomographic Assessments.

PubMed

Gropp, Kathryn E; Carlson, Cathy S; Evans, Mark G; Bagi, Cedo M; Reagan, William J; Hurst, Susan I; Shelton, David L; Zorbas, Mark A

2018-01-01

Tanezumab, an anti-nerve growth factor (NGF) antibody, is in development for management of chronic pain. During clinical trials of anti-NGF antibodies, some patients reported unexpected adverse events requiring total joint replacements, resulting in a partial clinical hold on all NGF inhibitors. Three nonclinical toxicology studies were conducted to evaluate the effects of tanezumab or the murine precursor muMab911 on selected bone and joint endpoints and biomarkers in cynomolgus monkeys, Sprague-Dawley rats, and C57BL/6 mice. Joint and bone endpoints included histology, immunohistochemistry, microcomputed tomography (mCT) imaging, and serum biomarkers of bone physiology. Responses of bone endpoints to tanezumab were evaluated in monkeys at 4 to 30 mg/kg/week for 26 weeks and in rats at 0.2 to 10 mg/kg twice weekly for 28 days. The effects of muMab911 at 10 mg/kg/week for 12 weeks on selected bone endpoints were determined in mice. Tanezumab and muMab911 had no adverse effects on any bone or joint parameter. There were no test article-related effects on bone or joint histology, immunohistochemistry, or structure. Reversible, higher osteocalcin concentrations occurred only in the rat study. No deleterious effects were observed in joints or bones in monkeys, rats, or mice administered high doses of tanezumab or muMab911.

Digital electronic bone growth stimulator

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kronberg, J.W.

1995-05-09

A device is described for stimulating bone tissue by applying a low level alternating current signal directly to the patient`s skin. A crystal oscillator, a binary divider chain and digital logic gates are used to generate the desired waveforms that reproduce the natural electrical characteristics found in bone tissue needed for stimulating bone growth and treating osteoporosis. The device, powered by a battery, contains a switch allowing selection of the correct waveform for bone growth stimulation or osteoporosis treatment so that, when attached to the skin of the patient using standard skin contact electrodes, the correct signal is communicated tomore » the underlying bone structures. 5 figs.« less

Digital electronic bone growth stimulator

DOEpatents

Kronberg, J.W.

1995-05-09

A device is described for stimulating bone tissue by applying a low level alternating current signal directly to the patient`s skin. A crystal oscillator, a binary divider chain and digital logic gates are used to generate the desired waveforms that reproduce the natural electrical characteristics found in bone tissue needed for stimulating bone growth and treating osteoporosis. The device, powered by a battery, contains a switch allowing selection of the correct waveform for bone growth stimulation or osteoporosis treatment so that, when attached to the skin of the patient using standard skin contact electrodes, the correct signal is communicated to the underlying bone structures. 5 figs.

Development of an Autologous Macrophage-based Adoptive Gene Transfer Strategy to Treat Posttraumatic Osteoarthritis (PTOA) and Osteoarithritis (OA)

DTIC Science & Technology

2014-09-01

evidence for intra- articular fractures, existence of substantial subchondral bone erosion at the surface of articular plate, and formation of bone spurs...small growths called osteophytes ) on the edges is seen in the PTOA joint but not on the intact contralateral knee joint. This provides addition

Development of an Autologous Macrophage-Based Adoptive Gene Transfer Strategy to Treat Posttraumatic Osteoarthritis (PTOA) and Osteoarithritis (OA)

DTIC Science & Technology

2014-09-01

mouse. Clear evidence for intra- articular fractures, existence of substantial subchondral bone erosion at the surface of articular plate, and formation...of bone spurs (small growths called osteophytes ) on the edges is seen in the PTOA joint but not on the intact contralateral knee joint. This

Hyoid bone development: An assessment of optimal CT scanner parameters and 3D volume rendering techniques

PubMed Central

Cotter, Meghan M.; Whyms, Brian J.; Kelly, Michael P.; Doherty, Benjamin M.; Gentry, Lindell R.; Bersu, Edward T.; Vorperian, Houri K.

2015-01-01

The hyoid bone anchors and supports the vocal tract. Its complex shape is best studied in three dimensions, but it is difficult to capture on computed tomography (CT) images and three-dimensional volume renderings. The goal of this study was to determine the optimal CT scanning and rendering parameters to accurately measure the growth and developmental anatomy of the hyoid and to determine whether it is feasible and necessary to use these parameters in the measurement of hyoids from in vivo CT scans. Direct linear and volumetric measurements of skeletonized hyoid bone specimens were compared to corresponding CT images to determine the most accurate scanning parameters and three-dimensional rendering techniques. A pilot study was undertaken using in vivo scans from a retrospective CT database to determine feasibility of quantifying hyoid growth. Scanning parameters and rendering technique affected accuracy of measurements. Most linear CT measurements were within 10% of direct measurements; however, volume was overestimated when CT scans were acquired with a slice thickness greater than 1.25 mm. Slice-by-slice thresholding of hyoid images decreased volume overestimation. The pilot study revealed that the linear measurements tested correlate with age. A fine-tuned rendering approach applied to small slice thickness CT scans produces the most accurate measurements of hyoid bones. However, linear measurements can be accurately assessed from in vivo CT scans at a larger slice thickness. Such findings imply that investigation into the growth and development of the hyoid bone, and the vocal tract as a whole, can now be performed using these techniques. PMID:25810349

Hyoid Bone Development: An Assessment Of Optimal CT Scanner Parameters and Three-Dimensional Volume Rendering Techniques.

PubMed

Cotter, Meghan M; Whyms, Brian J; Kelly, Michael P; Doherty, Benjamin M; Gentry, Lindell R; Bersu, Edward T; Vorperian, Houri K

2015-08-01

The hyoid bone anchors and supports the vocal tract. Its complex shape is best studied in three dimensions, but it is difficult to capture on computed tomography (CT) images and three-dimensional volume renderings. The goal of this study was to determine the optimal CT scanning and rendering parameters to accurately measure the growth and developmental anatomy of the hyoid and to determine whether it is feasible and necessary to use these parameters in the measurement of hyoids from in vivo CT scans. Direct linear and volumetric measurements of skeletonized hyoid bone specimens were compared with corresponding CT images to determine the most accurate scanning parameters and three-dimensional rendering techniques. A pilot study was undertaken using in vivo scans from a retrospective CT database to determine feasibility of quantifying hyoid growth. Scanning parameters and rendering technique affected accuracy of measurements. Most linear CT measurements were within 10% of direct measurements; however, volume was overestimated when CT scans were acquired with a slice thickness greater than 1.25 mm. Slice-by-slice thresholding of hyoid images decreased volume overestimation. The pilot study revealed that the linear measurements tested correlate with age. A fine-tuned rendering approach applied to small slice thickness CT scans produces the most accurate measurements of hyoid bones. However, linear measurements can be accurately assessed from in vivo CT scans at a larger slice thickness. Such findings imply that investigation into the growth and development of the hyoid bone, and the vocal tract as a whole, can now be performed using these techniques. © 2015 Wiley Periodicals, Inc.

Bone growth marks reveal protracted growth in New Zealand kiwi (Aves, Apterygidae)

PubMed Central

Bourdon, Estelle; Castanet, Jacques; de Ricqlès, Armand; Scofield, Paul; Tennyson, Alan; Lamrous, Hayat; Cubo, Jorge

2009-01-01

The presence of bone growth marks reflecting annual rhythms in the cortical bone of non-avian tetrapods is now established as a general phenomenon. In contrast, ornithurines (the theropod group including modern birds and their closest relatives) usually grow rapidly in less than a year, such that no annual rhythms are expressed in bone cortices, except scarce growth marks restricted to the outer cortical layer. So far, cyclical growth in modern birds has been restricted to the Eocene Diatryma, the extant parrot Amazona amazonica and the extinct New Zealand (NZ) moa (Dinornithidae). Here we show the presence of lines of arrested growth in the long bones of the living NZ kiwi (Apteryx spp., Apterygidae). Kiwis take 5–6 years to reach full adult body size, which indicates a delayed maturity and a slow reproductive cycle. Protracted growth probably evolved convergently in moa and kiwi sometime since the Middle Miocene, owing to the severe climatic cooling in the southwest Pacific and the absence of mammalian predators. PMID:19515655

Ablation of the pro-apoptotic protein Bax protects mice from glucocorticoid-induced bone growth impairment.

PubMed

Zaman, Farasat; Chrysis, Dionisios; Huntjens, Kirsten; Fadeel, Bengt; Sävendahl, Lars

2012-01-01

Dexamethasone (Dexa) is a widely used glucocorticoid to treat inflammatory diseases; however, a multitude of undesired effects have been reported to arise from this treatment including osteoporosis, obesity, and in children decreased longitudinal bone growth. We and others have previously shown that glucocorticoids induce apoptosis in growth plate chondrocytes. Here, we hypothesized that Bax, a pro-apoptotic member of the Bcl-2 family, plays a key role in Dexa-induced chondrocyte apoptosis and bone growth impairment. Indeed, experiments in the human HCS-2/8 chondrocytic cell line demonstrated that silencing of Bax expression using small-interfering (si) RNA efficiently blocked Dexa-induced apoptosis. Furthermore, ablation of Bax in female mice protected against Dexa-induced bone growth impairment. Finally, Bax activation by Dexa was confirmed in human growth plate cartilage specimens cultured ex vivo. Our findings could therefore open the door for new therapeutic approaches to prevent glucocorticoid-induced bone growth impairment through specific targeting of Bax.

The effect of rigid fixation on growth of the neurocranium.

PubMed

Wong, L; Dufresne, C R; Richtsmeier, J T; Manson, P N

1991-09-01

The effects on skull growth of plating the coronal suture and frontal bone were studied in New Zealand White rabbits. Three-dimensional coordinate landmarks were digitized and analyzed to determine the differences in form between operated and unoperated animals using Euclidian distance matrix analysis. This method compares sets of interlandmark distances in three dimensions and was used to demonstrate changes induced by plating. We interpret these changes in morphology to be the result of differences in growth between the operated and unoperated groups. Periosteal elevation alone (n = 6) resulted in a minimal local growth increase. Coronal suture plating (n = 8) resulted in local growth restriction with contralateral and adjacent size increases. Frontal bone plating (n = 6) without crossing a suture line also resulted in local growth restriction and adjacent bone size increases. The timing of intervention in relation to the completion of bone growth may explain the magnitude of clinically apparent effects. Changes in bones adjacent to those directly manipulated may be an attempt to maintain a normal skull volume.

The emerging connections between IGF1, the intestinal microbiome, Lactobacillus strains and bone growth.

PubMed

Poinsot, Pierre; Schwarzer, Martin; Peretti, Noël; Leulier, François

2018-07-01

In most animal species, postnatal growth is controlled by conserved insulin/insulin-like growth factor (IGF) signaling. In mammals, juvenile growth is characterized by a longitudinal bone growth resulting from the ossification of the growth plate. This ossification is under IGF1 influence through endocrine and paracrine mechanisms. Moreover, the nutritional status has been largely described as an important factor influencing the insulin/insulin-like growth factor signaling. It is now well established that the gut microbiota modulates the nutrient availability of its host. Hence, studies of the interaction between nutritional status, gut microbiota and bone growth have recently emerged. Here, we review recent findings using experimental models about the impact of gut bacteria on the somatotropic axis and its consequence on the bone growth. We also discuss the perspectives of these studies in opening an entire field for clinical interventions. © 2018 Society for Endocrinology.

Sex steroids during bone growth: a comparative study between mouse models for hypogonadal and senile osteoporosis.

PubMed

Ophoff, J; Venken, K; Callewaert, F; Boonen, S; Bouillon, R; Vanderschueren, D

2009-10-01

In this study, the role of disturbed bone mineral acquisition during puberty in the pathogenesis of osteoporosis was studied. To this end, a mouse model for senile and hypogonadal osteoporosis was used. Longitudinal follow-up showed that bone fragility in both models results from deficient bone build-up during early puberty. Male osteoporosis may result from impaired bone growth. This study characterizes the mechanisms of deficient peak bone mass acquisition in models for senile (SAMP6) and hypogonadal (orchidectomized SAMR1) osteoporosis. Bone mineral acquisition was investigated longitudinally in SAMP6 and orchidectomized SAMR1 mice (eight to ten animals per group) using peripheral quantitative computed tomography and histomorphometry. Additionally, the effects of long-term 5alpha-dihydrotestosterone (DHT) and 17beta-estradiol (E2) replacement were studied. Statistical analysis was performed using ANOVA and Student's t test. SAMP6 mice showed an early (4 weeks) medullary expansion of the cortex due to impaired endocortical bone formation (-43%). Despite compensatory periosteal bone formation (+47%), cortical thickness was severely reduced in 20-week-old SAMP6 versus SAMR1. Orchidectomy reduced periosteal apposition between 4 and 8 weeks of age and resulted in high bone turnover and less trabecular bone gain in SAMP6 and SAMR1. DHT and E2 stimulated periosteal expansion and trabecular bone in orchidectomized SAMP6 and SAMR1. E2 stimulated endocortical apposition in SAMP6. Moreover, sex steroid action occurred between 4 and 8 weeks of age. Bone fragility in both models resulted from deficient bone build-up during early puberty. DHT and E2 improved bone mass acquisition in orchidectomized animals, suggesting a role for AR and ER in male skeletal development.

Modeling of time dependent localized flow shear stress and its impact on cellular growth within additive manufactured titanium implants.

PubMed

Zhang, Ziyu; Yuan, Lang; Lee, Peter D; Jones, Eric; Jones, Julian R

2014-11-01

Bone augmentation implants are porous to allow cellular growth, bone formation and fixation. However, the design of the pores is currently based on simple empirical rules, such as minimum pore and interconnects sizes. We present a three-dimensional (3D) transient model of cellular growth based on the Navier-Stokes equations that simulates the body fluid flow and stimulation of bone precursor cellular growth, attachment, and proliferation as a function of local flow shear stress. The model's effectiveness is demonstrated for two additive manufactured (AM) titanium scaffold architectures. The results demonstrate that there is a complex interaction of flow rate and strut architecture, resulting in partially randomized structures having a preferential impact on stimulating cell migration in 3D porous structures for higher flow rates. This novel result demonstrates the potential new insights that can be gained via the modeling tool developed, and how the model can be used to perform what-if simulations to design AM structures to specific functional requirements. © 2014 Wiley Periodicals, Inc.

Insulin-Like Growth Factor Regulates Peak Bone Mineral Density in Mice by Both Growth Hormone-Dependent and -Independent Mechanisms

PubMed Central

Mohan, Subburaman; Richman, Charmaine; Guo, Rongqing; Amaar, Yousef; Donahue, Leah Rea; Wergedal, Jon; Baylink, David J.

2010-01-01

To evaluate the relative contribution of the GH/IGF axis to the development of peak bone mineral density (BMD), we measured skeletal changes in IGF-I knockout (KO), IGF-II KO, and GH-deficient lit/lit mice and their corresponding control mice at d 23 (prepubertal), 31 (pubertal), and 56 (postpubertal) in the entire femur by dual energy x-ray absorptiometry and in the mid-diaphysis by peripheral quantitative computed tomography. Lack of growth factors resulted in different degrees of failure of skeletal growth depending on the growth period and the growth factor involved. At d 23, femoral length, size, and BMD were reduced by 25–40%, 15–17%, and 8–10%, respectively, in mice deficient in IGF-I, IGF-II, and GH compared with the control mice. During puberty, BMD increased by 40% in control mice and by 15% in IGF-II KO and GH-deficient mice, whereas it did not increase in the IGF-I KO mice. Disruption of IGF-I, but not IGF-II, completely prevented the periosteal expansion that occurs during puberty, whereas it was reduced by 50% in GH-deficient mice. At d 56, femoral length, size, and BMD were reduced by 40–55%, 11–18%, and 25–32%, respectively, in mice deficient in IGF-I, IGF-II, and GH compared with the control mice. Our data demonstrate that: 1) mice deficient in IGF-I exhibit a greater impairment in bone accretion than mice deficient in IGF-II or GH; 2) GH/IGF-I, but not IGF-II, is critical for puberty-induced bone growth; and 3) IGF-I effects on bone accretion during prepuberty are mediated predominantly via mechanisms independent of GH, whereas during puberty they are mediated via both GH-dependent and GH-independent mechanisms. PMID:12586770

Estimating differences in volumetric flat bone growth in pediatric patients by radiation treatment method

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hua Chiaho; Shukla, Hemant I.; Merchant, Thomas E.

2007-02-01

Purpose: To estimate potential differences in volumetric bone growth in children with sarcoma treated with intensity-modulated (IMRT) and conformal (CRT) radiation therapy using an empiric dose-effect model. Methods and Materials: A random coefficient model was used to estimate potential volumetric bone growth of 36 pelvic bones (ischiopubis and ilium) from 11 patients 4 years after radiotherapy. The model incorporated patient age, pretreatment bone volume, integral dose >35 Gy, and time since completion of radiation therapy. Three dosimetry plans were entered into the model: the actual CRT/IMRT plan, a nontreated comparable IMRT/CRT plan, and an idealized plan in which dose wasmore » delivered only to the planning target volume. The results were compared with modeled normal bone growth. Results: The model predicted that by using the idealized, IMRT, and CRT approaches, patients would maintain 93%, 87%, and 84%, respectively (p = 0.06), of their expected normal growth. Patients older than 10 years would maintain 98% of normal growth, regardless of treatment method. Those younger than 10 years would maintain 87% (idealized), 76% (IMRT), or 70% (CRT) of their expected growth (p = 0.015). Post hoc testing (Tukey) revealed that the CRT and IMRT approaches differed significantly from the idealized one but not from each other. Conclusions: Dose-effect models facilitate the comparison of treatment methods and potential interventions. Although treatment methods do not alter the growth of flat bones in older pediatric patients, they may significantly impact bone growth in children younger than age 10 years, especially as we move toward techniques with high conformity and sharper dose gradient.« less

How long bones grow children: Mechanistic paths to variation in human height growth.

PubMed

Lampl, Michelle; Schoen, Meriah

2017-03-01

Eveleth and Tanner's descriptive documentation of worldwide variability in human growth provided evidence of the interaction between genetics and environment during development that has been foundational to the science of human growth. There remains a need, however, to describe the mechanistic foundations of variability in human height growth patterns. A review of research documenting cellular activities at the endochondral growth plate aims to show how the unique microenvironment and cell functions during the sequential phases of the chondrocyte lifecycle affect long bone elongation, a fundamental source of height growth. There are critical junctures within the chondrocytic differentiation cascade at which environmental influences are integrated and have the ability to influence progression to the hypertrophic chondrocyte phase, the primary driver of long bone elongation. Phenotypic differences in height growth patterns reflect variability in amplitude and frequency of discretely timed hypertrophic cellular expansion events, the cellular basis of saltation and stasis growth biology. Final height is a summary of the dynamic processes carried out by the growth plate cellular machinery. As these cell-level mechanisms unfold in an individual, time-specific manner, there are many critical points at which a genetic growth program can be enhanced or perturbed. Recognizing both the complexity and fluidity of this adaptive system questions the likelihood of a single, optimal growth pattern and instead identifies a larger bandwidth of saltatory frequencies for "normal" growth. Further inquiry into mechanistic sources of variability acting at critical organizational points of chondrogenesis can provide new opportunities for growth interventions. © 2017 Wiley Periodicals, Inc.

Nutrition in Cardioskeletal Health123

PubMed Central

Hill Gallant, Kathleen M; Weaver, Connie M; Towler, Dwight A; Thuppal, Sowmyanarayanan V; Bailey, Regan L

2016-01-01

Bone and heart health are linked through a variety of cellular, endocrine, and metabolic mechanisms, including the bidirectional effects of mineral-regulating hormones parathyroid hormone and fibroblast growth factor 23. Nutrition plays an important role in the development of both cardiovascular and bone disease. This review describes current knowledge on the relations between the cardiovascular system and bone and the influence of key nutrients involved in mineral metabolism—calcium, vitamin D, and phosphorus—on heart and bone health, as well as the racial/ethnic differences in cardiovascular disease and osteoporosis and the influence that nutrition has on these disparities. PMID:27184281

Growth hormone and bone health.

PubMed

Bex, Marie; Bouillon, Roger

2003-01-01

Growth hormone (GH) and insulin-like growth factor-I have major effects on growth plate chondrocytes and all bone cells. Untreated childhood-onset GH deficiency (GHD) markedly impairs linear growth as well as three-dimensional bone size. Adult peak bone mass is therefore about 50% that of adults with normal height. This is mainly an effect on bone volume, whereas true bone mineral density (BMD; g/cm(3)) is virtually normal, as demonstrated in a large cohort of untreated Russian adults with childhood-onset GHD. The prevalence of fractures in these untreated childhood-onset GHD adults was, however, markedly and significantly increased in comparison with normal Russian adults. This clearly indicates that bone mass and bone size matter more than true bone density. Adequate treatment with GH can largely correct bone size and in several studies also bone mass, but it usually requires more than 5 years of continuous treatment. Adult-onset GHD decreases bone turnover and results in a mild deficit, generally between -0.5 and -1.0 z-score, in bone mineral content and BMD of the lumbar spine, radius and femoral neck. Cross-sectional surveys and the KIMS data suggest an increased incidence of fractures. GH replacement therapy increases bone turnover. The three controlled studies with follow-up periods of 18 and 24 months demonstrated a modest increase in BMD of the lumbar spine and femoral neck in male adults with adult-onset GHD, whereas no significant changes in BMD were observed in women. GHD, whether childhood- or adult-onset, impairs bone mass and strength. Appropriate substitution therapy can largely correct these deficiencies if given over a prolonged period. GH therapy for other bone disorders not associated with primary GHD needs further study but may well be beneficial because of its positive effects on the bone remodelling cycle. Copyright 2003 S. Karger AG, Basel

Mechanical Signaling for Bone Modeling and Remodeling

PubMed Central

Robling, Alexander G.; Turner, Charles H.

2012-01-01

Proper development of the skeleton in utero and during growth requires mechanical stimulation. Loading results in adaptive changes in bone that strengthen bone structure. Bone’s adaptive response is regulated by the ability of resident bone cells to perceive and translate mechanical energy into a cascade of structural and biochemical changes within the cells — a process known as mechanotransduction. Mechanotransduction pathways are among the most anabolic in bone, and consequently, there is great interest in elucidating how mechanical loading produces its observed effects, including increased bone formation, reduced bone loss, changes in bone cell differentiation and lifespan, among others. A molecular understanding of these processes is developing, and with it comes a profound new insight into the biology of bone. In this article, we review the nature of the physical stimulus to which bone cells mount an adaptive response, including the identity of the sensor cells, their attributes and physical environment, and putative mechanoreceptors they express. Particular attention is allotted to the focal adhesion and Wnt signaling, in light of their emerging role in bone mechanotransduction. The cellular mechanisms for increased bone loss during disuse, and reduced bone loss during loading are considered. Finally, we summarize the published data on bone cell accommodation, whereby bone cells stop responding to mechanical signaling events. Collectively, these data highlight the complex yet finely orchestrated process of mechanically regulated bone homeostasis. PMID:19817708

Bringing new life to damaged bone: the importance of angiogenesis in bone repair and regeneration.

PubMed

Stegen, Steve; van Gastel, Nick; Carmeliet, Geert

2015-01-01

Bone has the unique capacity to heal without the formation of a fibrous scar, likely because several of the cellular and molecular processes governing bone healing recapitulate the events during skeletal development. A critical component in bone healing is the timely appearance of blood vessels in the fracture callus. Angiogenesis, the formation of new blood vessels from pre-existing ones, is stimulated after fracture by the local production of numerous angiogenic growth factors. The fracture vasculature not only supplies oxygen and nutrients, but also stem cells able to differentiate into osteoblasts and in a later phase also the ions necessary for mineralization. This review provides a concise report of the regulation of angiogenesis by bone cells, its importance during bone healing and its possible therapeutic applications in bone tissue engineering. This article is part of a Special Issue entitled "Stem Cells and Bone". Copyright © 2014 Elsevier Inc. All rights reserved.

Effects of Huang Bai (Phellodendri Cortex) on bone growth and pubertal development in adolescent female rats.

PubMed

Lee, Sun Haeng; Lee, Hyun Jeong; Lee, Sung Hyun; Kim, Young-Sik; Lee, Donghun; Chun, Jiu; Lee, Jin Yong; Kim, Hocheol; Chang, Gyu Tae

2018-01-01

To evaluate the effects of Huang Bai ( Phellodendron amurense ) on growth and maturation in adolescent female rats. Female Sprague-Dawley rats (28 days old; n = 72) were divided into six daily treatment groups: control (distilled water), Huang Bai (100 and 300 mg/kg), recombinant human GH (rhGH; 20 μg/kg), estradiol (1 μg/kg), and triptorelin (100 μg). Body weight, food intake, and vaginal opening were measured daily from postnatal day (PND) 28 to PND 43. Tetracycline (20 mg/kg) was injected on PND 41. After sacrifice on PND 43, the ovaries and uterus were weighed, and the tibias were fixed in 4% paraformaldehyde. Decalcified and dehydrated tibias were sectioned at a thickness of 40 μm, and sectioned tissues were examined with a fluorescence microscope. Insulin-like growth factor (IGF)-1 and bone morphogenetic protein (BMP)-2 were detected using immunohistochemistry. Relative to controls, body weight was higher in the triptorelin group. Bone growth rate increased in the Huang Bai 100 mg/kg (354.00 ± 31.1 μm/day), rhGH (367.10 ± 27.11 μm/day), and triptorelin (374.50 ± 25.37 μm/day) groups. Expression of IGF-1 and BMP-2 in the hypertrophic zone was higher in all experimental groups. Vaginal opening occurred earlier in the estradiol group (PND 33.58 ± 1.62) than in controls and later in the triptorelin group (PND > 43). Ovarian and uterine weights were lower in the oestradiol and triptorelin groups. However, Huang Bai had nonsignificant effects on vaginal opening and the weights of ovaries and the uterus. Huang Bai stimulated bone growth by upregulating IGF-1 and BMP-2 in the growth plate. However, it had no effect on pubertal development.

Loss of bone sialoprotein leads to impaired endochondral bone development and mineralization.

PubMed

Holm, Erik; Aubin, Jane E; Hunter, Graeme K; Beier, Frank; Goldberg, Harvey A

2015-02-01

Bone sialoprotein (BSP) is an anionic phosphoprotein in the extracellular matrix of mineralized tissues, and a promoter of biomineralization and osteoblast development. Previous studies on the Bsp-deficient mouse (Bsp(-/-)) have demonstrated a significant bone and periodontal tissue phenotype in adulthood. However, the role of BSP during early long bone development is not known. To address this, early endochondral ossification in the Bsp(-/-) mouse was studied. Embryonic day 15.5 (E15.5) wild-type (WT) tibiae showed early stages of ossification that were absent in Bsp(-/-) mice. At E16.5, mineralization had commenced in the Bsp(-/-) mice, but staining for mineral was less intense and more dispersed compared with that in WT controls. Tibiae from Bsp(-/-) mice also demonstrated decreased mineralization and shortened length at postnatal day 0.5 (P0.5) compared to WT bones. There was no detectable difference in the number of tartrate-resistant acid phosphatase-positive foci at P0.5, although the P0.5 Bsp(-/-) tibiae had decreased Vegfα expression compared with WT tissue. Due to the shortened tibiae the growth plates were examined and determined to be of normal overall length. However, the length of the resting zone was increased in P0.5 Bsp(-/-) tibiae whereas that of the proliferative zone was decreased, with no change in the hypertrophic zone length of Bsp(-/-) mice. A reduction in cells positive for Ki-67, an S-phase cell-cycle marker, was noted in the proliferative zone. Decreased numbers of TUNEL-positive hypertrophic chondrocytes were also apparent in the Bsp(-/-) tibial growth plates, suggesting decreased apoptosis. Expression of the osteogenic markers Alp1, Col1a1, Sp7, Runx2, and Bglap was reduced in the endochondral bone of the neonatal Bsp(-/-) compared to WT tibiae. These results suggest that BSP is an important and multifaceted protein that regulates both chondrocyte proliferation and apoptosis as well as transition from cartilage to bone during development of endochondral bone. Copyright © 2014 Elsevier Inc. All rights reserved.

Effect of ethnicity and sex on the growth of the axial and appendicular skeleton of children living in a developing country.

PubMed

Nyati, Lukhanyo H; Norris, Shane A; Cameron, Noel; Pettifor, John M

2006-05-01

Bones in the axial and appendicular skeletons exhibit heterogeneous growth patterns between different ethnic and sex groups. However, the influence of this differential growth on the expression of bone mineral content is not yet established. The aims of the present study were to investigate: 1) whether there are ethnic and sex differences in axial and appendicular dimensions of South African children; and 2) whether regional segment length is a better predictor of bone mass than stature. Anthropometric measurements of stature, weight, sitting height, and limb lengths were taken on 368 black and white, male and female 9-year-old children. DXA (dual-energy x-ray absorptiometry) scans of the distal ulna, distal radius, and hip and lumbar spine were also obtained. Analyses of covariance were performed to assess differences in limb lengths, adjusted for differences in stature. Multiple regression analyses were used to assess significant predictors of site-specific bone mass. Stature-adjusted means of limb lengths show that black boys have longer legs and humeri but shorter trunks than white boys. In addition, black children have longer forearms than white children, and girls have longer thighs than boys. The regression analysis demonstrated that site-specific bone mass was more strongly associated with regional segment length than stature, but this had little effect on the overall pattern of ethnic and sex differences. In conclusion, there is a differential effect of ethnicity and sex on the growth of the axial and appendicular skeletons, and regional segment length is a better predictor of site-specific bone mass than stature. Copyright 2005 Wiley-Liss, Inc.

Vitamin B12–dependent taurine synthesis regulates growth and bone mass

PubMed Central

Roman-Garcia, Pablo; Quiros-Gonzalez, Isabel; Mottram, Lynda; Lieben, Liesbet; Sharan, Kunal; Wangwiwatsin, Arporn; Tubio, Jose; Lewis, Kirsty; Wilkinson, Debbie; Santhanam, Balaji; Sarper, Nazan; Clare, Simon; Vassiliou, George S.; Velagapudi, Vidya R.; Dougan, Gordon; Yadav, Vijay K.

2014-01-01

Both maternal and offspring-derived factors contribute to lifelong growth and bone mass accrual, although the specific role of maternal deficiencies in the growth and bone mass of offspring is poorly understood. In the present study, we have shown that vitamin B12 (B12) deficiency in a murine genetic model results in severe postweaning growth retardation and osteoporosis, and the severity and time of onset of this phenotype in the offspring depends on the maternal genotype. Using integrated physiological and metabolomic analysis, we determined that B12 deficiency in the offspring decreases liver taurine production and associates with abrogation of a growth hormone/insulin-like growth factor 1 (GH/IGF1) axis. Taurine increased GH-dependent IGF1 synthesis in the liver, which subsequently enhanced osteoblast function, and in B12-deficient offspring, oral administration of taurine rescued their growth retardation and osteoporosis phenotypes. These results identify B12 as an essential vitamin that positively regulates postweaning growth and bone formation through taurine synthesis and suggests potential therapies to increase bone mass. PMID:24911144

Long bone histology of the stem salamander Kokartus honorarius (Amphibia: Caudata) from the Middle Jurassic of Kyrgyzstan

PubMed Central

Skutschas, Pavel; Stein, Koen

2015-01-01

Kokartus honorarius from the Middle Jurassic (Bathonian) of Kyrgyzstan is one of the oldest salamanders in the fossil record, characterized by a mixture of plesiomorphic morphological features and characters shared with crown-group salamanders. Here we present a detailed histological analysis of its long bones. The analysis of a growth series demonstrates a significant histological maturation during ontogeny, expressed by the progressive appearance of longitudinally oriented primary vascular canals, primary osteons, growth marks, remodelling features in primary bone tissues, as well as progressive resorption of the calcified cartilage, formation of endochondral bone and development of cartilaginous to bony trabeculae in the epiphyses. Apart from the presence of secondary osteons, the long bone histology of Kokartus is very similar to that of miniaturized temnospondyls, other Jurassic stem salamanders, miniaturized seymouriamorphs and modern crown-group salamanders. We propose that the presence of secondary osteons in Kokartus honorarius is a plesiomorphic feature, and the loss of secondary osteons in the long bones of crown-group salamanders as well as in those of miniaturized temnospondyls is the result of miniaturization processes. Hitherto, all stem salamander long bong histology (Kokartus, Marmorerpeton and ‘salamander A’) has been generally described as having paedomorphic features (i.e. the presence of Katschenko's Line and a layer of calcified cartilage), these taxa were thus most likely neotenic forms. The absence of clear lines of arrested growth and annuli in long bones of Kokartus honorarius suggests that the animals lived in an environment with stable local conditions. PMID:25682890

Long bone histology of the stem salamander Kokartus honorarius (Amphibia: Caudata) from the Middle Jurassic of Kyrgyzstan.

PubMed

Skutschas, Pavel; Stein, Koen

2015-04-01

Kokartus honorarius from the Middle Jurassic (Bathonian) of Kyrgyzstan is one of the oldest salamanders in the fossil record, characterized by a mixture of plesiomorphic morphological features and characters shared with crown-group salamanders. Here we present a detailed histological analysis of its long bones. The analysis of a growth series demonstrates a significant histological maturation during ontogeny, expressed by the progressive appearance of longitudinally oriented primary vascular canals, primary osteons, growth marks, remodelling features in primary bone tissues, as well as progressive resorption of the calcified cartilage, formation of endochondral bone and development of cartilaginous to bony trabeculae in the epiphyses. Apart from the presence of secondary osteons, the long bone histology of Kokartus is very similar to that of miniaturized temnospondyls, other Jurassic stem salamanders, miniaturized seymouriamorphs and modern crown-group salamanders. We propose that the presence of secondary osteons in Kokartus honorarius is a plesiomorphic feature, and the loss of secondary osteons in the long bones of crown-group salamanders as well as in those of miniaturized temnospondyls is the result of miniaturization processes. Hitherto, all stem salamander long bong histology (Kokartus, Marmorerpeton and 'salamander A') has been generally described as having paedomorphic features (i.e. the presence of Katschenko's Line and a layer of calcified cartilage), these taxa were thus most likely neotenic forms. The absence of clear lines of arrested growth and annuli in long bones of Kokartus honorarius suggests that the animals lived in an environment with stable local conditions. © 2015 Anatomical Society.

Effect of ionizing radiation on the bone growth of the proximal part of pelvic limb (in Slovak)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Horak, J.; Horakova, A.; Chlebovsky, O.

1971-01-01

BS>The effect of x radiation was studied on the growth of os ilium, the femur, the tibia, and the fibula in the fetus of rats. Pregnant female rats were exposed to a dose of 250 R, this either of single irradiation on the 11th, 12th, 13th, 14th, and 15th days following fertilization or of chronic irradiation applied over the 1st to the 19th day of pregnancy. The fetuses were removed on the 19th day of pregnancy. The exposure was ascertained to inhibit or to stimulate the growth in dependence on the degree of the development of the fetus at amore » time of exposure. It was verified that during development, the bones manifested stages of increased radiosensitivity as well as of relative radioresistance. The most marked changes were observed in the fibula. (auth)« less

Novel Osteogenic Ti-6Al-4V Device For Restoration Of Dental Function In Patients With Large Bone Deficiencies: Design, Development And Implementation

PubMed Central

Cohen, D. J.; Cheng, A.; Kahn, A.; Aviram, M.; Whitehead, A. J.; Hyzy, S. L.; Clohessy, R. M.; Boyan, B. D.; Schwartz, Z.

2016-01-01

Custom devices supporting bone regeneration and implant placement are needed for edentulous patients with large mandibular deficiencies where endosteal implantation is not possible. We developed a novel subperiosteal titanium-aluminum-vanadium bone onlay device produced by additive manufacturing (AM) and post-fabrication osteogenic micro-/nano-scale surface texture modification. Human osteoblasts produced osteogenic and angiogenic factors when grown on laser-sintered nano-/micro-textured surfaces compared to smooth surfaces. Surface-processed constructs caused higher bone-to-implant contact, vertical bone growth into disk pores (microCT and histomorphometry), and mechanical pull-out force at 5 and 10 w on rat calvaria compared to non surface-modified constructs, even when pre-treating the bone to stimulate osteogenesis. Surface-modified wrap-implants placed around rabbit tibias osseointegrated by 6 w. Finally, patient-specific constructs designed to support dental implants produced via AM and surface-processing were implanted on edentulous mandibular bone. 3 and 8 month post-operative images showed new bone formation and osseointegration of the device and indicated stability of the dental implants. PMID:26854193

Novel Osteogenic Ti-6Al-4V Device For Restoration Of Dental Function In Patients With Large Bone Deficiencies: Design, Development And Implementation.

PubMed

Cohen, D J; Cheng, A; Kahn, A; Aviram, M; Whitehead, A J; Hyzy, S L; Clohessy, R M; Boyan, B D; Schwartz, Z

2016-02-08

Custom devices supporting bone regeneration and implant placement are needed for edentulous patients with large mandibular deficiencies where endosteal implantation is not possible. We developed a novel subperiosteal titanium-aluminum-vanadium bone onlay device produced by additive manufacturing (AM) and post-fabrication osteogenic micro-/nano-scale surface texture modification. Human osteoblasts produced osteogenic and angiogenic factors when grown on laser-sintered nano-/micro-textured surfaces compared to smooth surfaces. Surface-processed constructs caused higher bone-to-implant contact, vertical bone growth into disk pores (microCT and histomorphometry), and mechanical pull-out force at 5 and 10 w on rat calvaria compared to non surface-modified constructs, even when pre-treating the bone to stimulate osteogenesis. Surface-modified wrap-implants placed around rabbit tibias osseointegrated by 6 w. Finally, patient-specific constructs designed to support dental implants produced via AM and surface-processing were implanted on edentulous mandibular bone. 3 and 8 month post-operative images showed new bone formation and osseointegration of the device and indicated stability of the dental implants.

Skeletal Effects of Growth Hormone and Insulin-like Growth Factor-I Therapy

PubMed Central

Lindsey, Richard C.; Mohan, Subburaman

2015-01-01

The growth hormone/insulin-like growth factor (GH/IGF) axis is critically important for the regulation of bone formation, and deficiencies in this system have been shown to contribute to the development of osteoporosis and other diseases of low bone mass. The GH/IGF axis is regulated by a complex set of hormonal and local factors which can act to regulate this system at the level of the ligands, receptors, IGF binding proteins (IGFBPs), or IGFBP proteases. A combination of in vitro studies, transgenic animal models, and clinical human investigations has provided ample evidence of the importance of the endocrine and local actions of both GH and IGF-I, the two major components of the GH/IGF axis, in skeletal growth and maintenance. GH- and IGF-based therapies provide a useful avenue of approach for the prevention and treatment of diseases such as osteoporosis. PMID:26408965

Epigenetic regulation of fetal bone development and placental transfer of nutrients: progress for osteoporosis.

PubMed

Bocheva, Georgeta; Boyadjieva, Nadka

2011-12-01

Osteoporosis is a common age-related disorder and causes acute and long-term disability and economic cost. Many factors influence the accumulation of bone minerals, including heredity, diet, physical activity, gender, endocrine functions, and risk factors such as alcohol, drug abuse, some pharmacological drugs or cigarette smoking. The pathology of bone development during intrauterine life is a factor for osteoporosis. Moreover, the placental transfer of nutrients plays an important role in the building of bones of fetuses. The importance of maternal calcium intake and vitamin D status are highlighted in this review. Various environmental factors including nutrition state or maternal stress may affect the epigenetic state of a number of genes during fetal development of bones. Histone modifications as histone hypomethylation, histone hypermethylation, hypoacetylation, etc. are involved in chromatin remodeling, known to contribute to the epigenetic landscape of chromosomes, and play roles in both fetal bone development and osteoporosis. This review will give an overview of epigenetic modulation of bone development and placental transfer of nutrients. In addition, the data from animal and human studies support the role of epigenetic modulation of calcium and vitamin D in the pathogenesis of osteoporosis. We review the evidence suggesting that various genes are involved in regulation of osteoclast formation and differentiation by osteoblasts and stem cells. Epigenetic changes in growth factors as well as cytokines play a rol in fetal bone development. On balance, the data suggest that there is a link between epigenetic changes in placental transfer of nutrients, including calcium and vitamin D, abnormal intrauterine bone development and pathogenesis of osteoporosis.

IGFBP-4 regulates adult skeletal growth in a sex-specific manner.

PubMed

Maridas, David E; DeMambro, Victoria E; Le, Phuong T; Nagano, Kenichi; Baron, Roland; Mohan, Subburaman; Rosen, Clifford J

2017-04-01

Insulin-like growth factor-1 (IGF-1) and its binding proteins are critical mediators of skeletal growth. Insulin-like growth factor-binding protein 4 (IGFBP-4) is highly expressed in osteoblasts and inhibits IGF-1 actions in vitro Yet, in vivo studies suggest that it could potentiate IGF-1 and IGF-2 actions. In this study, we hypothesized that IGFBP-4 might potentiate the actions of IGF-1 on the skeleton. To test this, we comprehensively studied 8- and 16-week-old Igfbp4 -/- mice. Both male and female adult Igfbp4 -/- mice had marked growth retardation with reductions in body weight, body and femur lengths, fat proportion and lean mass at 8 and 16 weeks. Marked reductions in aBMD and aBMC were observed in 16-week-old Igfbp4 -/- females, but not in males. Femoral trabecular BV/TV and thickness, cortical fraction and thickness in 16-week-old Igfbp4 -/- females were significantly reduced. However, surprisingly, males had significantly more trabeculae with higher connectivity density than controls. Concordantly, histomorphometry revealed higher bone resorption and lower bone formation in Igfbp4 -/- females. In contrast, Igfbp4 -/- males had lower mineralized surface/bone surface. Femoral expression of Sost and circulating levels of sclerostin were reduced but only in Igfbp4 -/- males. Bone marrow stromal cultures from mutants showed increased osteogenesis, whereas osteoclastogenesis was markedly increased in cells from Igfbp4 -/- females but decreased in males. In sum, our results indicate that loss of Igfbp4 affects mesenchymal stromal cell differentiation, regulates osteoclastogenesis and influences both skeletal development and adult bone maintenance. Thus, IGFBP-4 modulates the skeleton in a gender-specific manner, acting as both a cell autonomous and cell non-autonomous factor. © 2017 The authors.

Identification of a constitutive law for trabecular bone samples under remodeling in the framework of irreversible thermodynamics

NASA Astrophysics Data System (ADS)

Louna, Zineeddine; Goda, Ibrahim; Ganghoffer, Jean-François

2018-01-01

We construct in the present paper constitutive models for bone remodeling based on micromechanical analyses at the scale of a representative unit cell (RUC) including a porous trabecular microstructure. The time evolution of the microstructure is simulated as a surface remodeling process by relating the surface growth remodeling velocity to a surface driving force incorporating a (surface) Eshelby tensor. Adopting the framework of irreversible thermodynamics, a 2D constitutive model based on the setting up of the free energy density and a dissipation potential is identified from FE simulations performed over a unit cell representative of the trabecular architecture obtained from real bone microstructures. The static and evolutive effective properties of bone at the scale of the RUC are obtained by combining a methodology for the evaluation of the average kinematic and static variables over a prototype unit cell and numerical simulations with controlled imposed first gradient rates. The formulated effective growth constitutive law at the scale of the homogenized set of trabeculae within the RUC is of viscoplastic type and relates the average growth strain rate to the homogenized stress tensor. The postulated model includes a power law function of an effective stress chosen to depend on the first and second stress invariants. The model coefficients are calibrated from a set of virtual testing performed over the RUC subjected to a sequence of loadings. Numerical simulations show that overall bone growth does not show any growth kinematic hardening. The obtained results quantify the strength and importance of different types of external loads (uniaxial tension, simple shear, and biaxial loading) on the overall remodeling process and the development of elastic deformations within the RUC.

The SK-N-AS human neuroblastoma cell line develops osteolytic bone metastases with increased angiogenesis and COX-2 expression

PubMed Central

Tsutsumimoto, Takahiro; Williams, Paul; Yoneda, Toshiyuki

2014-01-01

Neuroblastoma (NB), which arises from embryonic neural crest cells, is the most common extra-cranial solid tumor of childhood. Approximately half of NB patients manifest bone metastasis accompanied with bone pain, fractures and bone marrow failure, leading to disturbed quality of life and poor survival. To study the mechanism of bone metastasis of NB, we established an animal model in which intracardiac inoculation of the SK-N-AS human NB cells in nude mice developed osteolytic bone metastases with increased osteoclastogenesis. SK-N-AS cells induced the expression of receptor activator of NF-κB ligand and osteoclastogenesis in mouse bone marrow cells in the co-culture. SK-N-AS cells expressed COX-2 mRNA and produced substantial amounts of prostaglandin E2 (PGE2). In contrast, the SK-N-DZ and SK-N-FI human NB cells failed to develop bone metastases, induce osteoclastogenesis, express COX-2 mRNA and produce PGE2. Immunohistochemical examination of SK-N-AS bone metastasis and subcutaneous tumor showed strong expression of COX-2. The selective COX-2 inhibitor NS-398 inhibited PGE2 production and suppressed bone metastases with reduced osteoclastogenesis. NS-398 also inhibited subcutaneous SK-N-AS tumor development with decreased angiogenesis and vascular endothelial growth factor-A expression. Of interest, metastasis to the adrenal gland, a preferential site for NB development, was also diminished by NS-398. Our results suggest that COX2/PGE2 axis plays a critical role in the pathophysiology of osteolytic bone metastases and tumor development of the SK-NS-AS human NB. Inhibition of angiogenesis by suppressing COX-2/PGE2 may be an effective therapeutic approach for children with NB. PMID:26909300

Skeletal manifestations of juvenile hypothyroidism and the impact of treatment on skeletal system.

PubMed

Gutch, Manish; Philip, Rajeev; Philip, Renjit; Toms, Ajit; Saran, Sanjay; Gupta, K K

2013-10-01

Thyroid hormone mediates growth and development of the skeleton through its direct effects and through its permissive effects on growth hormone. The effect of hypothyroidism on bone is well described in congenital hypothyroidism, but the impact of thyroid hormone deficiency on a growing skeleton, as it happens with juvenile hypothyroidism, is less defined. In addition, the extent to which the skeletal defects of juvenile hypothyroidism revert on the replacement of thyroid hormone is not known. A study was undertaken in 29 juvenile autoimmune hypothyroid patients to study the skeletal manifestations of juvenile hypothyroidism and the impact of treatment of hypothyroidism on the skeletal system of juvenile patients. Hypothyroidism has a profound impact on the skeletal system and delayed bone age, dwarfism, and thickened bands at the metaphyseal ends being the most common findings. Post treatment, skeletal findings like delayed bone age and dwarfism improved significantly, but there were no significant changes in enlargement of sella, presence of wormian bones, epihyseal dysgenesis, vertebral changes and thickened band at the metaphyseal ends. With the treatment of hypothyroidism, there is an exuberant advancement of bone age, the catch up of bone age being approximately double of the chronological age advancement.

Implantable sensor technology: measuring bone and joint biomechanics of daily life in vivo

PubMed Central

2013-01-01

Stresses and strains are major factors influencing growth, remodeling and repair of musculoskeletal tissues. Therefore, knowledge of forces and deformation within bones and joints is critical to gain insight into the complex behavior of these tissues during development, aging, and response to injury and disease. Sensors have been used in vivo to measure strains in bone, intraarticular cartilage contact pressures, and forces in the spine, shoulder, hip, and knee. Implantable sensors have a high impact on several clinical applications, including fracture fixation, spine fixation, and joint arthroplasty. This review summarizes the developments in strain-measurement-based implantable sensor technology for musculoskeletal research. PMID:23369655

Role of Thyroid Hormones in Skeletal Development and Bone Maintenance

PubMed Central

Bassett, J. H. Duncan

2016-01-01

The skeleton is an exquisitely sensitive and archetypal T3-target tissue that demonstrates the critical role for thyroid hormones during development, linear growth, and adult bone turnover and maintenance. Thyrotoxicosis is an established cause of secondary osteoporosis, and abnormal thyroid hormone signaling has recently been identified as a novel risk factor for osteoarthritis. Skeletal phenotypes in genetically modified mice have faithfully reproduced genetic disorders in humans, revealing the complex physiological relationship between centrally regulated thyroid status and the peripheral actions of thyroid hormones. Studies in mutant mice also established the paradigm that T3 exerts anabolic actions during growth and catabolic effects on adult bone. Thus, the skeleton represents an ideal physiological system in which to characterize thyroid hormone transport, metabolism, and action during development and adulthood and in response to injury. Future analysis of T3 action in individual skeletal cell lineages will provide new insights into cell-specific molecular mechanisms and may ultimately identify novel therapeutic targets for chronic degenerative diseases such as osteoporosis and osteoarthritis. This review provides a comprehensive analysis of the current state of the art. PMID:26862888

Regulation of Bone Metabolism by Serotonin.

PubMed

Lavoie, Brigitte; Lian, Jane B; Mawe, Gary M

2017-01-01

The processes of bone growth and turnover are tightly regulated by the actions of various signaling molecules, including hormones, growth factors, and cytokines. Imbalances in these processes can lead to skeletal disorders such as osteoporosis or high bone mass disease. It is becoming increasingly clear that serotonin can act through a number of mechanisms, and at different locations in the body, to influence the balance between bone formation and resorption. Its actions on bone metabolism can vary, based on its site of synthesis (central or peripheral) as well as the cells and subtypes of receptors that are activated. Within the central nervous system, serotonergic neurons act via the hypothalamus to suppress sympathetic input to the bone. Since sympathetic input inhibits bone formation, brain serotonin has a net positive effect on bone growth. Gut-derived serotonin is thought to inhibit bone growth by attenuating osteoblast proliferation via activation of receptors on pre-osteoblasts. There is also evidence that serotonin can be synthesized within the bone and act to modulate bone metabolism. Osteoblasts, osteoclasts, and osteocytes all have the machinery to synthesize serotonin, and they also express the serotonin-reuptake transporter (SERT). Understanding the roles of serotonin in the tightly balanced system of bone modeling and remodeling is a clinically relevant goal. This knowledge can clarify bone-related side effects of drugs that affect serotonin signaling, including serotonin-specific reuptake inhibitors (SSRIs) and receptor agonists and antagonists, and it can potentially lead to therapeutic approaches for alleviating bone pathologies.

A synergistic approach to the design, fabrication and evaluation of 3D printed micro and nano featured scaffolds for vascularized bone tissue repair

PubMed Central

Holmes, Benjamin; Bulusu, Kartik; Plesniak, Michael; Zhang, Lijie Grace

2016-01-01

3D bioprinting has begun to show great promise in advancing the development of functional tissue/organ replacements. However, to realize the true potential of 3D bioprinted tissues for clinical use requires the fabrication of an interconnected and effective vascular network. Solving this challenge is critical, as human tissue relies on an adequate network of blood vessels to transport oxygen, nutrients, other chemicals, biological factors and waste, in and out of the tissue. Here, we have successfully designed and printed a series of novel 3D bone scaffolds with both bone formation supporting structures and highly interconnected 3D microvascular mimicking channels, for efficient and enhanced osteogenic bone regeneration as well as vascular cell growth. Using a chemical functionalization process, we have conjugated our samples with nano hydroxyapatite (nHA), for the creation of novel micro and nano featured devices for vascularized bone growth. We evaluated our scaffolds with mechanical testing, hydrodynamic measurements and in vitro human mesenchymal stem cell (hMSC) adhesion (4 h), proliferation (1, 3 and 5 d) and osteogenic differentiation (1, 2 and 3 weeks). These tests confirmed bone-like physical properties and vascular-like flow profiles, as well as demonstrated enhanced hMSC adhesion, proliferation and osteogenic differentiation. Additional in vitro experiments with human umbilical vein endothelial cells also demonstrated improved vascular cell growth, migration and organization on micro-nano featured scaffolds. PMID:26758780

A synergistic approach to the design, fabrication and evaluation of 3D printed micro and nano featured scaffolds for vascularized bone tissue repair

NASA Astrophysics Data System (ADS)

Holmes, Benjamin; Bulusu, Kartik; Plesniak, Michael; Zhang, Lijie Grace

2016-02-01

3D bioprinting has begun to show great promise in advancing the development of functional tissue/organ replacements. However, to realize the true potential of 3D bioprinted tissues for clinical use requires the fabrication of an interconnected and effective vascular network. Solving this challenge is critical, as human tissue relies on an adequate network of blood vessels to transport oxygen, nutrients, other chemicals, biological factors and waste, in and out of the tissue. Here, we have successfully designed and printed a series of novel 3D bone scaffolds with both bone formation supporting structures and highly interconnected 3D microvascular mimicking channels, for efficient and enhanced osteogenic bone regeneration as well as vascular cell growth. Using a chemical functionalization process, we have conjugated our samples with nano hydroxyapatite (nHA), for the creation of novel micro and nano featured devices for vascularized bone growth. We evaluated our scaffolds with mechanical testing, hydrodynamic measurements and in vitro human mesenchymal stem cell (hMSC) adhesion (4 h), proliferation (1, 3 and 5 d) and osteogenic differentiation (1, 2 and 3 weeks). These tests confirmed bone-like physical properties and vascular-like flow profiles, as well as demonstrated enhanced hMSC adhesion, proliferation and osteogenic differentiation. Additional in vitro experiments with human umbilical vein endothelial cells also demonstrated improved vascular cell growth, migration and organization on micro-nano featured scaffolds.

A synergistic approach to the design, fabrication and evaluation of 3D printed micro and nano featured scaffolds for vascularized bone tissue repair.

PubMed

Holmes, Benjamin; Bulusu, Kartik; Plesniak, Michael; Zhang, Lijie Grace

2016-02-12

3D bioprinting has begun to show great promise in advancing the development of functional tissue/organ replacements. However, to realize the true potential of 3D bioprinted tissues for clinical use requires the fabrication of an interconnected and effective vascular network. Solving this challenge is critical, as human tissue relies on an adequate network of blood vessels to transport oxygen, nutrients, other chemicals, biological factors and waste, in and out of the tissue. Here, we have successfully designed and printed a series of novel 3D bone scaffolds with both bone formation supporting structures and highly interconnected 3D microvascular mimicking channels, for efficient and enhanced osteogenic bone regeneration as well as vascular cell growth. Using a chemical functionalization process, we have conjugated our samples with nano hydroxyapatite (nHA), for the creation of novel micro and nano featured devices for vascularized bone growth. We evaluated our scaffolds with mechanical testing, hydrodynamic measurements and in vitro human mesenchymal stem cell (hMSC) adhesion (4 h), proliferation (1, 3 and 5 d) and osteogenic differentiation (1, 2 and 3 weeks). These tests confirmed bone-like physical properties and vascular-like flow profiles, as well as demonstrated enhanced hMSC adhesion, proliferation and osteogenic differentiation. Additional in vitro experiments with human umbilical vein endothelial cells also demonstrated improved vascular cell growth, migration and organization on micro-nano featured scaffolds.

Lifelong intake of flaxseed or menhaden oil to provide varying n-6 to n-3 PUFA ratios modulate bone microarchitecture during growth, but not after OVX in Sprague-Dawley rats.

PubMed

Longo, Amanda B; Sullivan, Philip J; Peters, Sandra J; LeBlanc, Paul J; Wohl, Gregory R; Ward, Wendy E

2017-08-01

Skeletal health is a lifelong process impacted by environmental factors, including nutrient intake. The n-3 source and PUFA ratio affect bone health in growing rats, or following ovariectomy (OVX), but no study has investigated the longitudinal effect of PUFA-supplementation throughout these periods of bone development. One-month-old, Sprague-Dawley rats (n = 98) were randomized to receive one of four diets from 1 through 6 months of age. Diets were modified from AIN-93G to contain a varying amount and source of n-3 (flaxseed versus menhaden oil) to provide an n-6 to n-3 ratio of 10:1 or 5:1. At 3 (prior to SHAM or OVX) and 6 months of age, bone microarchitecture of the tibia was quantified using in vivo micro-computed tomography (SkyScan 1176, Bruker microCT). Providing 5:1 (flaxseed) resulted in lower trabecular thickness and medullary area and greater cortical area fraction during growth compared to diets with a 10:1 PUFA ratio, but many of these differences were not apparent following OVX. PUFA-supplementation at levels attainable in human diet modulates some bone structure outcomes during periods of growth, but is not an adequate strategy for the prevention of OVX-induced bone loss in rats. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Silk scaffolds in bone tissue engineering: An overview.

PubMed

Bhattacharjee, Promita; Kundu, Banani; Naskar, Deboki; Kim, Hae-Won; Maiti, Tapas K; Bhattacharya, Debasis; Kundu, Subhas C

2017-11-01

Bone tissue plays multiple roles in our day-to-day functionality. The frequency of accidental bone damage and disorder is increasing worldwide. Moreover, as the world population continues to grow, the percentage of the elderly population continues to grow, which results in an increased number of bone degenerative diseases. This increased elderly population pushes the need for artificial bone implants that specifically employ biocompatible materials. A vast body of literature is available on the use of silk in bone tissue engineering. The current work presents an overview of this literature from materials and fabrication perspective. As silk is an easy-to-process biopolymer; this allows silk-based biomaterials to be molded into diverse forms and architectures, which further affects the degradability. This makes silk-based scaffolds suitable for treating a variety of bone reconstruction and regeneration objectives. Silk surfaces offer active sites that aid the mineralization and/or bonding of bioactive molecules that facilitate bone regeneration. Silk has also been blended with a variety of polymers and minerals to enhance its advantageous properties or introduce new ones. Several successful works, both in vitro and in vivo, have been reported using silk-based scaffolds to regenerate bone tissues or other parts of the skeletal system such as cartilage and ligament. A growing trend is observed toward the use of mineralized and nanofibrous scaffolds along with the development of technology that allows to control scaffold architecture, its biodegradability and the sustained releasing property of scaffolds. Further development of silk-based scaffolds for bone tissue engineering, taking them up to and beyond the stage of human trials, is hoped to be achieved in the near future through a cross-disciplinary coalition of tissue engineers, material scientists and manufacturing engineers. The state-of-art of silk biomaterials in bone tissue engineering, covering their wide applications as cell scaffolding matrices to micro-nano carriers for delivering bone growth factors and therapeutic molecules to diseased or damaged sites to facilitate bone regeneration, is emphasized here. The review rationalizes that the choice of silk protein as a biomaterial is not only because of its natural polymeric nature, mechanical robustness, flexibility and wide range of cell compatibility but also because of its ability to template the growth of hydroxyapatite, the chief inorganic component of bone mineral matrix, resulting in improved osteointegration. The discussion extends to the role of inorganic ions such as Si and Ca as matrix components in combination with silk to influence bone regrowth. The effect of ions or growth factor-loaded vehicle incorporation into regenerative matrix, nanotopography is also considered. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Bone remodelling in Neanderthal mandibles from the El Sidrón site (Asturias, Spain)

PubMed Central

Martinez-Maza, Cayetana; Rosas, Antonio; García-Vargas, Samuel; Estalrrich, Almudena; de la Rasilla, Marco

2011-01-01

Skull morphology results from the bone remodelling mechanism that underlies the specific bone growth dynamics. Histological study of the bone surface from Neanderthal mandible specimens of El Sidrón (Spain) provides information about the distribution of the remodelling fields (bone remodelling patterns or BRP) indicative of the bone growth directions. In comparison with other primate species, BRP shows that Neanderthal mandibles from the El Sidrón (Spain) sample present a specific BRP. The interpretation of this map allows inferences concerning the growth directions that explain specific morphological traits of the Neanderthal mandible, such as its quadrangular shape and the posterior location of the mental foramen. PMID:21307043

Abnormal Canine Bone Development Associated with Hypergravity Exposure

NASA Technical Reports Server (NTRS)

Morgan, J. P.; Fisher, G. L.; McNeill, K. L.; Oyama, J.

1979-01-01

Chronic centrifugation of 85- to 92-day-old Beagles at 2.0 x g and 2.6 x g for 26 weeks during the time of active skeletal growth caused skeletal abnormalities in the radius and the ulna of ten of 11 dogs. The pattern of change mimicked that found in naturally occurring and experimentally induced premature distal ulnar physeal closure or delayed growth at this physis. Minimal changes in bone density were detected by sensitive photon absorptiometric techniques. Skeletal abnormalities also were found in five of the six cage-control dogs, although the run-control dogs were radiographically normal.

Role of HIF-1α in skeletal development

PubMed Central

Wan, Chao; Shao, Jin; Gilbert, Shawn R.; Riddle, Ryan C.; Long, Fanxin; Johnson, Randall S.; Schipani, Ernestina; Clemens, Thomas L.

2011-01-01

Angiogenesis and osteogenesis are tightly coupled during bone development and regeneration. Mesenchymal cells in the developing stroma elicit angiogenic signals to recruit new blood vessels into bone. Reciprocal signals, likely emanating from the incoming vascular endothelium, stimulate mesenchymal cell specification through additional interactions with cells within the vascular stem cell niche. The hypoxia-inducible factor-1 alpha (HIF-1) pathway has been identified as a key component in this process. We demonstrated that overexpression of HIF-1 in mature osteoblasts through disruption of the von Hippel-Lindau protein profoundly increases angiogenesis and osteogenesis; these processes appear to be coupled by cell nonautonomous mechanisms involving the action of vascular endothelial growth factor (VEGF) on the endothelial cells. The same occurred in the model of injury-mediated bone regeneration (distraction osteogenesis). Surprisingly, manipulation of HIF-1 does not influence angiogenesis of the skull bones, where earlier activation of HIF-1 in the condensing mesenchyme upregulates osterix during cranial bone formation. PMID:20392254

Effect of Irrigation Time of Antiseptic Solutions on Bone Cell Viability and Growth Factor Release.

PubMed

Sawada, Kosaku; Nakahara, Ken; Haga-Tsujimura, Maiko; Fujioka-Kobayashi, Masako; Iizuka, Tateyuki; Miron, Richard J

2018-03-01

Antiseptic solutions are commonly utilized to treat local infection in the oral and maxillofacial region. However, surrounding vital bone is also exposed to antiseptic agents during irrigation and may have a potential negative impact on bone survival. The aim of the present study was therefore to investigate the effect of rinsing time with various antiseptic solutions on bone cell viability, as well as their subsequent release of growth factors important for bone regeneration. The bone samples collected from porcine mandible were rinsed in the following commonly utilized antiseptic solutions; povidone-iodine (0.5%), chlorhexidine digluconate (CHX, 0.2%), hydrogen peroxide (1%), and sodium hypochlorite (0.25%) for 1, 5, 10, 20, 30, or 60 minutes and assessed for cell viability and release of growth factors including vascular endothelial growth factor, transforming growth factor beta 1, bone morphogenetic protein 2, receptor activator of nuclear factor kappa-B ligand, and interleukin-1 beta by enzyme-linked immunosorbent assay. It was found in all the tested groups that the long exposure of any of the tested antiseptic solutions drastically promoted higher cell death. Sodium hypochlorite demonstrated the significantly highest cell death and at all time points. Interestingly, bone cell viability was highest in the CHX group post short-term rinsing of 1, 5, or 10 minutes when compared with the other 4 tested groups. A similar trend was also observed in subsequent growth factor release. The present study demonstrated that of the 4 tested antiseptic solutions, short-term CHX rinsing (ideally within 1 minute) favored bone cell viability and growth factor release. Clinical protocols should be adapted accordingly.

Different Indices of Fetal Growth Predict Bone Size and Volumetric Density at 4 Years of Age

PubMed Central

Harvey, Nicholas C; Mahon, Pamela A; Robinson, Sian M; Nisbet, Corrine E; Javaid, M Kassim; Crozier, Sarah R; Inskip, Hazel M; Godfrey, Keith M; Arden, Nigel K; Dennison, Elaine M; Cooper, Cyrus

2011-01-01

We have demonstrated previously that higher birth weight is associated with greater peak and later-life bone mineral content and that maternal body build, diet, and lifestyle influence prenatal bone mineral accrual. To examine prenatal influences on bone health further, we related ultrasound measures of fetal growth to childhood bone size and density. We derived Z-scores for fetal femur length and abdominal circumference and conditional growth velocity from 19 to 34 weeks’ gestation from ultrasound measurements in participants in the Southampton Women’s Survey. A total of 380 of the offspring underwent dual-energy X-ray absorptiometry (DXA) at age 4 years [whole body minus head bone area (BA), bone mineral content (BMC), areal bone mineral density (aBMD), and estimated volumetric BMD (vBMD)]. Volumetric bone mineral density was estimated using BMC adjusted for BA, height, and weight. A higher velocity of 19- to 34-week fetal femur growth was strongly associated with greater childhood skeletal size (BA: r = 0.30, p < .0001) but not with volumetric density (vBMD: r = 0.03, p = .51). Conversely, a higher velocity of 19- to 34-week fetal abdominal growth was associated with greater childhood volumetric density (vBMD: r = 0.15, p = .004) but not with skeletal size (BA: r = 0.06, p = .21). Both fetal measurements were positively associated with BMC and aBMD, indices influenced by both size and density. The velocity of fetal femur length growth from 19 to 34 weeks’ gestation predicted childhood skeletal size at age 4 years, whereas the velocity of abdominal growth (a measure of liver volume and adiposity) predicted volumetric density. These results suggest a discordance between influences on skeletal size and volumetric density. PMID:20437610

Investigation of Peri-Implant Bone Healing Using Autologous Plasma Rich in Growth Factors in the Canine Mandible After 12 Weeks: A Pilot Study

PubMed Central

Birang, Reza; Tavakoli, Mohammad; Shahabouei, Mohammad; Torabi, Alireza; Dargahi, Ali; Soolari, Ahmad

2011-01-01

Introduction: Faster reconstruction of patients’ masticatory systems is the aim of modern dentistry. A number of studies have indicated that application of growth factors to the surface of a dental implant leads to accelerated and enhanced osseointegration. The objective of the present study was to investigate the effect of plasma rich in growth factors on peri-implant bone healing. Materials and Methods: For the purpose of this study, two healthy, mixed-breed canines were selected, and the premolars were extracted from both sides of the mandible. Three months after premolar removal, 12 implants, each 5 mm in diameter and 10 mm in length, were placed in osteotomy sites on both sides of the mandible. Prior to placement, plasma rich in growth factors was applied to the surfaces of six implants, while the other six were used without plasma rich in growth factors. The implants were removed after 12 weeks along with the bone surrounding the sites using a trephine bur. One mesiodistal section containing the surrounding bone from each implant block, 50 µm in diameter, was prepared for histologic and histomorphometric investigation with an optical microscope. Results: The sites with implants treated with plasma rich in growth factors showed more bone-to-implant contact compared to control sites. Also, higher values for bone trabecular thickness and bone maturity were recorded for the PRGF-treated sites than for the control sites. Conclusion: Application of plasma rich in growth factors to the surface of an implant may enhance the bone healing process as well as bone-to-implant contact, thereby helping to achieve faster osseointegration. PMID:22145011

Effects of Imbalanced Muscle Loading on Hip Joint Development and Maturation

PubMed Central

Ford, Caleb A.; Nowlan, Niamh C.; Thomopoulos, Stavros; Killian, Megan L.

2017-01-01

The mechanical loading environment influences the development and maturation of joints. In this study, the influence of imbalanced muscular loading on joint development was studied using localized chemical denervation of hip stabilizing muscle groups in neonatal mice. It was hypothesized that imbalanced muscle loading, targeting either gluteal muscles or quadriceps muscles, would lead to bilateral hip joint asymmetry, as measured by acetabular coverage, femoral head volume and bone morphometry, and femoral-acetabular shape. The contralateral hip joints as well as age-matched, uninjected mice were used as controls. Altered bone development was analyzed using micro-computed tomography, histology, and image registration techniques at postnatal days (P) 28, 56, and 120. This study found that unilateral muscle unloading led to reduced acetabular coverage of the femoral head, lower total volume, lower bone volume ratio, and lower mineral density, at all three time points. Histologically, the femoral head was smaller in unloaded hips, with thinner triradiate cartilage at P28 and thinner cortical bone at P120 compared to contralateral hips. Morphological shape changes were evident in unloaded hips at P56. Unloaded hips had lower trabecular thickness and increased trabecular spacing of the femoral head compared to contralateral hips. The present study suggests that decreased muscle loading of the hip leads to altered bone and joint shape and growth during postnatal maturation. Statement of Clinical Significance: Adaptations from altered muscle loading during postnatal growth investigated in this study have implications on developmental hip disorders that result from asymmetric loading, such as patients with limb-length inequality or dysplasia. PMID:27391299

Loss of transcription factor early growth response gene 1 results in impaired endochondral bone repair

PubMed Central

Reumann, Marie K.; Strachna, Olga; Yagerman, Sarah; Torrecilla, Daniel; Kim, Jihye; Doty, Steven B.; Lukashova, Lyudmila; Boskey, Adele L.; Mayer-Kuckuk, Philipp

2011-01-01

Transcription factors that play a role in ossification during development are expected to participate in postnatal fracture repair since the endochondral bone formation that occurs in embryos is recapitulated during fracture repair. However, inherent differences exist between bone development and fracture repair, including a sudden disruption of tissue integrity followed by an inflammatory response. This raises the possibility that repair-specific transcription factors participate in bone healing. Here, we assessed the consequence of loss of early growth response gene 1 (EGR-1) on endochondral bone healing because this transcription factor has been shown to modulate repair in vascularized tissues. Model fractures were created in ribs of wild type (wt) and EGR-1−/− mice. Differences in tissue morphology and composition between these two animal groups were followed over 28 post fracture days (PFDs). In wt mice, bone healing occurred in healing phases characteristic of endochondral bone repair. A similar healing sequence was observed in EGR-1−/− mice but was impaired by alterations. A persistent accumulation of fibrin between the disconnected bones was observed on PFD7 and remained pronounced in the callus on PFD14. Additionally, the PFD14 callus was abnormally enlarged and showed increased deposition of mineralized tissue. Cartilage ossification in the callus was associated with hyper-vascularity and -proliferation. Moreover, cell deposits located in proximity to the callus within skeletal muscle were detected on PFD14. Despite these impairments, repair in EGR-1−/− callus advanced on PFD28, suggesting EGR-1 is not essential for healing. Together, this study provides genetic evidence that EGR-1 is a pleiotropic regulator of endochondral fracture repair. PMID:21726677

Loss of transcription factor early growth response gene 1 results in impaired endochondral bone repair.

PubMed

Reumann, Marie K; Strachna, Olga; Yagerman, Sarah; Torrecilla, Daniel; Kim, Jihye; Doty, Stephen B; Lukashova, Lyudmila; Boskey, Adele L; Mayer-Kuckuk, Philipp

2011-10-01

Transcription factors that play a role in ossification during development are expected to participate in postnatal fracture repair since the endochondral bone formation that occurs in embryos is recapitulated during fracture repair. However, inherent differences exist between bone development and fracture repair, including a sudden disruption of tissue integrity followed by an inflammatory response. This raises the possibility that repair-specific transcription factors participate in bone healing. Here, we assessed the consequence of loss of early growth response gene 1 (EGR-1) on endochondral bone healing because this transcription factor has been shown to modulate repair in vascularized tissues. Model fractures were created in ribs of wild type (wt) and EGR-1(-/-) mice. Differences in tissue morphology and composition between these two animal groups were followed over 28 post fracture days (PFDs). In wt mice, bone healing occurred in healing phases characteristic of endochondral bone repair. A similar healing sequence was observed in EGR-1(-/-) mice but was impaired by alterations. A persistent accumulation of fibrin between the disconnected bones was observed on PFD7 and remained pronounced in the callus on PFD14. Additionally, the PFD14 callus was abnormally enlarged and showed increased deposition of mineralized tissue. Cartilage ossification in the callus was associated with hyper-vascularity and -proliferation. Moreover, cell deposits located in proximity to the callus within skeletal muscle were detected on PFD14. Despite these impairments, repair in EGR-1(-/-) callus advanced on PFD28, suggesting EGR-1 is not essential for healing. Together, this study provides genetic evidence that EGR-1 is a pleiotropic regulator of endochondral fracture repair. Copyright © 2011 Elsevier Inc. All rights reserved.

Deletion of Core-binding factor β (Cbfβ) in mesenchymal progenitor cells provides new insights into Cbfβ/Runxs complex function in cartilage and bone development

PubMed Central

Wu, Mengrui; Li, Chenguan; Zhu, Guochun; Wang, Yiping; Jules, Joel; Lu, Yun; McConnell, Matthew; Wang, Yong-Jun; Shao, Jian-Zhong; Li, Yi-Ping; Chen, Wei

2015-01-01

Core-binding factor β (Cbfβ) is a subunit of the Cbf family of heterodimeric transcription factors which plays a critical role in skeletal development through its interaction with the Cbfα subunits, also known as Runt-related transcription factors (Runxs). However, the mechanism by which Cbfβ regulates cartilage and bone development remains unclear. Existing Cbfβ-deficient mouse models cannot specify the role of Cbfβ in skeletal cell lineage. Herein, we sought to specifically address the role of Cbfβ in cartilage and bone development by using a conditional knockout (CKO) approach. A mesenchymal-specific Cbfβ CKO mouse model was generated by using the Dermo1-Cre mouse line to specifically delete Cbfβ in mesenchymal stem cells, which give rise to osteoblasts and chondrocytes. Surprisingly, the mutant mice had under-developed larynx and tracheal cartilage causing alveolus defects which led to death shortly after birth from suffocation. Also, the mutant mice exhibited severe skeletal deformities from defective intramembranous and endochondral ossification, owing to delayed chondrocyte maturation and impaired osteoblast differentiation. Almost all bones of the mutant mice, including the calvariae, vertebrae, tibiae, femurs, ribs, limbs and sternums were defective. Importantly, we showed that Cbfβ was expressed throughout the skeleton during both embryonic and postnatal development, which explains the multiple-skeletal defects observed in the mutant mice. Consistently, Cbfβ deficiency impaired both chondrocyte proliferation and hypertrophy zone hypertrophy during growth-plate development in the long bones of mutant mice. Notably, Cbfβ, Runx1 and Runx2 displayed different expression patterns in the growth plates of the wildtype mice indicating that Cbfβ/Runx1 complex and Cbfβ/Runx2 complex may regulate chondrocyte proliferation and hypertrophy, respectively, in a spatial and temporal manner. Cbfβ deletion in the mesenchymal progenitors impacted bone development by dramatically down-regulating Collagen X (Col X) and Osterix (Osx), but had a dispensable effect on osteoclast development. Collectively, the results demonstrate that Cbfβ mediates cartilage and bone development by interacting with Runx1 and Runx2 to regulate the expressions of Col X and Osx for chondrocyte and osteoblast development. These findings not only reveal a critical role for Cbfβ in cartilage and bone development, but also facilitate the design of novel therapeutic approaches for skeletal diseases. PMID:24798493

Deletion of core-binding factor β (Cbfβ) in mesenchymal progenitor cells provides new insights into Cbfβ/Runxs complex function in cartilage and bone development.

PubMed

Wu, Mengrui; Li, Chenguan; Zhu, Guochun; Wang, Yiping; Jules, Joel; Lu, Yun; McConnell, Matthew; Wang, Yong-Jun; Shao, Jian-Zhong; Li, Yi-Ping; Chen, Wei

2014-08-01

Core-binding factor β (Cbfβ) is a subunit of the Cbf family of heterodimeric transcription factors, which plays a critical role in skeletal development through its interaction with the Cbfα subunits, also known as Runt-related transcription factors (Runxs). However, the mechanism by which Cbfβ regulates cartilage and bone development remains unclear. Existing Cbfβ-deficient mouse models cannot specify the role of Cbfβ in skeletal cell lineage. Herein, we sought to specifically address the role of Cbfβ in cartilage and bone development by using a conditional knockout (CKO) approach. A mesenchymal-specific Cbfβ CKO mouse model was generated by using the Dermo1-Cre mouse line to specifically delete Cbfβ in mesenchymal stem cells, which give rise to osteoblasts and chondrocytes. Surprisingly, the mutant mice had under-developed larynx and tracheal cartilage, causing alveolus defects that led to death shortly after birth from suffocation. Also, the mutant mice exhibited severe skeletal deformities from defective intramembranous and endochondral ossification, owing to delayed chondrocyte maturation and impaired osteoblast differentiation. Almost all bones of the mutant mice, including the calvariae, vertebrae, tibiae, femurs, ribs, limbs and sternums were defective. Importantly, we showed that Cbfβ was expressed throughout the skeleton during both embryonic and postnatal development, which explains the multiple-skeletal defects observed in the mutant mice. Consistently, Cbfβ deficiency impaired both chondrocyte proliferation and hypertrophy zone hypertrophy during growth-plate development in the long bones of mutant mice. Notably, Cbfβ, Runx1 and Runx2 displayed different expression patterns in the growth plates of the wild-type mice, indicating that Cbfβ/Runx1 complex and Cbfβ/Runx2 complex may regulate chondrocyte proliferation and hypertrophy, respectively, in a spatial and temporal manner. Cbfβ deletion in the mesenchymal progenitors affected bone development by dramatically down-regulating Collagen X (Col X) and Osterix (Osx) but had a dispensable effect on osteoclast development. Collectively, the results demonstrate that Cbfβ mediates cartilage and bone development by interacting with Runx1 and Runx2 to regulate the expressions of Col X and Osx for chondrocyte and osteoblast development. These findings not only reveal a critical role for Cbfβ in cartilage and bone development but also facilitate the design of novel therapeutic approaches for skeletal diseases. Copyright © 2014. Published by Elsevier Inc.

Erythropoietic bone marrow in the pigeon: Development of its distribution and volume during growth and pneumatization of bones

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schepelmann, K.

1990-01-01

During postnatal development of the pigeon, a large portion of the skeleton becomes pneumatized, displacing the hemopoietic bone marrow. The consequences of pneumatization on distribution and quantity of bone marrow as well as the availability of other sites for hemopoiesis have been investigated. Hemopoietic marrow of differently aged pigeons divided into five groups from 1 week posthatching (p.h.) up to 6 months p.h. was labeled with Fe-59 and examined by serial whole-body sections. Autoradiography and morphometry as well as scintillation counts of single bones and organs were also carried out. No sign of a reactivation of embryonic sites of erythropoiesismore » was found. Bone marrow weight and its proportion of whole-body weight increased during the first 4 weeks p.h. from 0.54% to 2.44% and decreased in the following months to about 1.0%. The developing bone marrow showed a progressive distribution during the first months of life, eventually being distributed proportionally over the entire skeleton, except for the skull. At the age of 6 months p.h. bone marrow had been displaced, its volume decreasing in correlation to increasing pneumaticity and conversion to fatty marrow. This generates the characteristic pattern of bone marrow distribution in adult pigeons, which shows hemopoietic bone marrow in ulna, radius, femur, tibiotarsus, scapula, furcula, and the caudal vertebrae.« less

Controlled Dual Growth Factor Delivery From Microparticles Incorporated Within Human Bone Marrow-Derived Mesenchymal Stem Cell Aggregates for Enhanced Bone Tissue Engineering via Endochondral Ossification.

PubMed

Dang, Phuong N; Dwivedi, Neha; Phillips, Lauren M; Yu, Xiaohua; Herberg, Samuel; Bowerman, Caitlin; Solorio, Loran D; Murphy, William L; Alsberg, Eben

2016-02-01

Bone tissue engineering via endochondral ossification has been explored by chondrogenically priming cells using soluble mediators for at least 3 weeks to produce a hypertrophic cartilage template. Although recapitulation of endochondral ossification has been achieved, long-term in vitro culture is required for priming cells through repeated supplementation of inductive factors in the media. To address this challenge, a microparticle-based growth factor delivery system was engineered to drive endochondral ossification within human bone marrow-derived mesenchymal stem cell (hMSC) aggregates. Sequential exogenous presentation of soluble transforming growth factor-β1 (TGF-β1) and bone morphogenetic protein-2 (BMP-2) at various defined time courses resulted in varying degrees of chondrogenesis and osteogenesis as demonstrated by glycosaminoglycan and calcium content. The time course that best induced endochondral ossification was used to guide the development of the microparticle-based controlled delivery system for TGF-β1 and BMP-2. Gelatin microparticles capable of relatively rapid release of TGF-β1 and mineral-coated hydroxyapatite microparticles permitting more sustained release of BMP-2 were then incorporated within hMSC aggregates and cultured for 5 weeks following the predetermined time course for sequential presentation of bioactive signals. Compared with cell-only aggregates treated with exogenous growth factors, aggregates with incorporated TGF-β1- and BMP-2-loaded microparticles exhibited enhanced chondrogenesis and alkaline phosphatase activity at week 2 and a greater degree of mineralization by week 5. Staining for types I and II collagen, osteopontin, and osteocalcin revealed the presence of cartilage and bone. This microparticle-incorporated system has potential as a readily implantable therapy for healing bone defects without the need for long-term in vitro chondrogenic priming. Significance: This study demonstrates the regulation of chondrogenesis and osteogenesis with regard to endochondral bone formation in high-density stem cell systems through the controlled presentation of inductive factors from incorporated microparticles. This work lays the foundation for a rapidly implantable tissue engineering system that promotes bone repair via endochondral ossification, a pathway that can delay the need for a functional vascular network and has an intrinsic ability to promote angiogenesis. The modular nature of this system lends well to using different cell types and/or growth factors to induce endochondral bone formation, as well as the production of other tissue types. ©AlphaMed Press.

The biocompatibility of carbon hydroxyapatite/β-glucan composite for bone tissue engineering studied with Raman and FTIR spectroscopic imaging.

PubMed

Sroka-Bartnicka, Anna; Kimber, James A; Borkowski, Leszek; Pawlowska, Marta; Polkowska, Izabela; Kalisz, Grzegorz; Belcarz, Anna; Jozwiak, Krzysztof; Ginalska, Grazyna; Kazarian, Sergei G

2015-10-01

The spectroscopic approaches of FTIR imaging and Raman mapping were applied to the characterisation of a new carbon hydroxyapatite/β-glucan composite developed for bone tissue engineering. The composite is an artificial bone material with an apatite-forming ability for the bone repair process. Rabbit bone samples were tested with an implanted bioactive material for a period of several months. Using spectroscopic and chemometric methods, we were able to determine the presence of amides and phosphates and the distribution of lipid-rich domains in the bone tissue, providing an assessment of the composite's bioactivity. Samples were also imaged in transmission using an infrared microscope combined with a focal plane array detector. CaF2 lenses were also used on the infrared microscope to improve spectral quality by reducing scattering artefacts, improving chemometric analysis. The presence of collagen and lipids at the bone/composite interface confirmed biocompatibility and demonstrate the suitability of FTIR microscopic imaging with lenses in studying these samples. It confirmed that the composite is a very good background for collagen growth and increases collagen maturity with the time of the bone growth process. The results indicate the bioactive and biocompatible properties of this composite and demonstrate how Raman and FTIR spectroscopic imaging have been used as an effective tool for tissue characterisation.

Effects of different growth factors and carriers on bone regeneration: a systematic review.

PubMed

Khojasteh, Arash; Behnia, Hossein; Naghdi, Navid; Esmaeelinejad, Mohammad; Alikhassy, Zahra; Stevens, Mark

2013-12-01

The application and subsequent investigations in the use of varied osteogenic growth factors in bone regeneration procedures have grown dramatically over the past several years. Owing to this rapid gain in popularity and documentation, a review was undertaken to evaluate the in vivo effects of growth factors on bone regeneration. Using related key words, electronic databases (Medline, Embase, and Cochrane) were searched for articles published from 1999 to April 2010 to find growth factor application in bone regeneration in human or animal models. A total of 63 articles were matched with the inclusion criteria of this study. Bone morphogenetic protein 2 (BMP-2) was the most studied growth factor. Carriers for the delivery, experimental sites, and methods of evaluation were different, and therefore articles did not come to a general agreement. Within the limitations of this review, BMP-2 may be an appropriate growth factor for osteogenesis. Copyright © 2013 Elsevier Inc. All rights reserved.

The use of autologous blood-derived growth factors in bone regeneration

PubMed Central

Civinini, Roberto; Macera, Armando; Nistri, Lorenzo; Redl, Birgit; Innocenti, Massimo

2011-01-01

Platelet-rich plasma (PRP) is defined as a portion of the plasma fraction of autologous blood having platelet concentrations above baseline. When activated the platelets release growth factors that play an essential role in bone healing such as Platelet-derived Growth Factor, Transforming Growth Factor-β, Vascular Endothelial Growth Factor and others. Multiple basic science and in vivo animal studies agree that PRP has a role in the stimulation of the healing cascade in ligament, tendon, muscle cartilage and in bone regeneration in the last years PRP had a widespread diffusion in the treatment of soft tissue and bone healing. The purpose of this review is to describe the biological properties of platelets and its factors, the methods used for producing PRP, to provide a background on the underlying basic science and an overview of evidence based medicine on clinical application of PRP in bone healing. PMID:22461800

Development of polyurethanes for bone repair.

PubMed

Marzec, M; Kucińska-Lipka, J; Kalaszczyńska, I; Janik, H

2017-11-01

The purpose of this paper is to review recent developments on polyurethanes aimed at the design, synthesis, modifications, and biological properties in the field of bone tissue engineering. Different polyurethane systems are presented and discussed in terms of biodegradation, biocompatibility and bioactivity. A comprehensive discussion is provided of the influence of hard to soft segments ratio, catalysts, stiffness and hydrophilicity of polyurethanes. Interaction with various cells, behavior in vivo and current strategies in enhancing bioactivity of polyurethanes are described. The discussion on the incorporation of biomolecules and growth factors, surface modifications, and obtaining polyurethane-ceramics composites strategies is held. The main emphasis is placed on the progress of polyurethane applications in bone regeneration, including bone void fillers, shape memory scaffolds, and drug carrier. Copyright © 2017 Elsevier B.V. All rights reserved.

Tissue-nonspecific Alkaline Phosphatase Deficiency Causes Abnormal Craniofacial Bone Development in the Alpl−/− Mouse Model of Infantile Hypophosphatasia

PubMed Central

Liu, Jin; Nam, Hwa Kyung; Campbell, Cassie; Gasque, Kellen Cristina da Silva; Millán, José Luis; Hatch, Nan E.

2014-01-01

Tissue-nonspecific alkaline phosphatase (TNAP) is an enzyme present on the surface of mineralizing cells and their derived matrix vesicles that promotes hydroxyapatite crystal growth. Hypophosphatasia (HPP) is an inborn-error-of-metabolism that, dependent upon age of onset, features rickets or osteomalacia due to loss-of function mutations in the gene (Alpl) encoding TNAP. Craniosynostosis is prevalent in infants with HPP and other forms of rachitic disease but how craniosynostosis develops in these disorders is unknown. Objectives: Because craniosynostosis carries high morbidity, we are investigating craniofacial skeletal abnormalities in Alpl−/− mice to establish these mice as a model of HPP-associated craniosynostosis and determine mechanisms by which TNAP influences craniofacial skeletal development. Methods: Cranial bone, cranial suture and cranial base abnormalities were analyzed by micro-CT and histology. Craniofacial shape abnormalities were quantified using digital calipers. TNAP expression was suppressed in MC3T3E1(C4) calvarial cells by TNAP-specific shRNA. Cells were analyzed for changes in mineralization, gene expression, proliferation, apoptosis, matrix deposition and cell adhesion. Results: Alpl−/− mice feature craniofacial shape abnormalities suggestive of limited anterior-posterior growth. Craniosynostosis in the form of bony coronal suture fusion is present by three weeks after birth. Alpl−/− mice also exhibit marked histologic abnormalities of calvarial bones and the cranial base involving growth plates, cortical and trabecular bone within two weeks of birth. Analysis of calvarial cells in which TNAP expression was suppressed by shRNA indicates that TNAP deficiency promotes aberrant osteoblastic gene expression, diminished matrix deposition, diminished proliferation, increased apoptosis and increased cell adhesion. Conclusions: These findings demonstrate that Alpl−/− mice exhibit a craniofacial skeletal phenotype similar to that seen in infants with HPP, including true bony craniosynostosis in the context of severely diminished bone mineralization. Future studies will be required to determine if TNAP deficiency and other forms of rickets promote craniosynostosis directly through abnormal calvarial cell behavior, or indirectly due to deficient growth of the cranial base. PMID:25014884

In Situ Sensor Advancements for Osteoporosis Prevention, Diagnosis, and Treatment.

PubMed

Liu, Luting; Webster, Thomas J

2016-12-01

Osteoporosis is still a serious issue in healthcare, and will continue to increase due to the aging and growth of the population. Early diagnosis is the key to successfully treating many diseases. The earlier the osteoporosis is diagnosed, the more quickly people can take action to stop bone deterioration. Motivated by this, researchers and companies have begun developing smart in situ bone sensors in order to dramatically help people to monitor their bone mass density (BMD), bone strain or bone turnover markers (BTMs); promptly track early signs of osteoporosis; and even monitor the healing process following surgery or antiresorptive therapy. This paper focuses on the latest advancements in the field of bone biosensing materials and sensor technologies and how they can help now and in the future to detect disease and monitor bone health.

Biomaterials for Craniofacial Bone Engineering

PubMed Central

Tevlin, R.; McArdle, A.; Atashroo, D.; Walmsley, G.G.; Senarath-Yapa, K.; Zielins, E.R.; Paik, K.J.; Longaker, M.T.; Wan, D.C.

2014-01-01

Conditions such as congenital anomalies, cancers, and trauma can all result in devastating deficits of bone in the craniofacial skeleton. This can lead to significant alteration in function and appearance that may have significant implications for patients. In addition, large bone defects in this area can pose serious clinical dilemmas, which prove difficult to remedy, even with current gold standard surgical treatments. The craniofacial skeleton is complex and serves important functional demands. The necessity to develop new approaches for craniofacial reconstruction arises from the fact that traditional therapeutic modalities, such as autologous bone grafting, present myriad limitations and carry with them the potential for significant complications. While the optimal bone construct for tissue regeneration remains to be elucidated, much progress has been made in the past decade. Advances in tissue engineering have led to innovative scaffold design, complemented by progress in the understanding of stem cell–based therapy and growth factor enhancement of the healing cascade. This review focuses on the role of biomaterials for craniofacial bone engineering, highlighting key advances in scaffold design and development. PMID:25139365

Human bone marrow-derived MSCs can home to orthotopic breast cancer tumors and promote bone metastasis

PubMed Central

Goldstein, Robert H; Reagan, Michaela R; Anderson, Kristen; Kaplan, David L; Rosenblatt, Michael

2010-01-01

American women have a nearly 25% lifetime risk of developing breast cancer, with 20–40% of these patients developing life-threatening metastases. Over 70% of patients presenting with metastases have skeletal involvement, which signals progression to an incurable stage. Tumor-stroma cell interactions are only superficially understood, specifically regarding the ability of stromal cells to affect metastasis. In vivo models show that exogenously supplied hBMSCs (human bone-marrow derived stem cells) migrate to breast cancer tumors, but no reports have shown endogenous hBMSC migration from the bone to primary tumors. Here we present a model of in vivo hBMSC migration from a physiologic human bone environment to human breast tumors. Further, hBMSCs alter tumor growth and bone metastasis frequency. hBMSCs may home to certain breast tumors based on tumor-derived TGF-β1. Moreover, at the primary tumor IL-17B/IL-17BR signaling may mediate interactions between hBMSCs and breast cancer cells (BCCs). PMID:21159629

Reconstruction of Craniomaxillofacial Bone Defects Using Tissue-Engineering Strategies with Injectable and Non-Injectable Scaffolds

PubMed Central

Gaihre, Bipin; Uswatta, Suren; Jayasuriya, Ambalangodage C.

2017-01-01

Engineering craniofacial bone tissues is challenging due to their complex structures. Current standard autografts and allografts have many drawbacks for craniofacial bone tissue reconstruction; including donor site morbidity and the ability to reinstate the aesthetic characteristics of the host tissue. To overcome these problems; tissue engineering and regenerative medicine strategies have been developed as a potential way to reconstruct damaged bone tissue. Different types of new biomaterials; including natural polymers; synthetic polymers and bioceramics; have emerged to treat these damaged craniofacial bone tissues in the form of injectable and non-injectable scaffolds; which are examined in this review. Injectable scaffolds can be considered a better approach to craniofacial tissue engineering as they can be inserted with minimally invasive surgery; thus protecting the aesthetic characteristics. In this review; we also focus on recent research innovations with different types of stem-cell sources harvested from oral tissue and growth factors used to develop craniofacial bone tissue-engineering strategies. PMID:29156629

Biomaterial strategies for engineering implants for enhanced osseointegration and bone repair

PubMed Central

Agarwal, Rachit; García, Andrés J.

2015-01-01

Bone tissue has a remarkable ability to regenerate and heal itself. However, large bone defects and complex fractures still present a significant challenge to the medical community. Current treatments center on metal implants for structural and mechanical support and auto- or allo-grafts to substitute long bone defects. Metal implants are associated with several complications such as implant loosening and infections. Bone grafts suffer from donor site morbidity, reduced bioactivity, and risk of pathogen transmission. Surgical implants can be modified to provide vital biological cues, growth factors and cells in order to improve osseointegration and repair of bone defects. Here we review strategies and technologies to engineer metal surfaces to promote osseointegration with the host tissue. We also discuss strategies for modifying implants for cell adhesion and bone growth via integrin signaling and growth factor and cytokine delivery for bone defect repair. PMID:25861724

Effect of GH/IGF-1 on Bone Metabolism and Osteoporsosis

PubMed Central

Locatelli, Vittorio; Bianchi, Vittorio E.

2014-01-01

Background. Growth hormone (GH) and insulin-like growth factor (IGF-1) are fundamental in skeletal growth during puberty and bone health throughout life. GH increases tissue formation by acting directly and indirectly on target cells; IGF-1 is a critical mediator of bone growth. Clinical studies reporting the use of GH and IGF-1 in osteoporosis and fracture healing are outlined. Methods. A Pubmed search revealed 39 clinical studies reporting the effects of GH and IGF-1 administration on bone metabolism in osteopenic and osteoporotic human subjects and on bone healing in operated patients with normal GH secretion. Eighteen clinical studies considered the effect with GH treatment, fourteen studies reported the clinical effects with IGF-1 administration, and seven related to the GH/IGF-1 effect on bone healing. Results. Both GH and IGF-1 administration significantly increased bone resorption and bone formation in the most studies. GH/IGF-1 administration in patients with hip or tibial fractures resulted in increased bone healing, rapid clinical improvements. Some conflicting results were evidenced. Conclusions. GH and IGF-1 therapy has a significant anabolic effect. GH administration for the treatment of osteoporosis and bone fractures may greatly improve clinical outcome. GH interacts with sex steroids in the anabolic process. GH resistance process is considered. PMID:25147565

CD13-positive bone marrow-derived myeloid cells promote angiogenesis, tumor growth, and metastasis.

PubMed

Dondossola, Eleonora; Rangel, Roberto; Guzman-Rojas, Liliana; Barbu, Elena M; Hosoya, Hitomi; St John, Lisa S; Molldrem, Jeffrey J; Corti, Angelo; Sidman, Richard L; Arap, Wadih; Pasqualini, Renata

2013-12-17

Angiogenesis is fundamental to tumorigenesis and an attractive target for therapeutic intervention against cancer. We have recently demonstrated that CD13 (aminopeptidase N) expressed by nonmalignant host cells of unspecified types regulate tumor blood vessel development. Here, we compare CD13 wild-type and null bone marrow-transplanted tumor-bearing mice to show that host CD13(+) bone marrow-derived cells promote cancer progression via their effect on angiogenesis. Furthermore, we have identified CD11b(+)CD13(+) myeloid cells as the immune subpopulation directly regulating tumor blood vessel development. Finally, we show that these cells are specifically localized within the tumor microenvironment and produce proangiogenic soluble factors. Thus, CD11b(+)CD13(+) myeloid cells constitute a population of bone marrow-derived cells that promote tumor progression and metastasis and are potential candidates for the development of targeted antiangiogenic drugs.

Subsequent somatic axis and bone tissue metabolism responses to a low-zinc diet with or without phytase inclusion in broiler chickens.

PubMed

Muszyński, Siemowit; Tomaszewska, Ewa; Kwiecień, Małgorzata; Dobrowolski, Piotr; Tomczyk-Warunek, Agnieszka

2018-01-01

Zinc is required for normal bone development and cartilage formation. The purpose of this study was to assess the effect of with adding organic Zn (alone or phytase inclusion) at the reduced dose to growing male Ross 308 chickens on somatic axis and bone tissue metabolism. 200 one-day old broilers were divided into the negative control group fed diet without Zn or phytase inclusion, positive control group receiving Zn in the 100% of daily recommended dose from ZnO, and two experimental groups fed diet introduced Zn in 25% of daily recommendation as a glycine chelate (Zn-Gly) with or without phytase inclusion (500 FTU·kg-1). Supplemental organic Zn increased bone Zn and Mg content, serum IGF-1, growth hormone and leptin concentration. Additional phytase inclusion increased body weight gain, blood plasma Ca, Fe, Zn and osteocalcin concentration and tibia ash percentage when compared to the Zn-deprived control. Bone geometry, yield and ultimate strengths were enhanced in both organic Zn supplemented groups, and the overall mechanical strength parameters of bone were better in these groups than in the positive control group supplemented with standard dose of inorganic Zn. Also marked improvements in the thickness of articular and the growth plate cartilages as well as real bone volume and thickness of metaphyseal trabeculae were achieved in all broilers fed Zn-supplemented diet irrespective of phytase inclusion, however, the highest cancellous bone mass and the best trabecular structure were noted after ZnO supplementation. In concludion, although dietary organic Zn given to growing broilers in 25% of daily recommended dose improved general bone properties and mechanical strength, the obtained results do not allow to unambiguously state that organic Zn supplementation at this level, even after phytase inclusion, is sufficient for proper bone development.

Subsequent somatic axis and bone tissue metabolism responses to a low-zinc diet with or without phytase inclusion in broiler chickens

PubMed Central

Tomaszewska, Ewa; Kwiecień, Małgorzata; Dobrowolski, Piotr; Tomczyk-Warunek, Agnieszka

2018-01-01

Zinc is required for normal bone development and cartilage formation. The purpose of this study was to assess the effect of with adding organic Zn (alone or phytase inclusion) at the reduced dose to growing male Ross 308 chickens on somatic axis and bone tissue metabolism. 200 one-day old broilers were divided into the negative control group fed diet without Zn or phytase inclusion, positive control group receiving Zn in the 100% of daily recommended dose from ZnO, and two experimental groups fed diet introduced Zn in 25% of daily recommendation as a glycine chelate (Zn-Gly) with or without phytase inclusion (500 FTU·kg-1). Supplemental organic Zn increased bone Zn and Mg content, serum IGF-1, growth hormone and leptin concentration. Additional phytase inclusion increased body weight gain, blood plasma Ca, Fe, Zn and osteocalcin concentration and tibia ash percentage when compared to the Zn-deprived control. Bone geometry, yield and ultimate strengths were enhanced in both organic Zn supplemented groups, and the overall mechanical strength parameters of bone were better in these groups than in the positive control group supplemented with standard dose of inorganic Zn. Also marked improvements in the thickness of articular and the growth plate cartilages as well as real bone volume and thickness of metaphyseal trabeculae were achieved in all broilers fed Zn-supplemented diet irrespective of phytase inclusion, however, the highest cancellous bone mass and the best trabecular structure were noted after ZnO supplementation. In concludion, although dietary organic Zn given to growing broilers in 25% of daily recommended dose improved general bone properties and mechanical strength, the obtained results do not allow to unambiguously state that organic Zn supplementation at this level, even after phytase inclusion, is sufficient for proper bone development. PMID:29373588

Defective postnatal endochondral bone development by chondrocyte-specific targeted expression of parathyroid hormone type 2 receptor.

PubMed

Panda, Dibyendu Kumar; Goltzman, David; Karaplis, Andrew C

2012-12-15

The human parathyroid hormone type 2 receptor (PTH2R) is activated by PTH and by tuberoinfundibular peptide of 39 residues (TIP39), the latter likely acting as its natural ligand. Although the receptor is expressed at highest levels in the nervous system, we have observed that both PTH2R and TIP39 are expressed in the newborn mouse growth plate, with the receptor localizing in the resting zone and the ligand TIP39 localizing exclusively in prehypertrophic and hypertrophic chondrocytes. To address the role of PTH2R in postnatal skeletal growth and development, Col2a1-hPTH2R (PTH2R-Tg) transgenic mice were generated. The mice were viable and of nearly normal size at birth. Expression of the transgene in the growth plate was limited to chondrocytes. We found that chondrocyte proliferation was decreased, as determined by in vivo BrdU labeling of proliferating chondrocytes and CDK4 and p21 expression in the growth plate of Col2a1-hPTH2R transgenic mice. Similarly, the differentiation and maturation of chondrocytes was delayed, as characterized by decreased Sox9 expression and weaker immunostaining for the chondrocyte differentiation markers collagen type II and type X and proteoglycans. As well, there was altered expression of Gdf5, Wdr5, and β-catenin, factors implicated in chondrocyte maturation, proliferation, and differentiation.These effects impacted on the process of endochondral ossification, resulting in delayed formation of the secondary ossification center, and diminished trabecular bone volume. The findings substantiate a role for PTH2R signaling in postnatal growth plate development and subsequent bone mass acquisition.

Receptor tyrosine kinase inhibition causes simultaneous bone loss and excess bone formation within growing bone in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nurmio, Mirja, E-mail: Mirja.Nurmio@utu.fi; Department of Pediatrics, University of Turku; Joki, Henna, E-mail: Henna.Joki@utu.fi

During postnatal skeletal growth, adaptation to mechanical loading leads to cellular activities at the growth plate. It has recently become evident that bone forming and bone resorbing cells are affected by the receptor tyrosine kinase (RTK) inhibitor imatinib mesylate (STI571, Gleevec (registered)) . Imatinib targets PDGF, ABL-related gene, c-Abl, c-Kit and c-Fms receptors, many of which have multiple functions in the bone microenvironment. We therefore studied the effects of imatinib in growing bone. Young rats were exposed to imatinib (150 mg/kg on postnatal days 5-7, or 100 mg/kg on postnatal days 5-13), and the effects of RTK inhibition on bonemore » physiology were studied after 8 and 70 days (3-day treatment), or after 14 days (9-day treatment). X-ray imaging, computer tomography, histomorphometry, RNA analysis and immunohistochemistry were used to evaluate bone modeling and remodeling in vivo. Imatinib treatment eliminated osteoclasts from the metaphyseal osteochondral junction at 8 and 14 days. This led to a resorption arrest at the growth plate, but also increased bone apposition by osteoblasts, thus resulting in local osteopetrosis at the osteochondral junction. The impaired bone remodelation observed on day 8 remained significant until adulthood. Within the same bone, increased osteoclast activity, leading to bone loss, was observed at distal bone trabeculae on days 8 and 14. Peripheral quantitative computer tomography (pQCT) and micro-CT analysis confirmed that, at the osteochondral junction, imatinib shifted the balance from bone resorption towards bone formation, thereby altering bone modeling. At distal trabecular bone, in turn, the balance was turned towards bone resorption, leading to bone loss. - Research Highlights: > 3-Day imatinib treatment. > Causes growth plate anomalies in young rats. > Causes biomechanical changes and significant bone loss at distal trabecular bone. > Results in loss of osteoclasts at osteochondral junction.« less

Phylogenetic, functional, and structural components of variation in bone growth rate of amniotes.

PubMed

Cubo, Jorge; Legendre, Pierre; de Ricqlès, Armand; Montes, Laëtitia; de Margerie, Emmanuel; Castanet, Jacques; Desdevises, Yves

2008-01-01

The biological features observed in every living organism are the outcome of three sets of factors: historical (inherited by homology), functional (biological adaptation), and structural (properties inherent to the materials with which organs are constructed, and the morphogenetic rules by which they grow). Integrating them should bring satisfactory causal explanations of empirical data. However, little progress has been accomplished in practice toward this goal, because a methodologically efficient tool was lacking. Here we use a new statistical method of variation partitioning to analyze bone growth in amniotes. (1) Historical component. The variation of bone growth rates contains a significant phylogenetic signal, suggesting that the observed patterns are partly the outcome of shared ancestry. (2) Functional causation. High growth rates, although energy costly, may be adaptive (i.e., they may increase survival rates) in taxa showing short growth periods (e.g., birds). In ectothermic amniotes, low resting metabolic rates may limit the maximum possible growth rates. (3) Structural constraint. Whereas soft tissues grow through a multiplicative process, growth of mineralized tissues is accretionary (additive, i.e., mineralization fronts occur only at free surfaces). Bone growth of many amniotes partially circumvents this constraint: it is achieved not only at the external surface of the bone shaft, but also within cavities included in the bone cortex as it grows centrifugally. Our approach contributes to the unification of historicism, functionalism, and structuralism toward a more integrated evolutionary biology.

Optimization of Bone Health in Children before and after Renal Transplantation: Current Perspectives and Future Directions

PubMed Central

Sgambat, Kristen; Moudgil, Asha

2014-01-01

The accrual of healthy bone during the critical period of childhood and adolescence sets the stage for lifelong skeletal health. However, in children with chronic kidney disease (CKD), disturbances in mineral metabolism and endocrine homeostasis begin early on, leading to alterations in bone turnover, mineralization, and volume, and impairing growth. Risk factors for CKD–mineral and bone disorder (CKD–MBD) include nutritional vitamin D deficiency, secondary hyperparathyroidism, increased fibroblast growth factor 23 (FGF-23), altered growth hormone and insulin-like growth factor-1 axis, delayed puberty, malnutrition, and metabolic acidosis. After kidney transplantation, nutritional vitamin D deficiency, persistent hyperparathyroidism, tertiary FGF-23 excess, hypophosphatemia, hypomagnesemia, immunosuppressive therapy, and alteration of sex hormones continue to impair bone health and growth. As function of the renal allograft declines over time, CKD–MBD associated changes are reactivated, further impairing bone health. Strategies to optimize bone health post-transplant include healthy diet, weight-bearing exercise, correction of vitamin D deficiency and acidosis, electrolyte abnormalities, steroid avoidance, and consideration of recombinant human growth hormone therapy. Other drug therapies have been used in adult transplant recipients, but there is insufficient evidence for use in the pediatric population at the present time. Future therapies to be explored include anti-FGF-23 antibodies, FGF-23 receptor blockers, and treatments targeting the colonic microbiota by reduction of generation of bacterial toxins and adsorption of toxic end products that affect bone mineralization. PMID:24605319

Bone morphogenic protein: an elixir for bone grafting--a review.

PubMed

Shah, Prasun; Keppler, Louis; Rutkowski, James

2012-12-01

Bone morphogenetic proteins (BMPs) are multifunctional growth factors that belong to the transforming growth factor beta superfamily. This literature review focuses on the molecular biology of BMPs, their mechanism of action, and subsequent applications. It also discusses uses of BMPs in the fields of dentistry and orthopedics, research on methods of delivering BMPs, and their role in tissue regeneration. BMP has positive effects on bone grafts, and their calculated and timely use with other growth factors can provide extraordinary results in fractured or nonhealing bones. Use of BMP introduces new applications in the field of implantology and bone grafting. This review touches on a few unknown facts about BMP and this ever-changing field of research to improve human life.

[Osteoporosis treatment in patients with hyperthyroidism].

PubMed

Saito, Jun; Nishikawa, Tetsuo

2009-05-01

Childhood thyroid hormone (T3) is essential for the normal development of endochondral and intramembranous bone and plays an important role in the linear growth and maintenance of bone mass. In adult, T3 stimulates osteoclastic bone resorption mediated primarily by TR alpha and local conversion by deiodinase D2 may play a role in local activation. TSH seems to be an inhibitor of bone resorption and formation. In thyrotoxicosis patients with Graves' disease, there is increased bone remodelling, characterized by an imbalance between bone resorption and formation, which results in a decrease of bone mineral density (BMD) and an increased risk for osteoporotic fracture. Antithyroid treatment is able to reduce dramatically the bone resorption and to normalize BMD reduction. But previous hyperthyroidism is independently associated with an increased risk for fracture. Although further studies relating to the mechanism for possible impaired bone strength in these patients will be needed, bisphosphonates may be beneficial treatment for prevention of bone fractures in patients with severe risk for fractures, such as post-menopausal women.

GDF9 and BMP15 Expressions and Fine Structure Changes During Folliculogenesis in Polycystic Ovary Syndrome.

PubMed

Karagül, Meryem İlkay; Aktaş, Savaş; Coşkun Yılmaz, Banu; Yılmaz, Mustafa; Orekici Temel, Gülhan

2018-01-20

Polycystic ovary syndrome is the most frequently seen endocrine disorder in women of reproductive age with a prevalence of about 10%. To investigate the efficiency of growth differentiation factor 9 and bone morphogenetic protein 15 during folliculogenesis in a dehydroepiandrosterone-induced mouse Polycystic ovary syndrome model. Animal experimentation. Mice were divided into 3 groups: control, vehicle and Polycystic ovary syndrome. Polycystic ovary syndrome model mice were developed by the injection of dehydroepiandrosterone dissolved in 0.1 mL of sesame oil. Ovarian tissues were examined for growth differentiation factor 9 and bone morphogenetic protein 15 using immunofluorescent labelling and electron microscopic examinations. The immunoreactivity of growth differentiation factor 9 and bone morphogenetic protein 15 proteins decreased (p<0.05) in the Polycystic ovary syndrome group (27.73±8.43 and 24.85±7.03, respectively) compared with the control group (33.72±11.22 and 31.12±11.05, respectively) and vehicle group (33.95±10.75 and 29.99±10.72, respectively). Apoptotic changes were observed in granulosa cells, lipid vacuoles increased in Theca cells and thickening and irregularities were noted in the basal lamina of granulosa cells. An increased electron density in the zona pellucida in some of the multilaminar primary and secondary follicles in the Polycystic ovary syndrome model was also observed at the ultrastructural level. These results suggest that the decrease in the growth differentiation factor 9 and bone morphogenetic protein 15 expression initiated at the primary follicle stage effect the follicle development and zona pellucida structure and may cause subfertility or infertility in Polycystic ovary syndrome.

Effects of different levels of protein intake and physical training on growth and nutritional status of young rats.

PubMed

Ribeiro, Sandra Maria Lima; Rogero, Marcelo Macedo; Bacurau, Reury Frank Pereira; de Campos, Patrícia Lopes; Luz, Silmara dos Santos; Lancha, Antonio Herber; Tirapegui, Julio

2010-01-01

This study aimed to investigate the effects of physical training, and different levels of protein intake in the diet, on the growth and nutritional status of growing rats. Newly-weaned Wistar rats (n=48) were distributed into six experimental groups; three of them were subjected to physical swim training (1 h per day, 5 d per week, for 4 wk, after 2 wk of familiarization) and the other three were considered as controls (non-trained). Each pair of groups, trained and non-trained, received diets with a different level of protein in their composition: 14%, 21% or 28%. The animals were euthanized at the end of the training period and the following analyses were performed: proteoglycan synthesis as a biomarker of bone and cartilage growth, IGF-I (insulin-like growth factor-I) assay as a biomarker of growth and nutritional status, total RNA and protein concentration and protein synthesis measured in vivo using a large-dose phenylalanine method. As a main finding, increased dietary protein, combined with physical training, was able to improve neither tissue protein synthesis nor muscle growth. In addition, cartilage and bone growth seem to be deteriorated by the lower and the higher levels of protein intake. Our data allow us to conclude that protein enhancement in the diet, combined with physical exercise, does not stimulate tissue protein synthesis or muscle mass growth. Furthermore, physical training, combined with low protein intake, was not favorable to bone development in growing animals.

The development of curvature in the porcine radioulna

PubMed Central

Pantinople, Jess; McCabe, Kyle; Henderson, Keith; Milne, Nick

2017-01-01

Long bone curvature in animal limbs has long been a subject of interest and much work has explored why long bones should be curved. However, the ‘when’ and ‘how’ of curvature development is poorly understood. It has been shown that the rat tibia fails to attain its normal curvature if the action of muscles is removed early in life, but it is not clear if this is because the curvature fails to develop or if the bone becomes straighter without the action of muscles. No studies have examined the development of bone curvature in a normally developing quadruped, so this study tracks the course of curvature formation in the radioulna in a series of growing pigs. We also histologically examined the epiphyseal growth plates of these bones to determine if they contribute to the formation of curvature. In all three epiphyseal plates examined, the proliferative zone is thicker and more densely populated with chondrocytes on the cranial (convex) side than the caudal (concave) side. Frost’s chondral modelling theory would suggest that the cranial side of the bone is under more compression than the caudal side, and we conclude that this is due to the action of triceps extending the elbow by pulling on the olecranon process. These results support the idea that bone curvature is an adaptation to habitual loading, where longitudinal loads acting on the curved bone cause bending strains that counter the bending resulting from the habitual muscle action. PMID:28584714

The development of curvature in the porcine radioulna.

PubMed

Pantinople, Jess; McCabe, Kyle; Henderson, Keith; Richards, Hazel L; Milne, Nick

2017-01-01

Long bone curvature in animal limbs has long been a subject of interest and much work has explored why long bones should be curved. However, the 'when' and 'how' of curvature development is poorly understood. It has been shown that the rat tibia fails to attain its normal curvature if the action of muscles is removed early in life, but it is not clear if this is because the curvature fails to develop or if the bone becomes straighter without the action of muscles. No studies have examined the development of bone curvature in a normally developing quadruped, so this study tracks the course of curvature formation in the radioulna in a series of growing pigs. We also histologically examined the epiphyseal growth plates of these bones to determine if they contribute to the formation of curvature. In all three epiphyseal plates examined, the proliferative zone is thicker and more densely populated with chondrocytes on the cranial (convex) side than the caudal (concave) side. Frost's chondral modelling theory would suggest that the cranial side of the bone is under more compression than the caudal side, and we conclude that this is due to the action of triceps extending the elbow by pulling on the olecranon process. These results support the idea that bone curvature is an adaptation to habitual loading, where longitudinal loads acting on the curved bone cause bending strains that counter the bending resulting from the habitual muscle action.

Distal radius geometry and skeletal strength indices after peripubertal artistic gymnastics.

PubMed

Dowthwaite, J N; Scerpella, T A

2011-01-01

Development of optimal skeletal strength should decrease adult bone fragility. Nongymnasts (NON): were compared with girls exposed to gymnastics during growth (EX/GYM: ), using peripheral quantitative computed tomography (pQCT) to evaluate postmenarcheal bone geometry, density, and strength. Pre- and perimenarcheal gymnastic loading yields advantages in indices of postmenarcheal bone geometry and skeletal strength. Two prior studies using pQCT have reported bone density and size advantages in Tanner I/II gymnasts, but none describe gymnasts' bone properties later in adolescence. The current study used pQCT to evaluate whether girls exposed to gymnastics during late childhood growth and perimenarcheal growth exhibited greater indices of distal radius geometry, density, and skeletal strength. Postmenarcheal subjects underwent 4% and 33% distal radius pQCT scans, yielding: 1) vBMD and cross-sectional areas (CSA) (total bone, compartments); 2) polar strength-strain index; 3) index of structural strength in axial compression. Output was compared for EX/GYM: vs. NON: , adjusting for gynecological age and stature (maturity and body size), reporting means, standard errors, and significance. Sixteen postmenarcheal EX/GYM: (age 16.7 years; gynecological age 3.4 years) and 13 NON: (age 16.2 years; gynecological age 3.6 years) were evaluated. At both diaphysis and metaphysis, EX/GYM: exhibited greater CSA and bone strength indices than NON; EX/GYM: exhibited 79% larger intramedullary CSA than NON: (p < 0.05). EX/GYM: had significantly higher 4% trabecular vBMD; differences were not detected for 4% total vBMD and 33% cortical vBMD. Following pre-/perimenarcheal gymnastic exposure, relative to nongymnasts, postmenarcheal EX/GYM: demonstrated greater indices of distal radius geometry and skeletal strength (metaphysis and diaphysis) with greater metaphyseal trabecular vBMD; larger intramedullary cavity size was particularly striking.

Distal radius geometry and skeletal strength indices after peripubertal artistic gymnastics

PubMed Central

Scerpella, T. A.

2011-01-01

Summary Development of optimal skeletal strength should decrease adult bone fragility. Nongymnasts (NON) were compared with girls exposed to gymnastics during growth (EX/GYM), using peripheral quantitative computed tomography (pQCT) to evaluate postmenarcheal bone geometry, density, and strength. Pre- and perimenarcheal gymnastic loading yields advantages in indices of postmenarcheal bone geometry and skeletal strength. Introduction Two prior studies using pQCT have reported bone density and size advantages in Tanner I/II gymnasts, but none describe gymnasts’ bone properties later in adolescence. The current study used pQCT to evaluate whether girls exposed to gymnastics during late childhood growth and perimenarcheal growth exhibited greater indices of distal radius geometry, density, and skeletal strength. Methods Postmenarcheal subjects underwent 4% and 33% distal radius pQCT scans, yielding: 1) vBMD and cross-sectional areas (CSA) (total bone, compartments); 2) polar strength-strain index; 3) index of structural strength in axial compression. Output was compared for EX/GYM vs. NON, adjusting for gynecological age and stature (maturity and body size), reporting means, standard errors, and significance. Results Sixteen postmenarcheal EX/GYM (age 16.7 years; gynecological age 3.4 years) and 13 NON (age 16.2 years; gynecological age 3.6 years) were evaluated. At both diaphysis and metaphysis, EX/GYM exhibited greater CSA and bone strength indices than NON; EX/GYM exhibited 79% larger intramedullary CSA than NON (p<0.05). EX/GYM had significantly higher 4% trabecular vBMD; differences were not detected for 4% total vBMD and 33% cortical vBMD. Conclusions Following pre-/perimenarcheal gymnastic exposure, relative to nongymnasts, postmenarcheal EX/GYM demonstrated greater indices of distal radius geometry and skeletal strength (metaphysis and diaphysis) with greater metaphyseal trabecular vBMD; larger intramedullary cavity size was particularly striking. PMID:20419293

Bone morphogenetic protein-mediated interaction of periosteum and diaphysis. Citric acid and other factors influencing the generation of parosteal bone.

PubMed

Kübler, N; Urist, M R

1990-09-01

In rabbits, after long-bone growth is complete and the cambium layer regresses, mesenchymal-type cells with embryonic potential (competence) for bone development persist in the adventitial layer of periosteum. These cells are not determined osteoprogenitor cells (stem cells) because bone tissue differentiation does not occur when adult periosteum is transplanted into a heterotopic site. In this respect, adventitial cells differ from bone marrow stroma cells. In a parosteal orthotopic site in the space between the adult periosteum and diaphysis, implants of bone morphogenetic protein (BMP) and associated noncollagenous proteins (BMP/NCP) induce adventitia and adjacent muscle connective-tissue-derived cells to switch from a fibrogenetic to a chondroosteoprogenetic pattern of bone development. The quantity of induced bone is proportional to the dose of BMP/NCP in the range from 10 to 50 mg; immature rabbits produced larger deposits than mature rabbits in response to BMP/NCP. Preoperative local intramuscular injections of citric, edetic, or hyaluronic acids in specified concentrations markedly enhanced subperiosteal BMP/NCP-induced bone formation. The quantity of bovine or human BMP/NCP-induced bone formation in rabbits is also increased by very low-dose immunosuppression but not by bone mineral, tricalcium phosphate ceramic, inorganic calcium salts, or various space-occupying, unspecific chemical irritants. Although composities of BMP/NCP and allogeneic rabbit tendon collagen increased the quantity of bone in a parosteal site, in a heterotopic site the composite failed to induce bone formation. In a parosteal site, the conditions permitting BMP/NCP-induced bone formation develop, and the end product of the morphogenetic response is a duplicate diaphysis. How BMP reactivates the morphogenetic process in postfetal mesenchymal-type adventitial cells persisting in adult periosteum (including adjacent muscle attachments) is not known.

Skeletal development in Pan paniscus with comparisons to Pan troglodytes.

PubMed

Bolter, Debra R; Zihlman, Adrienne L

2012-04-01

Fusion of skeletal elements provides markers for timing of growth and is one component of a chimpanzee's physical development. Epiphyseal closure defines bone growth and signals a mature skeleton. Most of what we know about timing of development in chimpanzees derives from dental studies on Pan troglodytes. Much less is known about the sister species, Pan paniscus, with few in captivity and a wild range restricted to central Africa. Here, we report on the timing of skeletal fusion for female captive P. paniscus (n = 5) whose known ages range from 0.83 to age 11.68 years. Observations on the skeletons were made after the individuals were dissected and bones cleaned. Comparisons with 10 female captive P. troglodytes confirm a generally uniform pattern in the sequence of skeletal fusion in the two captive species. We also compared the P. paniscus to a sample of three unknown-aged female wild P. paniscus, and 10 female wild P. troglodytes of known age from the Taï National Park, Côte d'Ivoire. The sequence of teeth emergence to bone fusion is generally consistent between the two species, with slight variations in late juvenile and subadult stages. The direct-age comparisons show that skeletal growth in captive P. paniscus is accelerated compared with both captive and wild P. troglodytes populations. The skeletal data combined with dental stages have implications for estimating the life stage of immature skeletal materials of wild P. paniscus and for more broadly comparing the skeletal growth rates among captive and wild chimpanzees (Pan), Homo sapiens, and fossil hominins. Copyright © 2012 Wiley Periodicals, Inc.

Osteochondroma of the Scapula with Accessory Nerve (XI) Compression.

PubMed

Beauchamp-Chalifour, Philippe; Pelet, Stéphane

2018-01-01

Osteochondroma is the most common benign bone tumor and is characterized as a cartilage-capped bony stalk. This lesion usually develops from the growth plate of long bones. Most osteochondromas are asymptomatic. Neurovascular compressions or cosmetic issues can occur in specific locations. Malignant transformation is extremely rare, and MRI can help evaluate these lesions. Symptomatic mass and malignancy features are the main surgical indications. Uncommonly, an osteochondroma can develop from flat bones. We present the case of a 25-year-old patient with a right scapula osteochondroma causing an accessory nerve compression. The mass was surgically removed, and the diagnosis was confirmed. The patient fully recovered at the latest 3-year follow-up visit.

Adipose, bone and muscle tissues as new endocrine organs: role of reciprocal regulation for osteoporosis and obesity development.

PubMed

Migliaccio, Silvia; Greco, Emanuela A; Wannenes, Francesca; Donini, Lorenzo M; Lenzi, Andrea

2014-01-01

The belief that obesity is protective against osteoporosis has recently been revised. In fact, the latest epidemiologic and clinical studies show that a high level of fat mass, but also reduced muscle mass, might be a risk factor for osteoporosis and fragility fractures. Furthermore, increasing evidence seems to indicate that different components such as myokines, adipokines and growth factors, released by both fat and muscle tissues, could play a key role in the regulation of skeletal health and in low bone mineral density and, thus, in osteoporosis development. This review considers old and recent data in the literature to further evaluate the relationship between fat, bone and muscle tissue.

Tissue engineering skeletal muscle for orthopaedic applications

NASA Technical Reports Server (NTRS)

Payumo, Francis C.; Kim, Hyun D.; Sherling, Michael A.; Smith, Lee P.; Powell, Courtney; Wang, Xiao; Keeping, Hugh S.; Valentini, Robert F.; Vandenburgh, Herman H.

2002-01-01

With current technology, tissue-engineered skeletal muscle analogues (bioartificial muscles) generate too little active force to be clinically useful in orthopaedic applications. They have been engineered genetically with numerous transgenes (growth hormone, insulinlike growth factor-1, erythropoietin, vascular endothelial growth factor), and have been shown to deliver these therapeutic proteins either locally or systemically for months in vivo. Bone morphogenetic proteins belonging to the transforming growth factor-beta superfamily are osteoinductive molecules that drive the differentiation pathway of mesenchymal cells toward the chondroblastic or osteoblastic lineage, and stimulate bone formation in vivo. To determine whether skeletal muscle cells endogenously expressing bone morphogenetic proteins might serve as a vehicle for systemic bone morphogenetic protein delivery in vivo, proliferating skeletal myoblasts (C2C12) were transduced with a replication defective retrovirus containing the gene for recombinant human bone morphogenetic protein-6 (C2BMP-6). The C2BMP-6 cells constitutively expressed recombinant human bone morphogenetic protein-6 and synthesized bioactive recombinant human bone morphogenetic protein-6, based on increased alkaline phosphatase activity in coincubated mesenchymal cells. C2BMP-6 cells did not secrete soluble, bioactive recombinant human bone morphogenetic protein-6, but retained the bioactivity in the cell layer. Therefore, genetically-engineered skeletal muscle cells might serve as a platform for long-term delivery of osteoinductive bone morphogenetic proteins locally.

Intracranial pressure changes during mouse development.

PubMed

Moazen, Mehran; Alazmani, Ali; Rafferty, Katherine; Liu, Zi-Jun; Gustafson, Jennifer; Cunningham, Michael L; Fagan, Michael J; Herring, Susan W

2016-01-04

During early stages of postnatal development, pressure from the growing brain as well as cerebrospinal fluid, i.e. intracranial pressure (ICP), load the calvarial bones. It is likely that such loading contributes to the peripheral bone formation at the sutural edges of calvarial bones, especially shortly after birth when the brain is growing rapidly. The aim of this study was to quantify ICP during mouse development. A custom pressure monitoring system was developed and calibrated. It was then used to measure ICP in a total of seventy three wild type mice at postnatal (P) day 3, 10, 20, 31 and 70. Retrospectively, the sample in each age group with the closest ICP to the average value was scanned using micro-computed tomography to estimate cranial growth. ICP increased from 1.33±0.87mmHg at P3 to 1.92±0.78mmHg at P10 and 3.60±1.08mmHg at P20. In older animals, ICP plateaued at about 4mmHg. There were statistically significant differences between the ICP at the P3 vs. P20, and P10 vs. P20. In the samples that were scanned, intracranial volume and skull length followed a similar pattern of increase up to P20 and then plateaued at older ages. These data are consistent with the possibility of ICP being a contributing factor to bone formation at the sutures during early stages of development. The data can be further used for development and validation of computational models of skull growth. Copyright © 2015 Elsevier Ltd. All rights reserved.

A TRANSPLANTABLE NEW GROWTH OF THE FOWL, PRODUCING CARTILAGE AND BONE

PubMed Central

Tytler, W. H.

1913-01-01

An osteochondrosarcoma of the common fowl, designated in this laboratory as Chicken Tumor VII, has been successfully transplanted to seven successive series of hosts. The original growth contained bone and cartilage, was attached to the sternal keel of an otherwise healthy chicken, and appeared to have arisen from this structure. In the growths derived from its transplantation cartilage is regularly laid down, followed later by bone in case the host lives long enough. The prechondral tissue consists of spindle-shaped or multipolar cells of the fibroblast type. The histological character and the behavior of this prechondral tissue show that it is sarcomatous, a fact further proven by one recent case in which the tumor has metastasized. The secondary growth in this instance consisted of prechondral tissue in which a cartilaginous change was taking place. The tumor could not be transferred to pigeons, the one foreign species tested, but grew readily in chickens of two alien breeds. Reinoculation experiments suggest the occurrence of a natural, individual immunity, and of a certain degree of acquired resistance. In one fowl visceral growths developed following an intravenous injection of tumor emulsion, although whether they were due to this cause or were secondary to the large implantation growths in the muscles is uncertain. Recently the tumor has been transmitted by means of the filtrate from a Berkefeld filter. PMID:19867658

Growth factors and cytokines in patients with long bone fractures and associated spinal cord injury.

PubMed

Khallaf, Fathy G; Kehinde, Elijah O; Mostafa, Ahmed

2016-06-01

The aim of the study was to test the effect of acute traumatic spinal cord injury of quadriplegia or paraplegia on bone healing in patients with associated long bone fractures and to investigate the molecular and cellular events of the underlying mechanism for a possible acceleration. Healing indicators of long bone fractures and growth factors, IGF-II, platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), Activin-A, and cytokine I-L-1, in the patients' blood were calculated and measured for 21 patients with spinal cord injuries and associated long bone fractures in prospective controlled study and compared to 20 patients with only spinal cord injuries, 30 patients with only long bone fractures, and 30 healthy volunteers. The study results showed that long bone fractures in patients with associated acute traumatic spinal cord injury of quadriplegia or paraplegia heal more expectedly, faster, and with exuberant florid union callus (P > 0.001) and show statistically significant higher levels of growth factors like PDGF, VEGF, Activin-A, and cytokine I-L-1, along the 3 weeks of follow-up (P > 0.005). I-IGF-II showed statistically significant subnormal level along the whole follow-up period in the same patients (P > 0.005). We concluded that long bone fractures in spinal cord injury patients heal more expectedly, faster, and with exuberant and florid callus formation; growth factors like IGF-II, PDGF, VEGF, Activin-A, and cytokine I-L-I have roles as mediators, in molecular events and as byproducts of the subtle mechanism of accelerated osteogenesis in these patients and may represent therapeutic potentials to serve as agents to enhance bone repair.

The pattern of trabecular bone microarchitecture in the distal femur of typically developing children and its effect on processing of magnetic resonance images.

PubMed

Modlesky, Christopher M; Whitney, Daniel G; Carter, Patrick T; Allerton, Brianne M; Kirby, Joshua T; Miller, Freeman

2014-03-01

Magnetic resonance imaging (MRI) is used to assess trabecular bone microarchitecture in humans; however, image processing can be labor intensive and time consuming. One aim of this study was to determine the pattern of trabecular bone microarchitecture in the distal femur of typically developing children. A second aim was to determine the proportion and location of magnetic resonance images that need to be processed to yield representative estimates of trabecular bone microarchitecture. Twenty-six high resolution magnetic resonance images were collected immediately above the growth plate in the distal femur of 6-12year-old typically developing children (n=40). Measures of trabecular bone microarchitecture [i.e., apparent trabecular bone volume to total volume (appBV/TV), trabecular number (appTb.N), trabecular thickness (appTb.Th) and trabecular separation (appTb.Sp)] in the lateral aspect of the distal femur were determined using the twenty most central images (20IM). The average values for appBV/TV, appTb.N, appTb.Th and appTb.Sp from 20IM were compared to the average values from 10 images (10IM), 5 images (5IM) and 3 images (3IM) equally dispersed throughout the total image set and one image (1IM) from the center of the total image set using linear regression analysis. The resulting mathematical models were cross-validated using the leave-one-out technique. Distance from the growth plate was strongly and inversely related to appBV/TV (r(2)=0.68, p<0.001) and appTb.N (r(2)=0.92, p<0.001) and was strongly and positively related to appTb.Sp (r(2)=0.86, p<0.001). The relationship between distance from the growth plate and appTb.Th was not linear (r(2)=0.06, p=0.28), but instead it was quadratic and statistically significant (r(2)=0.54, p<0.001). Trabecular bone microarchitecture estimates from 10IM, 5IM, 3IM and 1IM were not different from estimates from 20IM (p>0.05). However, there was a progressive decrease in the strength of the relationships as a smaller proportion of images were used to predict estimates from 20IM (r(2)=0.98 to 0.99 using 10IM, 0.94 to 0.96 using 5IM, 0.87 to 0.90 using 3IM and 0.66 to 0.72 using 1IM; all p<0.001). Using the resulting mathematical models and the leave-one-out cross-validation analysis, measures of trabecular bone microarchitecture estimated from the 10IM and 5IM partial image sets agreed extremely well with estimates from 20IM. The findings indicate that partial magnetic resonance image sets can be used to provide reasonable estimates of trabecular bone microarchitecture status in the distal femur of typically developing children. However, because the relative amount of trabecular bone in the distal femur decreases with distance from the growth plate due to a decrease in trabecular number, careful positioning of the region of interest and sampling from throughout the region of interest is necessary. Copyright © 2013 Elsevier Inc. All rights reserved.

Role of estrogen receptor signaling in skeletal response to leptin in female ob/ob mice.

PubMed

Turner, Russell T; Philbrick, Kenneth A; Kuah, Amida F; Branscum, Adam J; Iwaniec, Urszula T

2017-06-01

Leptin, critical in regulation of energy metabolism, is also important for normal bone growth, maturation and turnover. Compared to wild type (WT) mice, bone mass is lower in leptin-deficient ob/ob mice. Osteopenia in growing ob/ob mice is due to decreased bone accrual, and is associated with reduced longitudinal bone growth, impaired cancellous bone maturation and increased marrow adipose tissue (MAT). However, leptin deficiency also results in gonadal dysfunction, disrupting production of gonadal hormones which regulate bone growth and turnover. The present study evaluated the role of increased estrogen in mediating the effects of leptin on bone in ob/ob mice. Three-month-old female ob/ob mice were randomized into one of the 3 groups: (1) ob/ob  + vehicle (veh), (2) ob/ob  + leptin (leptin) or (3) ob/ob  + leptin and the potent estrogen receptor antagonist ICI 182,780 (leptin + ICI). Age-matched WT mice received vehicle. Leptin (40 µg/mouse, daily) and ICI (10 µg/mouse, 2×/week) were administered by subcutaneous injection for 1 month and bone analyzed by X-ray absorptiometry, microcomputed tomography and static and dynamic histomorphometry. Uterine weight did not differ between ob/ob mice and ob/ob mice receiving leptin + ICI, indicating that ICI successfully blocked the uterine response to leptin-induced increases in estrogen levels. Compared to leptin-treated ob/ob mice, ob/ob mice receiving leptin + ICI had lower uterine weight; did not differ in weight loss, MAT or bone formation rate; and had higher longitudinal bone growth rate and cancellous bone volume fraction. We conclude that increased estrogen signaling following leptin treatment is dispensable for the positive actions of leptin on bone and may attenuate leptin-induced bone growth. © 2017 Society for Endocrinology.

The role of pleiotrophin in bone repair.

PubMed

Lamprou, Margarita; Kaspiris, Angelos; Panagiotopoulos, Elias; Giannoudis, Peter V; Papadimitriou, Evangelia

2014-12-01

Bone has an enormous capacity for growth, regeneration, and remodelling, largely due to induction of osteoblasts that are recruited to the site of bone formation. Although the pathways involved have not been fully elucidated, it is well accepted that the immediate environment of the cells is likely to play a role via cell–matrix interactions, mediated by several growth factors. Formation of new blood vessels is also significant and interdependent to bone formation, suggesting that enhancement of angiogenesis could be beneficial during the process of bone repair. Pleiotrophin (PTN), also called osteoblast-specific factor 1, is a heparin-binding angiogenic growth factor, with a well-defined and significant role in both physiological and pathological angiogenesis. In this review we summarise the existing evidence on the role of PTN in bone repair.

Genetics Home Reference: aromatase deficiency

MedlinePlus

... to impaired female sexual development, unusual bone growth, insulin resistance, and other signs and symptoms of aromatase deficiency . In women who are pregnant with an affected fetus, excess androgens in the ...

[Synthesis and characteristics of porous hydroxyapatite bioceramics].

PubMed

Niu, Jinlong; Zhang, Zhenxi; Jiang, Dazong

2002-06-01

The macroporous structure of human bone allows the ingrowth of the soft tissues and organic cells into the bone matrix, profits the development and metabolism of bone tissue, and adapts the bone to the change of load. There is great requirement for artificial biomimic porous bioactive ceramics with the similar structure of bone tissue that can be used clinically for repairing lost bone. Fine hydroxyapatite (HAp) powder produced by wet chemical reaction was mixed with hydrogen peroxide (H2O2), polyvinyl alcohol, methyl cellulose or other pores-making materials to form green cake. After drying at low temperature (below 100 degrees C) and decarbonizing at about 300 degrees C-400 degrees C, the spongy ceramic block was sintered at high temperature, thus, macroporous HAp bioceramic with interconnected pores and reasonable porosity and pore-diameter was manufactured. This kind of porous HAp bioceramics were intrinsically osteoinductive to a certain degree, but its outstanding property was that they can absorb human bone morphogenetic proteins and other bone growth factors to form composites, so that the macroporous HAp bioactive ceramic has appropriate feasibility for clinical application. From the point of biomedical application, the recent developments in synthesis and characteristics investigation of macroporous HAp are reviewed in this paper.

Effects of Exercise on Children.

ERIC Educational Resources Information Center

Rarick, G. Lawrence

Exercise is generally held to be a significant factor in the growth, development, and health of children and adolescents. The effects of physical activity regimens on general growth, as well as quantitative and qualitative changes, in animal muscle and bone tissue have been clearly demonstrated. Less is known about the role of exercise and related…

N-cadherin Regulation of Bone Growth and Homeostasis is Osteolineage Stage-Specific

PubMed Central

Fontana, Francesca; Hickman-Brecks, Cynthia L.; Salazar, Valerie S.; Revollo, Leila; Abou-Ezzi, Grazia; Grimston, Susan K.; Jeong, Sung Yeop; Watkins, Marcus; Fortunato, Manuela; Alippe, Yael; Link, Daniel C.; Mbalaviele, Gabriel; Civitelli, Roberto

2017-01-01

N-cadherin inhibits osteogenic cell differentiation and canonical Wnt/β-catenin signaling in vitro. However, in vivo both conditional Cdh2 ablation and overexpression in osteoblasts lead to low bone mass. We tested the hypothesis that N-cadherin has different effects on osteolineage cells depending upon their differentiation stage. Embryonic conditional osteolineage Cdh2 deletion in mice results in defective growth, low bone mass and reduced osteoprogenitor number. These abnormalities are prevented by delaying Cdh2 ablation until 1 month of age, thus targeting only committed and mature osteoblasts, suggesting they are the consequence of N-cadherin deficiency in osteoprogenitors. Indeed, diaphyseal trabecularization actually increases when Cdh2 is ablated postnatally. The sclerostin-insensitive Lrp5A214V mutant, associated with high bone mass, does not rescue the growth defect, but it overrides the low bone mass of embryonically Cdh2 deleted mice, suggesting N-cadherin interacts with Wnt signaling to control bone mass. Finally, bone accrual and β-catenin accumulation after administration of an anti-Dkk1 antibody are enhanced in N-cadherin deficient mice. Thus, while lack of N-cadherin in embryonic and perinatal age is detrimental to bone growth and bone accrual, in adult mice loss of N-cadherin in osteolineage cells favors bone formation. Hence, N-cadherin inhibition may widen the therapeutic window of osteoanabolic agents. PMID:28240364

The Biology of Bone Metastasis.

PubMed

Esposito, Mark; Guise, Theresa; Kang, Yibin

2018-06-01

Bone metastasis, or the development of secondary tumors within the bone of cancer patients, is a debilitating and incurable disease. Despite its morbidity, the biology of bone metastasis represents one of the most complex and intriguing of all oncogenic processes. This complexity derives from the intricately organized bone microenvironment in which the various stages of hematopoiesis, osteogenesis, and osteolysis are jointly regulated but spatially restricted. Disseminated tumor cells (DTCs) from various common malignancies such as breast, prostate, lung, and kidney cancers or myeloma are uniquely primed to subvert these endogenous bone stromal elements to grow into pathological osteolytic or osteoblastic lesions. This colonization process can be separated into three key steps: seeding, dormancy, and outgrowth. Targeting the processes of dormancy and initial outgrowth offers the most therapeutic promise. Here, we discuss the concepts of the bone metastasis niche, from controlling tumor-cell survival to growth into clinically detectable disease. Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved.

Animal Models of Bone Metastasis

PubMed Central

Simmons, J. K.; Hildreth, B. E.; Supsavhad, W.; Elshafae, S. M.; Hassan, B. B.; Dirksen, W. P.; Toribio, R. E.; Rosol, T. J.

2015-01-01

Bone is one of the most common sites of cancer metastasis in humans and is a significant source of morbidity and mortality. Bone metastases are considered incurable and result in pain, pathologic fracture, and decreased quality of life. Animal models of skeletal metastases are essential to improve the understanding of the molecular pathways of cancer metastasis and growth in bone and to develop new therapies to inhibit and prevent bone metastases. The ideal animal model should be clinically relevant, reproducible, and representative of human disease. Currently, an ideal model does not exist; however, understanding the strengths and weaknesses of the available models will lead to proper study design and successful cancer research. This review provides an overview of the current in vivo animal models used in the study of skeletal metastases or local tumor invasion into bone and focuses on mammary and prostate cancer, lymphoma, multiple myeloma, head and neck squamous cell carcinoma, and miscellaneous tumors that metastasize to bone. PMID:26021553

Evaluation of maxillary growth: is there any difference using relief incision during palatoplasty?

PubMed

Maluf, Ivan; Doro, Ubiratan; Fuchs, Taíse; dos Santos, Diego Esteves; dos Santos Sacomam, Franserg; da Silva Freitas, Renato; Roca, Guilherme Berto

2014-05-01

Scar retraction due to exposed bone in palatoplasty is the leading cause of constricted maxilla. Modern techniques have focused on minimizing the effects of scarring by reducing the exposure of the bone area. The objective of the study was to compare the palatal mucoperiosteal detachment with minimal lateral incision, followed by their synthesis, with the maintenance of lateral areas for relaxation (similar to the von Langenbeck technique) and evaluate the transversal development of the maxilla. A prospective, randomized study was conducted, in which the molding of the dental arch of 14 pigs in 2 stages (at 1 month and 5 months) was performed. The pigs were divided into 3 groups: group 1 underwent lateral incision of the palate for mucoperiosteal detachment and maintenance of bone exposure; group 2 underwent mucoperiosteal palatal detachment with lateral access and no bone exposure; and group 3, the control animals, did not undergo any surgical procedures. Measurements of the dental arches were compared between the groups to assess differences in the development of the maxillary transverse diameter. There were no animals lost during the study. Group 1 showed greater growth restriction of the transverse diameter of the maxilla (36%) when compared with groups 2 (56%) and 3 (59%). Groups 2 and 3 showed similar transverse maxillary development, with no statistical difference. The technique of mucoperiosteal detachment without lateral relief incision has the advantage of reducing future morbidity of a constricted maxilla. This study demonstrated that the technique described can reduce rates of maxillary underdevelopment, a significant complication inherent in the procedure for palatoplasty. The lateral incisions reduce maxillary growth by approximately 20% as compared with this technique. Level II of evidence.

Clinical efficacy of stem cell mediated osteogenesis and bioceramics for bone tissue engineering.

PubMed

Neman, Josh; Hambrecht, Amanda; Cadry, Cherie; Goodarzi, Amir; Youssefzadeh, Jonathan; Chen, Mike Y; Jandial, Rahul

2012-01-01

Lower back pain is a common disorder that often requires bony spinal fusion for long-term relief. Current arthrodesis procedures use bone grafts from autogenous bone, allogenic backed bone or synthetic materials. Autogenous bone grafts can result in donor site morbidity and pain at the donor site, while allogenic backed bone and synthetic materials have variable effectiveness. Given these limitations, researchers have focused on new treatments that will allow for safe and successful bone repair and regeneration. Mesenchymal stem cells (MSCs) have received attention for their ability to differentiate into osteoblasts, cells that synthesize the extracellular matrix and regulate matrix mineralization. Successful bone regeneration requires three elements: MSCs that serve as osteoblastic progenitors, osteoinductive growth factors and their pathways that promote development and differentiation of the cells as well as an osteoconductive scaffold that allows for the formation of a vascular network. Future treatments should strive to combine mesenchymal stem cells, cell-seeded scaffolds and gene therapy to optimize the efficiency and safety of tissue repair and bone regeneration.

The effects of treatment combining an agonist of gonadotropin-releasing hormone with growth hormone in pubertal patients with isolated growth hormone deficiency.

PubMed

Toublanc, J E; Couprie, C; Garnier, P; Job, J C

1989-06-01

The final height of patients treated with growth hormone for isolated growth hormone deficiency has, up to now, been subnormal, with a mean below -2 SD in the series reported, an insufficient height at the onset of puberty and a more or less accelerated bone maturation during puberty being two important factors of the poor results. A long-acting analogue of gonadoliberin, Trp6-GnRH, has been given to GH-treated patients with isolated growth hormone deficiency at the time they reached pubertal stage 2, in combination with unchanged doses of GH, for one year in 11 and for two years in 7 of them. It resulted in an increase in the height age/bone age ratio and a reduction of the height insufficiency for bone age. The increase was slight but significant after one year, and fair after two years, in spite of reduced annual growth rate. Post-analogue follow-up in 5 patients with continued GH treatment showed a good development of growth and of puberty. It is concluded that combination of the long-acting Trp6-GnRH analogue and GH for 1-2 years in patients with isolated growth hormone deficiency whose puberty starts with a very insufficient height may be an appropriate way to improve their growth parameters. Studies with increased doses of GH or increased frequency of injections could help to optimize the results. Several years of follow-up are needed for demonstrating the results on final height.

Technical Report: Correlation Between the Repair of Cartilage and Subchondral Bone in an Osteochondral Defect Using Bilayered, Biodegradable Hydrogel Composites.

PubMed

Lu, Steven; Lam, Johnny; Trachtenberg, Jordan E; Lee, Esther J; Seyednejad, Hajar; van den Beucken, Jeroen J J P; Tabata, Yasuhiko; Kasper, F Kurtis; Scott, David W; Wong, Mark E; Jansen, John A; Mikos, Antonios G

2015-12-01

The present work investigated correlations between cartilage and subchondral bone repair, facilitated by a growth factor-delivering scaffold, in a rabbit osteochondral defect model. Histological scoring indices and microcomputed tomography morphological parameters were used to evaluate cartilage and bone repair, respectively, at 6 and 12 weeks. Correlation analysis revealed significant associations between specific cartilage indices and subchondral bone parameters that varied with location in the defect (cortical vs. trabecular region), time point (6 vs. 12 weeks), and experimental group (insulin-like growth factor-1 only, bone morphogenetic protein-2 only, or both growth factors). In particular, significant correlations consistently existed between cartilage surface regularity and bone quantity parameters. Overall, correlation analysis between cartilage and bone repair provided a fuller understanding of osteochondral repair and can help drive informed studies for future osteochondral regeneration strategies.

Posttraumatic tibia valga: a case demonstrating asymmetric activity at the proximal growth plate on technetium bone scan

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zionts, L.E.; Harcke, H.T.; Brooks, K.M.

1987-07-01

Posttraumatic tibia valga is a well-recognized complication following fracture of the upper tibial metaphysis in young children. We present a case of a child who developed a valgus deformity following fracture of the proximal tibia and fibula in which quantitative bone scintigraphy at 5 months after injury demonstrated increased uptake at the proximal tibial growth plate with proportionally greater uptake on the medial side. This finding suggests that the valgus deformity in this patient was due to a relative increase in vascularity and consequent overgrowth of the medial portion of the proximal tibial physis.

High-dose bone morphogenetic protein-induced ectopic abdomen bone growth.

PubMed

Deutsch, Harel

2010-02-01

Infuse [bone morphogenetic protein (BMP)] is increasingly used in spinal fusion surgery. The authors report a rare complication of BMP use. This is a case report. A 55-year-old male underwent a thoracic T8 to the pelvis fusion for degenerative lumbar disc disease and pseudarthrosis at another institution. The procedure involved an anterior and posterior approach with the use of multiple units of BMP. The patient presented to our institution with complaints of weight loss, pain, tenderness, and increasing solid growth in the left lower quadrant several months after his surgery. A computed tomography revealed ectopic bone growth in the retroperitoneal area and pelvis contiguous to the anterior lumbar exposure. The anterior wound was re-explored, and a large sheet of ectopic bone was removed from the retroperitoneal space. We report a rare case of extraspinal ectopic bone growth because of the use of multiple packages of BMP. Copyright (c) 2010 Elsevier Inc. All rights reserved.

Meclozine promotes longitudinal skeletal growth in transgenic mice with achondroplasia carrying a gain-of-function mutation in the FGFR3 gene.

PubMed

Matsushita, Masaki; Hasegawa, Satoru; Kitoh, Hiroshi; Mori, Kensaku; Ohkawara, Bisei; Yasoda, Akihiro; Masuda, Akio; Ishiguro, Naoki; Ohno, Kinji

2015-02-01

Achondroplasia (ACH) is one of the most common skeletal dysplasias causing short stature owing to a gain-of-function mutation in the FGFR3 gene, which encodes the fibroblast growth factor receptor 3. We found that meclozine, an over-the-counter drug for motion sickness, inhibited elevated FGFR3 signaling in chondrocytic cells. To examine the feasibility of meclozine administration in clinical settings, we investigated the effects of meclozine on ACH model mice carrying the heterozygous Fgfr3(ach) transgene. We quantified the effect of meclozine in bone explant cultures employing limb rudiments isolated from developing embryonic tibiae from Fgfr3(ach) mice. We found that meclozine significantly increased the full-length and cartilaginous primordia of embryonic tibiae isolated from Fgfr3(ach) mice. We next analyzed the skeletal phenotypes of growing Fgfr3(ach) mice and wild-type mice with or without meclozine treatment. In Fgfr3(ach) mice, meclozine significantly increased the body length after 2 weeks of administration. At skeletal maturity, the bone lengths including the cranium, radius, ulna, femur, tibia, and vertebrae were significantly longer in meclozine-treated Fgfr3(ach) mice than in untreated Fgfr3(ach) mice. Interestingly, meclozine also increased bone growth in wild-type mice. The plasma concentration of meclozine during treatment was within the range that has been used in clinical settings for motion sickness. Increased longitudinal bone growth in Fgfr3(ach) mice by oral administration of meclozine in a growth period suggests potential clinical feasibility of meclozine for the improvement of short stature in ACH.

Requirement of alveolar bone formation for eruption of rat molars

PubMed Central

Wise, Gary E.; He, Hongzhi; Gutierrez, Dina L.; Ring, Sherry; Yao, Shaomian

2011-01-01

Tooth eruption is a localized event that requires a dental follicle (DF) to regulate the resorption of alveolar bone to form an eruption pathway. During the intra-osseous phase of eruption, the tooth moves through this pathway. The mechanism or motive force that propels the tooth through this pathway is controversial but many studies have shown that alveolar bone growth at the base of the crypt occurs during eruption. To determine if this bone growth (osteogenesis) was causal, experiments were designed in which the expression of an osteogenic gene in the DF, bone morphogenetic protein-6 (BMP6), was inhibited by injection of the 1st mandibular molar of the rat with an siRNA targeted against BMP6. The injection was followed by electroporation to promote uptake of the siRNA. In 45 first molars injected, eruption either was delayed or completely inhibited (7 molars). In the impacted molars, an eruption pathway formed but bone growth at the base of the crypt was greatly reduced as compared to the erupted first molar controls. These studies show that alveolar bone growth at the base of the crypt is required for tooth eruption and that BMP6 may be an essential gene for promoting this growth. PMID:21896048

Biofunctional Ionic-Doped Calcium Phosphates: Silk Fibroin Composites for Bone Tissue Engineering Scaffolding.

PubMed

Pina, S; Canadas, R F; Jiménez, G; Perán, M; Marchal, J A; Reis, R L; Oliveira, J M

2017-01-01

The treatment and regeneration of bone defects caused by traumatism or diseases have not been completely addressed by current therapies. Lately, advanced tools and technologies have been successfully developed for bone tissue regeneration. Functional scaffolding materials such as biopolymers and bioresorbable fillers have gained particular attention, owing to their ability to promote cell adhesion, proliferation, and extracellular matrix production, which promote new bone growth. Here, we present novel biofunctional scaffolds for bone regeneration composed of silk fibroin (SF) and β-tricalcium phosphate (β-TCP) and incorporating Sr, Zn, and Mn, which were successfully developed using salt-leaching followed by a freeze-drying technique. The scaffolds presented a suitable pore size, porosity, and high interconnectivity, adequate for promoting cell attachment and proliferation. The degradation behavior and compressive mechanical strengths showed that SF/ionic-doped TCP scaffolds exhibit improved characteristics for bone tissue engineering when compared with SF scaffolds alone. The in vitro bioactivity assays using a simulated body fluid showed the growth of an apatite layer. Furthermore, in vitro assays using human adipose-derived stem cells presented different effects on cell proliferation/differentiation when varying the doping agents in the biofunctional scaffolds. The incorporation of Zn into the scaffolds led to improved proliferation, while the Sr- and Mn-doped scaffolds presented higher osteogenic potential as demonstrated by DNA quantification and alkaline phosphatase activity. The combination of Sr with Zn led to an influence on cell proliferation and osteogenesis when compared with single ions. Our results indicate that biofunctional ionic-doped composite scaffolds are good candidates for further in vivo studies on bone tissue regeneration. © 2017 S. Karger AG, Basel.

Bone tissue engineering scaffolding: computer-aided scaffolding techniques.

PubMed

Thavornyutikarn, Boonlom; Chantarapanich, Nattapon; Sitthiseripratip, Kriskrai; Thouas, George A; Chen, Qizhi

Tissue engineering is essentially a technique for imitating nature. Natural tissues consist of three components: cells, signalling systems (e.g. growth factors) and extracellular matrix (ECM). The ECM forms a scaffold for its cells. Hence, the engineered tissue construct is an artificial scaffold populated with living cells and signalling molecules. A huge effort has been invested in bone tissue engineering, in which a highly porous scaffold plays a critical role in guiding bone and vascular tissue growth and regeneration in three dimensions. In the last two decades, numerous scaffolding techniques have been developed to fabricate highly interconnective, porous scaffolds for bone tissue engineering applications. This review provides an update on the progress of foaming technology of biomaterials, with a special attention being focused on computer-aided manufacturing (Andrade et al. 2002) techniques. This article starts with a brief introduction of tissue engineering (Bone tissue engineering and scaffolds) and scaffolding materials (Biomaterials used in bone tissue engineering). After a brief reviews on conventional scaffolding techniques (Conventional scaffolding techniques), a number of CAM techniques are reviewed in great detail. For each technique, the structure and mechanical integrity of fabricated scaffolds are discussed in detail. Finally, the advantaged and disadvantage of these techniques are compared (Comparison of scaffolding techniques) and summarised (Summary).

Demineralized bone matrix fibers formable as general and custom 3D printed mold-based implants for promoting bone regeneration.

PubMed

Rodriguez, Rudy U; Kemper, Nathan; Breathwaite, Erick; Dutta, Sucharita M; Hsu, Erin L; Hsu, Wellington K; Francis, Michael P

2016-07-26

Bone repair frequently requires time-consuming implant construction, particularly when using un-formed implants with poor handling properties. We therefore developed osteoinductive, micro-fibrous surface patterned demineralized bone matrix (DBM) fibers for engineering both defect-matched and general three-dimensional implants. Implant molds were filled with demineralized human cortical bone fibers there were compressed and lyophilized, forming mechanically strong shaped DBM scaffolds. Enzyme linked immunosorbent assays and mass spectrometry confirmed that DBM fibers contained abundant osteogenic growth factors (bone morphogenetic proteins, insulin-like growth factor-I) and extracellular matrix proteins. Mercury porosimetry and mechanical testing showed interconnected pores within the mechanically stable, custom DBM fiber scaffolds. Mesenchymal stem cells readily attached to the DBM and showed increasing metabolic activity over time. DBM fibers further increased alkaline phosphatase activity in C2C12 cells. In vivo, DBM implants elicited osteoinductive potential in a mouse muscle pouch, and also promoted spine fusion in a rat arthrodesis model. DBM fibers can be engineered into custom-shaped, osteoinductive and osteoconductive implants with potential for repairing osseous defects with precise fitment, potentially reducing operating time. By providing pre-formed and custom implants, this regenerative allograft may improve patient outcomes following surgical bone repair, while further advancing personalized orthopedic and craniomaxillofacial medicine using three-dimensional-printed tissue molds.

Precocity in a tiny titanosaur from the Cretaceous of Madagascar.

PubMed

Curry Rogers, Kristina; Whitney, Megan; D'Emic, Michael; Bagley, Brian

2016-04-22

Sauropod dinosaurs exhibit the largest ontogenetic size range among terrestrial vertebrates, but a dearth of very young individuals has hindered understanding of the beginning of their growth trajectory. A new specimen of Rapetosaurus krausei sheds light on early life in the smallest stage of one of the largest dinosaurs. Bones record rapid growth rates and hatching lines, indicating that this individual weighed ~3.4 kilograms at hatching. Just several weeks later, when it likely succumbed to starvation in a drought-stressed ecosystem, it had reached a mass of ~40 kilograms and was ~35 centimeters tall at the hip. Unexpectedly, Rapetosaurus limb bones grew isometrically throughout their development. Cortical remodeling, limb isometry, and thin calcified hypertrophic metaphyseal cartilages indicate an active, precocial growth strategy. Copyright © 2016, American Association for the Advancement of Science.

Effects of imbalanced muscle loading on hip joint development and maturation.

PubMed

Ford, Caleb A; Nowlan, Niamh C; Thomopoulos, Stavros; Killian, Megan L

2017-05-01

The mechanical loading environment influences the development and maturation of joints. In this study, the influence of imbalanced muscular loading on joint development was studied using localized chemical denervation of hip stabilizing muscle groups in neonatal mice. It was hypothesized that imbalanced muscle loading, targeting either gluteal muscles or quadriceps muscles, would lead to bilateral hip joint asymmetry, as measured by acetabular coverage, femoral head volume and bone morphometry, and femoral-acetabular shape. The contralateral hip joints as well as age-matched, uninjected mice were used as controls. Altered bone development was analyzed using micro-computed tomography, histology, and image registration techniques at postnatal days (P) 28, 56, and 120. This study found that unilateral muscle unloading led to reduced acetabular coverage of the femoral head, lower total volume, lower bone volume ratio, and lower mineral density, at all three time points. Histologically, the femoral head was smaller in unloaded hips, with thinner triradiate cartilage at P28 and thinner cortical bone at P120 compared to contralateral hips. Morphological shape changes were evident in unloaded hips at P56. Unloaded hips had lower trabecular thickness and increased trabecular spacing of the femoral head compared to contralateral hips. The present study suggests that decreased muscle loading of the hip leads to altered bone and joint shape and growth during postnatal maturation. Statement of Clinical Significance: Adaptations from altered muscle loading during postnatal growth investigated in this study have implications on developmental hip disorders that result from asymmetric loading, such as patients with limb-length inequality or dysplasia. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1128-1136, 2017. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Predicting the impact of combined therapies on myeloma cell growth using a hybrid multi-scale agent-based model.

PubMed

Ji, Zhiwei; Su, Jing; Wu, Dan; Peng, Huiming; Zhao, Weiling; Nlong Zhao, Brian; Zhou, Xiaobo

2017-01-31

Multiple myeloma is a malignant still incurable plasma cell disorder. This is due to refractory disease relapse, immune impairment, and development of multi-drug resistance. The growth of malignant plasma cells is dependent on the bone marrow (BM) microenvironment and evasion of the host's anti-tumor immune response. Hence, we hypothesized that targeting tumor-stromal cell interaction and endogenous immune system in BM will potentially improve the response of multiple myeloma (MM). Therefore, we proposed a computational simulation of the myeloma development in the complicated microenvironment which includes immune cell components and bone marrow stromal cells and predicted the effects of combined treatment with multi-drugs on myeloma cell growth. We constructed a hybrid multi-scale agent-based model (HABM) that combines an ODE system and Agent-based model (ABM). The ODEs was used for modeling the dynamic changes of intracellular signal transductions and ABM for modeling the cell-cell interactions between stromal cells, tumor, and immune components in the BM. This model simulated myeloma growth in the bone marrow microenvironment and revealed the important role of immune system in this process. The predicted outcomes were consistent with the experimental observations from previous studies. Moreover, we applied this model to predict the treatment effects of three key therapeutic drugs used for MM, and found that the combination of these three drugs potentially suppress the growth of myeloma cells and reactivate the immune response. In summary, the proposed model may serve as a novel computational platform for simulating the formation of MM and evaluating the treatment response of MM to multiple drugs.

Accelerated Growth Plate Mineralization and Foreshortened Proximal Limb Bones in Fetuin-A Knockout Mice

PubMed Central

Gupta, Himadri S.; Schäfer, Cora; Krauss, Stefanie; Dunlop, John W. C.; Masic, Admir; Kerschnitzki, Michael; Zaslansky, Paul; Boesecke, Peter; Catalá-Lehnen, Philip; Schinke, Thorsten; Fratzl, Peter; Jahnen-Dechent, Willi

2012-01-01

The plasma protein fetuin-A/alpha2-HS-glycoprotein (genetic symbol Ahsg) is a systemic inhibitor of extraskeletal mineralization, which is best underscored by the excessive mineral deposition found in various tissues of fetuin-A deficient mice on the calcification-prone genetic background DBA/2. Fetuin-A is known to accumulate in the bone matrix thus an effect of fetuin-A on skeletal mineralization is expected. We examined the bones of fetuin-A deficient mice maintained on a C57BL/6 genetic background to avoid bone disease secondary to renal calcification. Here, we show that fetuin-A deficient mice display normal trabecular bone mass in the spine, but increased cortical thickness in the femur. Bone material properties, as well as mineral and collagen characteristics of cortical bone were unaffected by the absence of fetuin-A. In contrast, the long bones especially proximal limb bones were severely stunted in fetuin-A deficient mice compared to wildtype littermates, resulting in increased biomechanical stability of fetuin-A deficient femora in three-point-bending tests. Elevated backscattered electron signal intensities reflected an increased mineral content in the growth plates of fetuin-A deficient long bones, corroborating its physiological role as an inhibitor of excessive mineralization in the growth plate cartilage matrix - a site of vigorous physiological mineralization. We show that in the case of fetuin-A deficiency, active mineralization inhibition is a necessity for proper long bone growth. PMID:23091616

Growth plate closure: Apex view on bone scan

DOE Office of Scientific and Technical Information (OSTI.GOV)

Giles, P.H.; Trochei, M.; Yeates, K.

1984-01-01

Angular deformities of the extremities in children following premature closure of the growth plate are well known. The deformities depend on the position of an osseus bridge which forms between the epiphysis and metaphysis. Several surgical procedures including resection of the osseus bridge have been described, however, delineation of the site of fusion is difficult to define. The commonest site of growth plate arrest is the distal femoral or proximal tibial growth plate. A new technique using the bone scan has been developed which accurately defines the area and position of these osseus bridges. Two hours after injection of technetiummore » 99m methylene diphosphonate apex views of the affected distal femoral growth plate were performed. The knee was flexed into its smallest angle. Using a pinhole collimator the gamma camera was angled to face the affected growth plate end on. The image was collected onto computer and analysed by: (I) regions of interest over segments of the growth plate to calculate the relative area of total growth plate affected: (II) generating histograms: (III) thresholding or performing isocontours to accentuate abnormal areas. The growth plate is normally uniformly increased when compared to the normal shaft of the bone. Fusion across the plate appears as an area of diminished uptake. The apex view gives a unique functional map of the growth plate such that abnormal areas are displayed, and the site, size and position of osseus fusion obtained. The technique has the potential for determining the metabolic activity of the growth plate before and after surgery. Serial studies will allow assessment of regneration of the plate and reformation of new osseus bridges.« less

Engineering Pre-vascularized Scaffolds for Bone Regeneration.

PubMed

Barabaschi, Giada D G; Manoharan, Vijayan; Li, Qing; Bertassoni, Luiz E

2015-01-01

Survival of functional tissue constructs of clinically relevant size depends on the formation of an organized and uniformly distributed network of blood vessels and capillaries. The lack of such vasculature leads to spatio-temporal gradients in oxygen, nutrients and accumulation of waste products inside engineered tissue constructs resulting in negative biological events at the core of the scaffold. Unavailability of a well-defined vasculature also results in ineffective integration of scaffolds to the host vasculature upon implantation. Arguably, one of the greatest challenges in engineering clinically relevant bone substitutes, therefore, has been the development of vascularized bone scaffolds. Various approaches ranging from peptide and growth factor functionalized biomaterials to hyper-porous scaffolds have been proposed to address this problem with reasonable success. An emerging alternative to address this challenge has been the fabrication of pre-vascularized scaffolds by taking advantage of biomanufacturing techniques, such as soft- and photo-lithography or 3D bioprinting, and cell-based approaches, where functional capillaries are engineered in cell-laden scaffolds prior to implantation. These strategies seek to engineer pre-vascularized tissues in vitro, allowing for improved anastomosis with the host vasculature upon implantation, while also improving cell viability and tissue development in vitro. This book chapter provides an overview of recent methods to engineer pre-vascularized scaffolds for bone regeneration. We first review the development of functional blood capillaries in bony structures and discuss controlled delivery of growth factors, co-culture systems, and on-chip studies to engineer vascularized cell-laden biomaterials. Lastly, we review recent studies using microfabrication techniques and 3D printing to engineer pre-vascularized scaffolds for bone tissue engineering.

Bone density in limb-immobilized beagles: An animal model for bone loss in weightlessness

NASA Technical Reports Server (NTRS)

Wolinsky, Ira

1987-01-01

Prolonged weightlessness is man in space flight results in a slow progressive demineralization of bone accompanied by an increased calcium output in the urine resulting in negative calcium balances. This possibly irreversible bone loss may constitute a serious limiting factor to long duration manned space flight. In order to seek and test preventative measures an appropriate ground based animal model simulating weightlessness is necessary. Use of the mature Beagle in limb immobilization has been documented as an excellent model for orthopedic research since this animal most closely simulates the phenomenom of bone loss with regards to growth, remodeling, structure, chemistry and mineralization. The purpose of this project is to develop a research protocol for the study of bone loss in Beagles during and after cast immobilization of a hindleg; research will then be initiated.

Present status and future potential of enhancing bone healing using nanotechnology.

PubMed

Stylios, George; Wan, Taoyu; Giannoudis, Peter

2007-03-01

An overview of the current state of tissue engineering material systems used in bone healing is presented. A variety of fabrication processes have been developed that have resulted in porous implant substrates that can address unresolved clinical problems. The merits of these biomaterial systems are evaluated in the context of the mechanical properties and biomedical performances most suitable for bone healing. An optimal scaffold for bone tissue engineering applications should be biocompatible and act as a 3D template for in vitro and in vivo bone growth; in addition, its degradation products should be non-toxic and easily excreted by the body. To achieve these features, scaffolds must consist of an interconnected porous network of micro- and nanoscale to allow extensive body fluid transport through the pores, which will trigger bone ingrowth, cell migration, tissue ingrowth, and eventually vascularization.

Can we improve fixation and outcomes? Use of bone substitutes.

PubMed

Moroni, Antonio; Larsson, Sune; Hoang Kim, Amy; Gelsomini, Letizia; Giannoudis, Peter V

2009-07-01

Hip fractures secondary to osteoporosis are common in the elderly. Stabilizing these fractures until union is achieved is a challenge due to poor bone stock and insufficient purchase of the implant to the bone. The reported high rate of complications has prompted extensive research in the development of fixation techniques. Furthermore, manipulation of both the local fracture environment in terms of application of growth factors, scaffolds, and mesenchymal cells and the systemic administration of agents promoting bone formation and bone strength has been considered as a treatment option with promising results. There are only a few evidence-based studies reporting on fixation augmentation techniques. This article reports on the efficacy of bone graft substitutes for the fixation of hip fractures, in particular calcium phosphates, which have been used as granules, cements, and implant coatings.

Minimally invasive esthetic ridge preservation with growth-factor enhanced bone matrix.

PubMed

Nevins, Marc L; Said, Sherif

2017-12-28

Extraction socket preservation procedures are critical to successful esthetic implant therapy. Conventional surgical approaches are technique sensitive and often result in alteration of the soft tissue architecture, which then requires additional corrective surgical procedures. This case series report presents the ability of flapless surgical techniques combined with a growth factor-enhanced bone matrix to provide esthetic ridge preservation at the time of extraction for compromised sockets. When considering esthetic dental implant therapy, preservation, or further enhancement of the available tissue support at the time of tooth extraction may provide an improved esthetic outcome with reduced postoperative sequelae and decreased treatment duration. Advances in minimally invasive surgical techniques combined with recombinant growth factor technology offer an alternative for bone reconstruction while maintaining the gingival architecture for enhanced esthetic outcome. The combination of freeze-dried bone allograft (FDBA) and rhPDGF-BB (platelet-derived growth factor-BB) provides a growth-factor enhanced matrix to induce bone and soft tissue healing. The use of a growth-factor enhanced matrix is an option for minimally invasive ridge preservation procedures for sites with advanced bone loss. Further studies including randomized clinical trials are needed to better understand the extent and limits of these procedures. The use of minimally invasive techniques with growth factors for esthetic ridge preservation reduces patient morbidity associated with more invasive approaches and increases the predictability for enhanced patient outcomes. By reducing the need for autogenous bone grafts the use of this technology is favorable for patient acceptance and ease of treatment process for esthetic dental implant therapy. © 2017 Wiley Periodicals, Inc.

Stem cell- and growth factor-based regenerative therapies for avascular necrosis of the femoral head

PubMed Central

2012-01-01

Avascular necrosis (AVN) of the femoral head is a debilitating disease of multifactorial genesis, predominately affects young patients, and often leads to the development of secondary osteoarthritis. The evolving field of regenerative medicine offers promising treatment strategies using cells, biomaterial scaffolds, and bioactive factors, which might improve clinical outcome. Early stages of AVN with preserved structural integrity of the subchondral plate are accessible to retrograde surgical procedures, such as core decompression to reduce the intraosseous pressure and to induce bone remodeling. The additive application of concentrated bone marrow aspirates, ex vivo expanded mesenchymal stem cells, and osteogenic or angiogenic growth factors (or both) holds great potential to improve bone regeneration. In contrast, advanced stages of AVN with collapsed subchondral bone require an osteochondral reconstruction to preserve the physiological joint function. Analogously to strategies for osteochondral reconstruction in the knee, anterograde surgical techniques, such as osteochondral transplantation (mosaicplasty), matrix-based autologous chondrocyte implantation, or the use of acellular scaffolds alone, might preserve joint function and reduce the need for hip replacement. This review summarizes recent experimental accomplishments and initial clinical findings in the field of regenerative medicine which apply cells, growth factors, and matrices to address the clinical problem of AVN. PMID:22356811

Natural Polymer-Cell Bioconstructs for Bone Tissue Engineering.

PubMed

Titorencu, Irina; Albu, Madalina Georgiana; Nemecz, Miruna; Jinga, Victor V

2017-01-01

The major goal of bone tissue engineering is to develop bioconstructs which substitute the functionality of damaged natural bone structures as much as possible if critical-sized defects occur. Scaffolds that mimic the structure and composition of bone tissue and cells play a pivotal role in bone tissue engineering applications. First, composition, properties and in vivo synthesis of bone tissue are presented for the understanding of bone formation. Second, potential sources of osteoprogenitor cells have been investigated for their capacity to induce bone repair and regeneration. Third, taking into account that the main property to qualify one scaffold as a future bioconstruct for bone tissue engineering is the biocompatibility, the assessments which prove it are reviewed in this paper. Forth, various types of natural polymer- based scaffolds consisting in proteins, polysaccharides, minerals, growth factors etc, are discussed, and interaction between scaffolds and cells which proved bone tissue engineering concept are highlighted. Finally, the future perspectives of natural polymer-based scaffolds for bone tissue engineering are considered. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Modified Laminar Bone in Ampelosaurus atacis and Other Titanosaurs (Sauropoda): Implications for Life History and Physiology

PubMed Central

Klein, Nicole; Sander, P. Martin; Stein, Koen; Le Loeuff, Jean; Carballido, Jose L.; Buffetaut, Eric

2012-01-01

Background Long bone histology of the most derived Sauropoda, the Titanosauria suggests that titanosaurian long bone histology differs from the uniform bone histology of basal Sauropoda. Here we describe the long bone histology of the titanosaur Ampelosaurus atacis and compare it to that of basal neosauropods and other titanosaurs to clarify if a special titanosaur bone histology exists. Methodology/Principal Findings Ampelosaurus retains the laminar vascular organization of basal Sauropoda, but throughout most of cortical growth, the scaffolding of the fibrolamellar bone, which usually is laid down as matrix of woven bone, is laid down as parallel-fibered or lamellar bone matrix instead. The remodeling process by secondary osteons is very extensive and overruns the periosteal bone deposition before skeletal maturity is reached. Thus, no EFS is identifiable. Compared to the atypical bone histology of Ampelosaurus, the large titanosaur Alamosaurus shows typical laminar fibrolamellar bone. The titanosaurs Phuwiangosaurus, Lirainosaurus, and Magyarosaurus, although differing in certain features, all show this same low amount or absence of woven bone from the scaffolding of the fibrolamellar bone, indicating a clear reduction in growth rate resulting in a higher bone tissue organization. To describe the peculiar primary cortical bone tissue of Phuwiangosaurus, Ampelosaurus, Lirainosaurus, and Magyarosaurus, we here introduce a new term, “modified laminar bone” (MLB). Conclusions/Significance Importantly, MLB is as yet not known from extant animals. At least in Lirainosaurus and Magyarosaurus the reduction of growth rate indicated by MLB is coupled with a drastic body size reduction and maybe also a reduction in metabolic rate, interpreted as a result of dwarfing on the European islands during the Late Cretaceous. Phuwiangosaurus and Ampelosaurus both show a similar reduction in growth rate but not in body size, possibly indicating also a reduced metabolic rate. The large titanosaur Alamosaurus, on the other hand, retained the plesiomorphic bone histology of basal neosauropods. PMID:22615842

Paternal low protein diet programs preimplantation embryo gene expression, fetal growth and skeletal development in mice.

PubMed

Watkins, Adam J; Sirovica, Slobodan; Stokes, Ben; Isaacs, Mark; Addison, Owen; Martin, Richard A

2017-06-01

Defining the mechanisms underlying the programming of early life growth is fundamental for improving adult health and wellbeing. While the association between maternal diet, offspring growth and adult disease risk is well-established, the effect of father's diet on offspring development is largely unknown. Therefore, we fed male mice an imbalanced low protein diet (LPD) to determine the impact on post-fertilisation development and fetal growth. We observed that in preimplantation embryos derived from LPD fed males, expression of multiple genes within the central metabolic AMPK pathway was reduced. In late gestation, paternal LPD programmed increased fetal weight, however, placental weight was reduced, resulting in an elevated fetal:placental weight ratio. Analysis of gene expression patterns revealed increased levels of transporters for calcium, amino acids and glucose within LPD placentas. Furthermore, placental expression of the epigenetic regulators Dnmt1 and Dnmt3L were increased also, coinciding with altered patterns of maternal and paternal imprinted genes. More strikingly, we observed fetal skeletal development was perturbed in response to paternal LPD. Here, while offspring of LPD fed males possessed larger skeletons, their bones comprised lower volumes of high mineral density in combination with reduced maturity of bone apatite. These data offer new insight in the underlying programming mechanisms linking poor paternal diet at the time of conception with the development and growth of his offspring. Copyright © 2017 Elsevier B.V. All rights reserved.

Computed tomography analysis of guinea pig bone: architecture, bone thickness and dimensions throughout development

PubMed Central

Witkowska, Agata; Alibhai, Aziza; Hughes, Chloe; Price, Jennifer; Klisch, Karl; Sturrock, Craig J.

2014-01-01

The domestic guinea pig, Cavia aperea f. porcellus, belongs to the Caviidae family of rodents. It is an important species as a pet, a source of food and in medical research. Adult weight is achieved at 8–12 months and life expectancy is ∼5–6 years. Our aim was to map bone local thickness, structure and dimensions across developmental stages in the normal animal. Guinea pigs (n = 23) that had died of natural causes were collected and the bones manually extracted and cleaned. Institutional ethical permission was given under the UK Home Office guidelines and the Veterinary Surgeons Act. X-ray Micro Computed Tomography (microCT) was undertaken on the left and right scapula, humerus and femur from each animal to ascertain bone local thickness. Images were also used to undertake manual and automated bone measurements, volumes and surface areas, identify and describe nutrient, supratrochlear and supracondylar foramina. Statistical analysis between groups was carried out using ANOVA with post-hoc testing. Our data mapped a number of dimensions, and mean and maximum bone thickness of the scapula, humerus and femur in guinea pigs aged 0–1 month, 1–3 months, 3–6 months, 6 months–1 year and 1–4 years. Bone dimensions, growth rates and local bone thicknesses differed between ages and between the scapula, humerus and femur. The microCT and imaging software technology showed very distinct differences between the relative local bone thickness across the structure of the bones. Only one bone showed a singular nutrient foramen, every other bone had between 2 and 5, and every nutrient canal ran in an oblique direction. In contrast to other species, a supratrochlear foramen was observed in every humerus whereas the supracondylar foramen was always absent. Our data showed the bone local thickness, bone structure and measurements of guinea pig bones from birth to 4 years old. Importantly it showed that bone development continued after 1 year, the point at which most guinea pigs have reached full weight. This study is the first to show the high abundance (100% in this study) of the supratrochlear foramen within the guinea pig humerus and the complete absence of a supracondylar foramen, which is different to many other species and may also affect potential fracture points and frequencies. Understanding bone morphology and growth is essential in not only understanding the requirements of the healthy guinea pig, but also necessary in order to investigate disease states. PMID:25289194

Computed tomography analysis of guinea pig bone: architecture, bone thickness and dimensions throughout development.

PubMed

Witkowska, Agata; Alibhai, Aziza; Hughes, Chloe; Price, Jennifer; Klisch, Karl; Sturrock, Craig J; Rutland, Catrin S

2014-01-01

The domestic guinea pig, Cavia aperea f. porcellus, belongs to the Caviidae family of rodents. It is an important species as a pet, a source of food and in medical research. Adult weight is achieved at 8-12 months and life expectancy is ∼5-6 years. Our aim was to map bone local thickness, structure and dimensions across developmental stages in the normal animal. Guinea pigs (n = 23) that had died of natural causes were collected and the bones manually extracted and cleaned. Institutional ethical permission was given under the UK Home Office guidelines and the Veterinary Surgeons Act. X-ray Micro Computed Tomography (microCT) was undertaken on the left and right scapula, humerus and femur from each animal to ascertain bone local thickness. Images were also used to undertake manual and automated bone measurements, volumes and surface areas, identify and describe nutrient, supratrochlear and supracondylar foramina. Statistical analysis between groups was carried out using ANOVA with post-hoc testing. Our data mapped a number of dimensions, and mean and maximum bone thickness of the scapula, humerus and femur in guinea pigs aged 0-1 month, 1-3 months, 3-6 months, 6 months-1 year and 1-4 years. Bone dimensions, growth rates and local bone thicknesses differed between ages and between the scapula, humerus and femur. The microCT and imaging software technology showed very distinct differences between the relative local bone thickness across the structure of the bones. Only one bone showed a singular nutrient foramen, every other bone had between 2 and 5, and every nutrient canal ran in an oblique direction. In contrast to other species, a supratrochlear foramen was observed in every humerus whereas the supracondylar foramen was always absent. Our data showed the bone local thickness, bone structure and measurements of guinea pig bones from birth to 4 years old. Importantly it showed that bone development continued after 1 year, the point at which most guinea pigs have reached full weight. This study is the first to show the high abundance (100% in this study) of the supratrochlear foramen within the guinea pig humerus and the complete absence of a supracondylar foramen, which is different to many other species and may also affect potential fracture points and frequencies. Understanding bone morphology and growth is essential in not only understanding the requirements of the healthy guinea pig, but also necessary in order to investigate disease states.

Influence of muscle groups' activation on proximal femoral growth tendency.

PubMed

Yadav, Priti; Shefelbine, Sandra J; Pontén, Eva; Gutierrez-Farewik, Elena M

2017-12-01

Muscle and joint contact force influence stresses at the proximal growth plate of the femur and thus bone growth, affecting the neck shaft angle (NSA) and femoral anteversion (FA). This study aims to illustrate how different muscle groups' activation during gait affects NSA and FA development in able-bodied children. Subject-specific femur models were developed for three able-bodied children (ages 6, 7, and 11 years) using magnetic resonance images. Contributions of different muscle groups-hip flexors, hip extensors, hip adductors, hip abductors, and knee extensors-to overall hip contact force were computed. Specific growth rate for the growth plate was computed, and the growth was simulated in the principal stress direction at each element in the growth front. The predicted growth indicated decreased NSA and FA (of about [Formula: see text] over a four-month period) for able-bodied children. Hip abductors contributed the most, and hip adductors, the least, to growth rate. All muscles groups contributed to a decrease in predicted NSA ([Formula: see text]0.01[Formula: see text]-0.04[Formula: see text] and FA ([Formula: see text]0.004[Formula: see text]-[Formula: see text]), except hip extensors and hip adductors, which showed a tendency to increase the FA ([Formula: see text]0.004[Formula: see text]-[Formula: see text]). Understanding influences of different muscle groups on long bone growth tendency can help in treatment planning for growing children with affected gait.

Bone-Derived Growth Factors

PubMed Central

Capanna, R.; Campanacci, D.A.; De Biase, P.; Cuomo, P.; Lorenzoni, A.

2010-01-01

Bone regeneration is based on the synergy between osteconduction, osteoinduction and osteogenesis. In recent years, we have witnessed the birth and development of numerous osteoconductive substrates, created with the intention of replacing bone grafts, both autologous and homologous. Recently, attention has shifted to osteogenesis, in other words, to the study of mesenchymal cells and their differentiation into osteoblastic cell lines that can be cultured in vitro (as already seen with chondroblasts). Osteoinduction, too, has been shown to be equally important, ever since Urist’s 1967 study which drew attention to the demineralised bone matrix and its properties. The following twenty years led to the definition of bone morphogenetic protein (BMP) and finally to the marketing of the first ostegenic protein (OP-1) obtained by means of the gene recombination technique. The BMPs produced using this technique that, so far, have been shown to be most active are BMP-2 (Infuse) and BMP-7 (Osigraft). The BMPs are not the only molecules with osteoinductive capacity. Other molecules capable of influencing bone regeneration are: platelet-derived growth factors (PDGFs), the transforming growth factor-beta (TGF-β) family, insulin-like growth factor (IGF-I) and the acidic and basic fibroblast growth factors (FGFs). All these growth factors act in synergy with the BMPs, modulating their action and exerting an inductive and proliferative action on the cell lines responsible for regenerating the bone matrix. The literature has been literally invaded by studies, both experimental and preclinical, on these proteins (Termaat, 2005), and they have provided ample demonstration that the BMPs are effective in improving healing of fractures, pseudoarthrosis and spinal fusions. Important advantages of BMPs are the complete absence of risk of transmissible disease, given that they are produced using recombination technology; their purity, and thus absence of an immune response (although such a response could be linked to the carrier used to administer them); their efficacy, which derives from the use of a pre-established dose and not from the individual variability that is a specific feature of demineralized bone matrix homologous bone grafts. In addition to their use in fractures, pseudoarthrosis and spinal fusions, very recent studies are opening up new possibilities which may represent the future field of application of these proteins: Cook et al. (Cook, 2001, Barrack, 2003) have presented the first results obtained using OP-1 in prosthetic revisions carried out in the presence of bone defects; other authors have published a case report on osteonecrosis of the femoral head treated with grafts in association with OP-1; an Italian group is currently experimenting the use of OP-1 in distraction osteogenesis with the aim of speeding up the results that can be obtained using this already well-established technique. However, the most interesting results on the use of recombinant morphogenetic proteins are those obtained by Warnke et al. (2004), maxillo-facial surgeons who, by mixing synthetic spongious bone grafts, bone marrow concentrate and morphogenetic proteins, prepared a new, replacement mandible for implantation in a patient who had lost his own due to cancer, thereby creating new vacularised bone, tailored to that specific patient. The experimental applications of these new drugs are countless and, with regard to their therapeutic potential, the general feeling is that what we are seeing is only the tip of the iceberg. However, it is necessary to ensure that experiments in this field are always geared towards sustainable clinical applications and, to this end, they should be concentrated in a smaller number of centres and conducted in accordance with approved and recognised guidelines.

[Bone morphogenetic proteins (BMP): clinical application for reconstruction of bone defects].

PubMed

Sierra-García, Gerardo Daniel; Castro-Ríos, Rocío; Gónzalez-Horta, Azucena; Lara-Arias, Jorge; Chávez-Montes, Abelardo

2016-01-01

Since the introduction of bone morphogenetic proteins, their use has become an invaluable ally for the treatment of bone defects. These proteins are potent growth factors, related to angiogenic and osteogenic activity. The osteoinductive capacity of recombinant bone morphogenetic protein (rhBMP) in the formation of bone and cartilage has been confirmed in in vitro studies and evaluated in clinical trials. To obtain a therapeutic effect, administration is systemic, by injection over the physiological dose. Among the disadvantages, ectopic bone formation or high morbidity in cases of spinal fusion is observed. In this review, the roles of bone morphogenetic proteins in bone repair and clinical applications are analyzed. These findings represent advances in the study of bone regeneration and application of growth factors for more predictable results.

Normal development and growth of the human neurocranium and cranial base.

PubMed

Friede, H

1981-01-01

The literature on normal development and growth of certain areas of the human head is reviewed, starting with the early induction of the desmal neurocranium. the development of the brain capsule with its dural reinforcement bands and their connection with the basicranium is discussed, as is the primordial chondrocranium, including its bone replacement. Growth of the calvaria and the three cranial fossae is also analysed. Special interest is focused on the anterior fossa, as knowledge of the growth in this area is very important for an understanding of pathogenesis and possibilities of treating premature craniosynostosis. Finally it is stressed that close observation of the effects of treatment on this pathology may increase our knowledge of normal growth.

Recent advances in bone tissue engineering scaffolds

PubMed Central

Bose, Susmita; Roy, Mangal; Bandyopadhyay, Amit

2012-01-01

Bone disorders are of significant concern due to increase in the median age of our population. Traditionally, bone grafts have been used to restore damaged bone. Synthetic biomaterials are now being used as bone graft substitutes. These biomaterials were initially selected for structural restoration based on their biomechanical properties. Later scaffolds were engineered to be bioactive or bioresorbable to enhance tissue growth. Now scaffolds are designed to induce bone formation and vascularization. These scaffolds are often porous, biodegradable materials that harbor different growth factors, drugs, genes or stem cells. In this review, we highlight recent advances in bone scaffolds and discuss aspects that still need to be improved. PMID:22939815

A COMPUTATIONAL ANALYSIS OF BONE FORMATION IN THE CRANIAL VAULT USING A COUPLED REACTION-DIFFUSION-STRAIN MODEL

PubMed Central

LEE, CHANYOUNG; RICHTSMEIER, JOAN T.; KRAFT, REUBEN H.

2017-01-01

Bones of the murine cranial vault are formed by differentiation of mesenchymal cells into osteoblasts, a process that is primarily understood to be controlled by a cascade of reactions between extracellular molecules and cells. We assume that the process can be modeled using Turing’s reaction-diffusion equations, a mathematical model describing the pattern formation controlled by two interacting molecules (activator and inhibitor). In addition to the processes modeled by reaction-diffusion equations, we hypothesize that mechanical stimuli of the cells due to growth of the underlying brain contribute significantly to the process of cell differentiation in cranial vault development. Structural analysis of the surface of the brain was conducted to explore the effects of the mechanical strain on bone formation. We propose a mechanobiological model for the formation of cranial vault bones by coupling the reaction-diffusion model with structural mechanics. The mathematical formulation was solved using the finite volume method. The computational domain and model parameters are determined using a large collection of experimental data that provide precise three dimensional (3D) measures of murine cranial geometry and cranial vault bone formation for specific embryonic time points. The results of this study suggest that mechanical strain contributes information to specific aspects of bone formation. Our mechanobiological model predicts some key features of cranial vault bone formation that were verified by experimental observations including the relative location of ossification centers of individual vault bones, the pattern of cranial vault bone growth over time, and the position of cranial vault sutures. PMID:29225392

Vitamin A

MedlinePlus

Vitamins are substances that your body needs to grow and develop normally. Vitamin A plays a role in your Vision Bone growth Reproduction Cell functions Immune system Vitamin A is an antioxidant. It can come from ...

Dr. Quincy, Move Over!

ERIC Educational Resources Information Center

Mason, David H.

1988-01-01

Introduces a life science classroom activity for developing a knowledge of the human skeletal system, environmental poisoning, and bone growth pattern. Provides the situation, an organizational flow chart, relevant information materials, and directions. (YP)

mTORC1 Plays an Important Role in Skeletal Development by Controlling Preosteoblast Differentiation

PubMed Central

Matthews, Mary P.; Martin, Sally K.; Xie, Jianling; Ooi, Soo Siang; Walkley, Carl R.; Codrington, John D.; Ruegg, Markus A.; Hall, Michael N.; Proud, Christopher G.; Gronthos, Stan; Zannettino, Andrew C. W.

2017-01-01

ABSTRACT The mammalian target of rapamycin complex 1 (mTORC1) is activated by extracellular factors that control bone accrual. However, the direct role of this complex in osteoblast biology remains to be determined. To investigate this question, we disrupted mTORC1 function in preosteoblasts by targeted deletion of Raptor (Rptor) in Osterix-expressing cells. Deletion of Rptor resulted in reduced limb length that was associated with smaller epiphyseal growth plates in the postnatal skeleton. Rptor deletion caused a marked reduction in pre- and postnatal bone accrual, which was evident in skeletal elements derived from both intramembranous and endochondrial ossification. The decrease in bone accrual, as well as the associated increase in skeletal fragility, was due to a reduction in osteoblast function. In vitro, osteoblasts derived from knockout mice display a reduced osteogenic potential, and an assessment of bone-developmental markers in Rptor knockout osteoblasts revealed a transcriptional profile consistent with an immature osteoblast phenotype suggesting that osteoblast differentiation was stalled early in osteogenesis. Metabolic labeling and an assessment of cell size of Rptor knockout osteoblasts revealed a significant decrease in protein synthesis, a major driver of cell growth. These findings demonstrate that mTORC1 plays an important role in skeletal development by regulating mRNA translation during preosteoblast differentiation. PMID:28069737

Gymnastics participation is associated with skeletal benefits in the distal forearm: a 6-month study using peripheral Quantitative Computed Tomography.

PubMed

Burt, L A; Ducher, G; Naughton, G A; Courteix, D; Greene, D A

2013-12-01

Musculoskeletal development of the upper limbs during exposure to weight-bearing loading is under-researched during early pubescent growth. The purpose was to assess the changes in upper body musculoskeletal strength in young girls following 6 months of non-elite gymnastics participation. Eighty-four girls, 6-12 years were divided into groups based on gymnastics participation: high-training (HGYM, 6-16 hr/wk), low-training (LGYM, 1-5 hr/wk), and non-gymnasts (NONGYM). Volumetric BMD, bone geometry, estimated bone strength and muscle size were assessed at the non-dominant forearm (4% and 66% radius and ulna) with pQCT. DXA assessed aBMD and body composition. Tests for explosive power, muscle strength, and endurance were also performed. Interaction effects were observed in all variables at the 4% radius. At the 66% ulna, HGYM and LGYM had greater bone mass, size and bone strength than NONGYM, furthermore a dose-response relationship was observed at this location. Body composition was better for HGYM than LGYM and NONGYM, however muscle function was better for HGYM and LGYM than NONGYM. The greatest changes were obtained with more than one gymnastics class per week. Separating gymnastics participation-related changes from those associated with normal growth and development remains difficult, particularly at the 4% radius.

Large Bone Vertical Augmentation Using a Three-Dimensional Printed TCP/HA Bone Graft: A Pilot Study in Dog Mandible.

PubMed

Carrel, Jean-Pierre; Wiskott, Anselm; Scherrer, Susanne; Durual, Stéphane

2016-12-01

Osteoflux is a three-dimensional printed calcium phosphate porous structure for oral bone augmentation. It is a mechanically stable scaffold with a well-defined interconnectivity and can be readily shaped to conform to the bone bed's morphology. An animal experiment is reported whose aim was to assess the performance and safety of the scaffold in promoting vertical growth of cortical bone in the mandible. Four three-dimensional blocks (10 mm length, 5 mm width, 5 mm height) were affixed to edentulous segments of the dog's mandible and covered by a collagen membrane. During bone bed preparation, particular attention was paid not to create defects 0.5 mm or more so that the real potential of the three-dimensional block in driving vertical bone growth can be assessed. Histomorphometric analyses were performed after 8 weeks. At 8 weeks, the three-dimensional blocks led to substantial vertical bone growth up to 4.5 mm from the bone bed. Between 0 and 1 mm in height, 44% of the surface was filled with new bone, at 1 to 3 mm it was 20% to 35%, 18% at 3 to 4, and ca. 6% beyond 4 mm. New bone was evenly distributed along in mesio-distal direction and formed a new crest contour in harmony with the natural mandibular shape. After two months of healing, the three-dimensional printed blocks conducted new bone growth above its natural bed, up to 4.5 mm in a canine mandibular model. Furthermore, the new bone was evenly distributed in height and density along the block. These results are very promising and need to be further evaluated by a complete powerful study using the same model. © 2016 Wiley Periodicals, Inc.

Whole body BMC in pediatric Crohn disease: independent effects of altered growth, maturation, and body composition.

PubMed

Burnham, Jon M; Shults, Justine; Semeao, Edisio; Foster, Bethany; Zemel, Babette S; Stallings, Virginia A; Leonard, Mary B

2004-12-01

Whole body BMC was assessed in 104 children and young adults with CD and 233 healthy controls. CD was associated with significant deficits in BMC and lean mass, relative to height. Adjustment for lean mass eliminated the bone deficit in CD. Steroid exposure was associated with short stature but not bone deficits relative to height. Children with Crohn disease (CD) have multiple risk factors for impaired bone accrual. The confounding effects of poor growth and delayed maturation limit the interpretation of prior studies of bone health in CD. The objective of this study was to assess BMC relative to growth, body composition, and maturation in CD compared with controls. Whole body BMC and lean mass were assessed by DXA in 104 CD subjects and 233 healthy controls, 4-26 years of age. Multivariable linear regression models were developed to sequentially adjust for differences in skeletal size, pubertal maturation, and muscle mass. BMC-for-height z scores were derived to determine CD-specific covariates associated with bone deficits. Subjects with CD had significantly lower height z score, body mass index z score, and lean mass relative to height compared with controls (all p < 0.0001). After adjustment for group differences in age, height, and race, the ratio of BMC in CD relative to controls was significantly reduced in males (0.86; 95% CI, 0.83, 0.94) and females (0.91; 95% CI, 0.85, 0.98) with CD. Adjustment for pubertal maturation did not alter the estimate; however, addition of lean mass to the model eliminated the bone deficit. Steroid exposure was associated with short stature but not bone deficits. This study shows the importance of considering differences in body size and composition when interpreting DXA data in children with chronic inflammatory conditions and shows an association between deficits in muscle mass and bone in pediatric CD.

The adipose organ and multiple myeloma: Impact of adipokines on tumor growth and potential sites for therapeutic intervention.

PubMed

Allegra, Alessandro; Innao, Vanessa; Gerace, Demetrio; Allegra, Andrea Gaetano; Vaddinelli, Doriana; Bianco, Oriana; Musolino, Caterina

2018-07-01

In addition to its capacity to store lipids the adipose tissue is now identified as a real organ with both endocrine and metabolic roles. Preclinical results indicate that modifying adipose tissue and bone marrow adipose tissue (BMAT) could be a successful multiple myeloma (MM) therapy. BMAT interrelates with bone marrow cells and other immune cells, and may influence MM disease progression. The BM adipocytes may have a role in MM progression, bone homing, chemoresistance, and relapse, due to local endocrine, paracrine, or metabolic factors. BM adipocytes isolated from MM subjects have been shown to increase myeloma growth in vitro and may preserve cells from chemotherapy-induced apoptosis. By producing free fatty acids and emitting signaling molecules such as growth factors and adipokines, BM adipocytes are both an energy font and an endocrine signaling factory. This review should suggest future research approaches toward developing novel treatments to target MM by targeting BMAT and its products. Copyright © 2018 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Diversity of Pubertal Development in Cartilage-Hair Hypoplasia; Two Illustrative Cases.

PubMed

Holopainen, Elina; Vakkilainen, Svetlana; Mäkitie, Outi

2018-08-01

Cartilage-hair hypoplasia (CHH) is a rare chondrodysplasia, including disproportionate short stature, hypoplastic hair, immunodeficiency, and increased risk of malignancies. Absent pubertal growth spurt and absent pubic hair complicate monitoring of pubertal development in these patients. Two CHH patients with delayed puberty and excessive growth failure are described. One of the girls had hypogonadotropic hypogonadism whereas the other had hyponormogonadotropic hypogonadism with no spontaneous pubertal development and slow response to estrogen therapy, both requiring permanent replacement therapy. Careful follow-up of pubertal development in individuals with CHH and other growth-restricting bone diseases is needed. In delayed pubertal development timely hormone therapy is essential to ensure maximal growth and well developed secondary sex characteristics. Copyright © 2018 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.

A comparison of hand wrist bone analysis with two different cervical vertebral analysis in measuring skeletal maturation.

PubMed

Pichai, Saravanan; Rajesh, M; Reddy, Naveen; Adusumilli, Gopinath; Reddy, Jayaprakash; Joshi, Bhavana

2014-09-01

Skeletal maturation is an integral part of individual pattern of growth and development and is a continuous process. Peak growth velocity in standing height is the most valid representation of the rate of overall skeletal growth. Ossification changes of hand wrist and cervical vertebrae are the reliable indicators of growth status of individual. The objective of this study was to compare skeletal maturation as measured by hand wrist bone analysis and cervical vertebral analysis. Hand wrist radiographs and lateral cephalograms of 72 subjects aged between 7 and 16 years both male and female from the patients visiting Department of Orthodontics and Dentofacial Orthopedics, R.V. Dental College and Hospital. The 9 stages were reduced to 5 stages to compare with cervical vertebral maturation stage by Baccetti et al. The Bjork, Grave and Brown stages were reduced to six intervals to compare with cervical vertebral maturational index (CVMI) staging by Hassel and Farman. These measurements were then compared with the hand wrist bone analysis, and the results were statistically analyzed using the Mann-Whitney test. There was no significant difference between the hand wrist analysis and the two different cervical vertebral analyses for assessing skeletal maturation. There was no significant difference between the two cervical vertebral analyses, but the CVMI method, which is visual method is less time consuming. Vertebral analysis on a lateral cephalogram is as valid as the hand wrist bone analysis with the advantage of reducing the radiation exposure of growing subjects.

Simple Signaling Molecules for Inductive Bone Regenerative Engineering

PubMed Central

Nelson, Stephen J.; Deng, Meng; Sethuraman, Swaminathan; Doty, Stephen B.; Lo, Kevin W. H.; Khan, Yusuf M.; Laurencin, Cato T.

2014-01-01

With greater than 500,000 orthopaedic procedures performed in the United States each year requiring a bone graft, the development of novel graft materials is necessary. We report that some porous polymer/ceramic composite scaffolds possess intrinsic osteoinductivity as shown through their capacity to induce in vivo host osteoid mineralization and in vitro stem cell osteogenesis making them attractive synthetic bone graft substitutes. It was discovered that certain low crystallinity ceramics partially dissociate into simple signaling molecules (i.e., calcium and phosphate ions) that induce stem cells to endogenously produce their own osteoinductive proteins. Review of the literature has uncovered a variety of simple signaling molecules (i.e., gases, ions, and redox reagents) capable of inducing other desirable stem cell differentiation through endogenous growth factor production. Inductive simple signaling molecules, which we have termed inducerons, represent a paradigm shift in the field of regenerative engineering where they can be utilized in place of recombinant protein growth factors. PMID:25019622

Recent Insights into the Regulation of the Growth Plate

PubMed Central

Lui, Julian C.; Nilsson, Ola; Baron, Jeffrey

2014-01-01

For most bones, elongation is driven primarily by chondrogenesis at the growth plates. This process results from chondrocyte proliferation, hypertrophy, and extracellular matrix secretion and is carefully orchestrated by complex networks of local paracrine factors and modulated by endocrine factors. We review here recent advances in the understanding of growth plate physiology. These advances include new approaches to study expression patterns of large numbers of genes in the growth plate, using microdissection followed by microarray. This approach has been combined with genome-wide association studies to provide insights into the regulation of the human growth plate. We also review recent studies elucidating the roles of bone morphogenetic proteins, fibroblast growth factors, C-type natriuretic peptide, and suppressor of cytokine signaling in the local regulation of growth plate chondrogenesis and longitudinal bone growth. PMID:24740736

Promotion of osteogenesis by a piezoelectric biological ceramic.

PubMed

Feng, J; Yuan, H; Zhang, X

1997-12-01

Hydroxyapatite (HA) ceramic and piezoelectric biological ceramic, hydroxyapatite and barium titanate (HABT), were implanted in the jawbones of dogs. Histological observation showed that, compared with HA ceramics, HABT promoted the growth and repair of the bone significantly, the tissue growth around the HABT ceramic was direction-dependent, the collagen arranged orderly and the bone grew orderly. The order growth of the bone increased the efficiency of osteogenesis on the surface of the implanted HABT ceramics.

Prostaglandin E2 Adds Bone to a Cancellous Bone Site with a Closed Growth Plate and Low Bone Turnover in Ovariectomized Rats

NASA Technical Reports Server (NTRS)

Ma, Y. F.; Ke, H. Z.; Jee, W. S. S.

1994-01-01

The objects of this study were to determine the responses of a cancellous bone site with a closed growth plate, (the distal tibial metaphysis (DTM), to ovariectomy (OVX) and OVX plus a prostaglandin E(2) treatment, and compare the site's response to previous findings reported for another site, the proximal tibial metaphysis (PTM). Thirty five 3-month old female Sprague-Dawley rats were divided into five groups; basal, sham OVX, and OVX+0, +1, or +6 mg PGE(2)/kg/d injected subcutaneously for 3 months and given double fluorescent labels before sacrifice. Cancellous bone histomorphometric analyses were performed on 20 micrometer thick undecalcified DTM sections. Similar to the PTM, the DTM showed age-related decreases in bone formation and increases in bone resorption, but it differed in that at 3 months POST OVX there was neither bone loss nor changes in formation endpoints. Giving 1 mg PGE(2)/kg/d to OVX rats prevented most age-related changes and maintained the bone formation histomorphometry near basal levels. Treating OVX rats with 6 mg PGE(2)/kd/d prevented age-related bone changes, added extra bone, and improved microanatomical structure by stimulating bone formation, without altering bone resportion. Futhermore, After PGE(2) admimnistration, the DTM, a cancellous bone site with a closed growth plate, increased bone formation more than did the cancellous bone in the PTM.

Prostaglandin E2 Adds Bone to a Cancellous Bone Site with a Closed Growth Plate and Low Bone Turnover in Ovariectomized Rats

NASA Technical Reports Server (NTRS)

Ma, Y. F.; Ke, H. Z.; Jee, W. S. S.

1994-01-01

The objects of this study were to determine the responses of a cancellous bone site with a closed growth plate (the distal tibial metaphysis, DTM) to ovariectomy (OVX) and OVX plus a prostaglandin E2 (PGE2) treatment, and compare the site's response to previous findings reported for another site (the proximal tibial metaphysis, PTM). Thirty-five 3-month old female Sprague-Dawley rats were divided into five groups: basal, sham-OVX, and OVX+0, +1, or +6 mg PGE2/kg/d injected subcutaneously for 3 months and given double fluorescent labels before sacrifice. Cancellous bone histomorphometric analyses were performed on 20-micron-thick undecalcified DTM sections. Similar to the PTM, the DTM showed age-related decreases in bone formation and increases in bone resorption, but it differed in that at 3 months post-OVX; there was neither bone loss nor changes in formation endpoints. Giving 1 mg PGE2/kg/d to OVX rats prevented most age-related changes and maintained the bone formation histomorphometry near basal levels. Treating OVX rats with 6 mg PGE2/kg/d prevented age-related bone changes, added extra bone, and improved microanatomical structure by stimulating bone formation without altering bone resorption. Furthermore, after PGE2 administration, the DTM, a cancellous bone site with a closed growth plate, inereased bone formation more than did the cancellous bone in the PTM.

Effects of In Utero Thyroxine Exposure on Murine Cranial Suture Growth

PubMed Central

Black, Laurel; Bennfors, Grace; Parsons, Trish E.; Elsalanty, Mohammed E.; Yu, Jack C.; Weinberg, Seth M.; Cray, James J.

2016-01-01

Large scale surveillance studies, case studies, as well as cohort studies have identified the influence of thyroid hormones on calvarial growth and development. Surveillance data suggests maternal thyroid disorders (hyperthyroidism, hypothyroidism with pharmacological replacement, and Maternal Graves Disease) are linked to as much as a 2.5 fold increased risk for craniosynostosis. Craniosynostosis is the premature fusion of one or more calvarial growth sites (sutures) prior to the completion of brain expansion. Thyroid hormones maintain proper bone mineral densities by interacting with growth hormone and aiding in the regulation of insulin like growth factors (IGFs). Disruption of this hormonal control of bone physiology may lead to altered bone dynamics thereby increasing the risk for craniosynostosis. In order to elucidate the effect of exogenous thyroxine exposure on cranial suture growth and morphology, wild type C57BL6 mouse litters were exposed to thyroxine in utero (control = no treatment; low ~167 ng per day; high ~667 ng per day). Thyroxine exposed mice demonstrated craniofacial dysmorphology (brachycranic). High dose exposed mice showed diminished area of the coronal and widening of the sagittal sutures indicative of premature fusion and compensatory growth. Presence of thyroid receptors was confirmed for the murine cranial suture and markers of proliferation and osteogenesis were increased in sutures from exposed mice. Increased Htra1 and Igf1 gene expression were found in sutures from high dose exposed individuals. Pathways related to the HTRA1/IGF axis, specifically Akt and Wnt, demonstrated evidence of increased activity. Overall our data suggest that maternal exogenous thyroxine exposure can drive calvarial growth alterations and altered suture morphology. PMID:27959899

Multifunctional mesoporous bioactive glasses for effective delivery of therapeutic ions and drug/growth factors.

PubMed

Wu, Chengtie; Chang, Jiang

2014-11-10

Regeneration of large-size bone defects represents a significant challenge clinically, which requires the use of scaffolds with multifunction, such as anti-bacterial activity, and stimulation of osteogenesis and angiogenesis. It is known that functional ions or drug/growth factors play an important role to stimulate tissue regeneration. Mesoporous bioactive glasses (MBG) possess excellent bioactivity and drug-delivery ability as well as effective ionic release in the body fluids microenvironment due to its specific mesoporous structure and large surface area. For these reasons, functional ions (e.g. lithium (Li), strontium (Sr), Copper (Cu) and Boron (B)) and drug/growth factors (e.g. dexamethasone, vascular endothelial growth factor (VEGF) and bone morphogenetic protein (BMP)) have been incorporated into MBG, which shows high loading efficiency and effective release. The release of therapeutic ions and drug/growth factors from MBG offers it multifunctional properties, such as improved osteogenesis, angiogenesis, anti-bacterial/cancer activity. However, there is no a systematic review about delivery of therapeutic ions and drugs/growth factors from MBG for the functional effect on the tissue regeneration despite that significant progress has been achieved in the past five years. Therefore, in this review, we mainly focused on the new advances for the functional effect of delivering therapeutic ions and drugs/growth factors on the ostegeogenesis, angiogenesis and antibacterial activity. It is expected that the review will offer new concept to develop multifunctional biomaterials for bone regeneration by the synergistic effect of therapeutic ions and drug/growth factors. Copyright © 2014 Elsevier B.V. All rights reserved.

Effects of In Utero Thyroxine Exposure on Murine Cranial Suture Growth.

PubMed

Howie, R Nicole; Durham, Emily L; Black, Laurel; Bennfors, Grace; Parsons, Trish E; Elsalanty, Mohammed E; Yu, Jack C; Weinberg, Seth M; Cray, James J

2016-01-01

Large scale surveillance studies, case studies, as well as cohort studies have identified the influence of thyroid hormones on calvarial growth and development. Surveillance data suggests maternal thyroid disorders (hyperthyroidism, hypothyroidism with pharmacological replacement, and Maternal Graves Disease) are linked to as much as a 2.5 fold increased risk for craniosynostosis. Craniosynostosis is the premature fusion of one or more calvarial growth sites (sutures) prior to the completion of brain expansion. Thyroid hormones maintain proper bone mineral densities by interacting with growth hormone and aiding in the regulation of insulin like growth factors (IGFs). Disruption of this hormonal control of bone physiology may lead to altered bone dynamics thereby increasing the risk for craniosynostosis. In order to elucidate the effect of exogenous thyroxine exposure on cranial suture growth and morphology, wild type C57BL6 mouse litters were exposed to thyroxine in utero (control = no treatment; low ~167 ng per day; high ~667 ng per day). Thyroxine exposed mice demonstrated craniofacial dysmorphology (brachycranic). High dose exposed mice showed diminished area of the coronal and widening of the sagittal sutures indicative of premature fusion and compensatory growth. Presence of thyroid receptors was confirmed for the murine cranial suture and markers of proliferation and osteogenesis were increased in sutures from exposed mice. Increased Htra1 and Igf1 gene expression were found in sutures from high dose exposed individuals. Pathways related to the HTRA1/IGF axis, specifically Akt and Wnt, demonstrated evidence of increased activity. Overall our data suggest that maternal exogenous thyroxine exposure can drive calvarial growth alterations and altered suture morphology.

Mesenchymal stem cells and alginate microcarriers for craniofacial bone tissue engineering: A review.

PubMed

Saltz, Adam; Kandalam, Umadevi

2016-05-01

Craniofacial bone is a complex structure with an intricate anatomical and physiological architecture. The defects that exist in this region therefore require a precise control of osteogenesis in their reconstruction. Unlike traditional surgical intervention, tissue engineering techniques mediate bone development with limited postoperative risk and cost. Alginate stands as the premier polymer in bone repair because of its mild ionotropic gelation and excellent biocompatibility, biodegradability, and injectability. Alginate microcarriers are candidates of choice to mediate cells and accommodate into 3-D environment. Several studies reported the use of alginate microcarriers for delivering cells, drugs, and growth factors. This review will explore the potential use of alginate microcarrier for stem cell systems and its application in craniofacial bone tissue engineering. © 2016 Wiley Periodicals, Inc.

Guided Bone Regeneration Using Collagen Scaffolds, Growth Factors, and Periodontal Ligament Stem Cells for Treatment of Peri-Implant Bone Defects In Vivo

PubMed Central

Scholz, Malte; Baudisch, Maria; Liese, Jan; Frerich, Bernhard; Lang, Hermann

2017-01-01

Introduction The aim of the study was an evaluation of different approaches for guided bone regeneration (GBR) of peri-implant defects in an in vivo animal model. Materials and Methods In minipigs (n = 15), peri-implant defects around calcium phosphate- (CaP-; n = 46) coated implants were created and randomly filled with (1) blank, (2) collagen/hydroxylapatite/β-tricalcium phosphate scaffold (CHT), (3) CHT + growth factor cocktail (GFC), (4) jellyfish collagen matrix, (5) jellyfish collagen matrix + GFC, (6) collagen powder, and (7) collagen powder + periodontal ligament stem cells (PDLSC). Additional collagen membranes were used for coverage of the defects. After 120 days of healing, bone growth was evaluated histologically (bone to implant contact (BIC;%)), vertical bone apposition (VBA; mm), and new bone height (NBH; %). Results In all groups, new bone formation was seen. Though, when compared to the blank group, no significant differences were detected for all parameters. BIC and NBH in the group with collagen matrix as well as the group with the collagen matrix + GFC were significantly less when compared to the collagen powder group (all: p < 0.003). Conclusion GBR procedures, in combination with CaP-coated implants, will lead to an enhancement of peri-implant bone growth. There was no additional significant enhancement of osseous regeneration when using GFC or PDLSC. PMID:28951742

Guided Bone Regeneration Using Collagen Scaffolds, Growth Factors, and Periodontal Ligament Stem Cells for Treatment of Peri-Implant Bone Defects In Vivo.

PubMed

Kämmerer, Peer W; Scholz, Malte; Baudisch, Maria; Liese, Jan; Wegner, Katharina; Frerich, Bernhard; Lang, Hermann

2017-01-01

The aim of the study was an evaluation of different approaches for guided bone regeneration (GBR) of peri-implant defects in an in vivo animal model. In minipigs ( n = 15), peri-implant defects around calcium phosphate- (CaP-; n = 46) coated implants were created and randomly filled with (1) blank, (2) collagen/hydroxylapatite/ β -tricalcium phosphate scaffold (CHT), (3) CHT + growth factor cocktail (GFC), (4) jellyfish collagen matrix, (5) jellyfish collagen matrix + GFC, (6) collagen powder, and (7) collagen powder + periodontal ligament stem cells (PDLSC). Additional collagen membranes were used for coverage of the defects. After 120 days of healing, bone growth was evaluated histologically (bone to implant contact (BIC;%)), vertical bone apposition (VBA; mm), and new bone height (NBH; %). In all groups, new bone formation was seen. Though, when compared to the blank group, no significant differences were detected for all parameters. BIC and NBH in the group with collagen matrix as well as the group with the collagen matrix + GFC were significantly less when compared to the collagen powder group (all: p < 0.003). GBR procedures, in combination with CaP-coated implants, will lead to an enhancement of peri-implant bone growth. There was no additional significant enhancement of osseous regeneration when using GFC or PDLSC.

Bone marrow adipocytes promote tumor growth in bone via FABP4-dependent mechanisms.

PubMed

Herroon, Mackenzie K; Rajagurubandara, Erandi; Hardaway, Aimalie L; Powell, Katelyn; Turchick, Audrey; Feldmann, Daniel; Podgorski, Izabela

2013-11-01

Incidence of skeletal metastases and death from prostate cancer greatly increases with age and obesity, conditions which increase marrow adiposity. Bone marrow adipocytes are metabolically active components of bone metastatic niche that modulate the function of neighboring cells; yet the mechanisms of their involvement in tumor behavior in bone have not been explored. In this study, using experimental models of intraosseous tumor growth and diet-induced obesity, we demonstrate the promoting effects of marrow fat on growth and progression of skeletal prostate tumors. We reveal that exposure to lipids supplied by marrow adipocytes induces expression of lipid chaperone FABP4, pro-inflammatory interleukin IL-1β, and oxidative stress protein HMOX-1 in metastatic tumor cells and stimulates their growth and invasiveness. We show that FABP4 is highly overexpressed in prostate skeletal tumors from obese mice and in bone metastasis samples from prostate cancer patients. In addition, we provide results suggestive of bi-directional interaction between FABP4 and PPARγ pathways that may be driving aggressive tumor cell behavior in bone. Together, our data provide evidence for functional relationship between bone marrow adiposity and metastatic prostate cancers and unravel the FABP4/IL-1β axis as a potential therapeutic target for this presently incurable disease.

Bone marrow adipocytes promote tumor growth in bone via FABP4-dependent mechanisms

PubMed Central

Herroon, Mackenzie K.; Rajagurubandara, Erandi; Hardaway, Aimalie L.; Powell, Katelyn; Turchick, Audrey; Feldmann, Daniel; Podgorski, Izabela

2013-01-01

Incidence of skeletal metastases and death from prostate cancer greatly increases with age and obesity, conditions which increase marrow adiposity. Bone marrow adipocytes are metabolically active components of bone metastatic niche that modulate the function of neighboring cells; yet the mechanisms of their involvement in tumor behavior in bone have not been explored. In this study, using experimental models of intraosseous tumor growth and diet-induced obesity, we demonstrate the promoting effects of marrow fat on growth and progression of skeletal prostate tumors. We reveal that exposure to lipids supplied by marrow adipocytes induces expression of lipid chaperone FABP4, pro-inflammatory interleukin IL-1β, and oxidative stress protein HMOX-1 in metastatic tumor cells and stimulates their growth and invasiveness. We show that FABP4 is highly overexpressed in prostate skeletal tumors from obese mice and in bone metastasis samples from prostate cancer patients. In addition, we provide results suggestive of bi-directional interaction between FABP4 and PPARγ pathways that may be driving aggressive tumor cell behavior in bone. Together, our data provide evidence for functional relationship between bone marrow adiposity and metastatic prostate cancers and unravel the FABP4/IL-1β axis as a potential therapeutic target for this presently incurable disease. PMID:24240026

Cholesteryl group- and acryloyl group-bearing pullulan nanogel to deliver BMP2 and FGF18 for bone tissue engineering.

PubMed

Fujioka-Kobayashi, Masako; Ota, Masato S; Shimoda, Asako; Nakahama, Ken-ichi; Akiyoshi, Kazunari; Miyamoto, Youji; Iseki, Sachiko

2012-10-01

To create a drug delivery system that allows the controlled release of proteins, such as growth factors, over a long-term period, cholesteryl group- and acryloyl group-bearing pullulan (CHPOA) nanogels were aggregated to form fast-degradable hydrogels (CHPOA/hydrogels) by cross-linking with thiol-bearing polyethylene glycol. The gold standard of clinical bone reconstruction therapy with a physiologically active material is treatment with recombinant human bone morphogenetic protein 2 (BMP2); however, this approach has limitations, such as inflammation, poor cost-efficiency, and varying interindividual susceptibility. In this study, two distinct growth factors, BMP2 and recombinant human fibroblast growth factor 18 (FGF18), were applied to a critical-size skull bone defect for bone repair by the CHPOA/hydrogel system. The CHPOA-FGF18/hydrogel displayed identical results to the control CHPOA-PBS/hydrogel, and the CHPOA-BMP2/hydrogel treatment imperfectly induced bone repair. By contrast, the CHPOA-FGF18 + BMP2/hydrogel treatment strongly enhanced and stabilized the BMP2-dependent bone repair, inducing osteoprogenitor cell infiltration inside and around the hydrogel. This report indicates that the CHPOA/hydrogel system can successfully deliver two different proteins to the bone defect to induce effective bone repair. The combination of the CHPOA/hydrogel system with the growth factors FGF18 and BMP2 might be a step towards efficient bone tissue engineering. Copyright © 2012 Elsevier Ltd. All rights reserved.

The cell biology of bone growth.

PubMed

Price, J S; Oyajobi, B O; Russell, R G

1994-02-01

The field of bone cell biology is clearly of relevance to the problem of stunting in children, as in the final analysis the cells of the growing long bone are the ultimate 'regulators'. It is the alterations in the functions of these cells that manifests as a reduction in height. Normal longitudinal growth is achieved by the coordinated recruitment, proliferation, differentiation, maturation and eventual death of the cells of growth plate and bone. Cellular activity is closely regulated by endocrine factors acting directly or indirectly, with factors produced locally and stored within the bone and cartilage microenvironment having a critical role in intercellular communication. Disruption of any of these processes can lead to growth disturbances, since it only requires a defect in a single gene to have profound effects. Studies in recent years have shed light on the biochemical and molecular effects of cytokines and growth factors and have shown that these regulatory molecules may mediate the effects of certain hormones important in controlling growth. However, the complex interrelationship of these molecules is still not clear. Notwithstanding, understanding of the mechanisms involved in bone remodelling is increasing, as this area attracts much research because of the high incidence of metabolic bone disease in Western society. Although studies of adult bone remodelling are of relevance, there is a requirement for increased research directed specifically at the mechanisms of endochondral ossification and its regulation. Longitudinal bone growth is a challenge to the cell biologist, since it is an accelerated cycle of cellular division and differentiation, within which it is not easy to separate events temporally and spatially. In addition, different regulatory mechanisms are probably important at different stages of growth. Another difficulty impeding progress in this field is the lack of appropriate animal models for research. Much information has come from studies involving rodents, and species differences must always be taken into account. Larger mammals such as the growing piglet or the calf are probably more appropriate for the study of postnatal longitudinal growth in man. If the mechanisms of stunting are to be established at a cellular level, a number of approaches need to be considered. Studies need to be designed using more appropriate animal models, and conditions such as nutritional intake, immunological challenges, chronic intestinal diseases and mechanical loading need to be manipulated. Any effects on longitudinal growth may then be studied temporally and correlated with non-invasive measurements including assays of hormones, cytokines, growth factors and proteins known to regulate their activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of extracellular matrix proteins on macrophage differentiation, growth, and function: comparison of liquid and agar culture systems

NASA Technical Reports Server (NTRS)

Armstrong, J. W.; Chapes, S. K.; Spooner, B. S. (Principal Investigator)

1994-01-01

Both spaceflight and skeletal unloading suppress the haematopoietic differentiation of macrophages (Sonnenfeld et al., Aviat. Space Environ. Med., 61:648-653, 1990; Armstrong et al., J. Appl. Physiol., 75:2734-2739, 1993). The mechanism behind this reduction in haematopoiesis has yet to be elucidated. However, changes in bone marrow extracellular matrix (ECM) may be involved. To further understand the role of ECM products in macrophage differentiation, we have performed experiments evaluating the effects of fibronectin, laminin, collagen type I, and collagen type IV on macrophage development and function. Bone marrow-derived macrophages cultured on four different ECM substrates in liquid culture medium showed less growth than those cultured on plastic. Significant morphological differences were seen on each of the substrates used. Phenotypically and functionally, as measured by class II major histocompatibility molecule (MHCII) expression, MAC-2 expression, and the secretion of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), these macrophages were similar. In contrast, bone marrow-derived macrophages cultured in suspension, using agar, showed no difference in growth when exposed to ECM proteins. However, IL-6 and TNF-alpha secretion was affected by fibronectin, laminin, collagen type I, and collagen type IV in a concentration-dependent manner. We conclude that the ECM products fibronectin, laminin, collagen type I, and collagen type IV have profound effects on macrophage development and function. Additionally, we suggest that an ECM-supplemented agar culture system provides an environment more analogous to in vivo bone marrow than does a traditional liquid culture system.

IGFBP-4 regulates adult skeletal growth in a sex-specific manner

PubMed Central

DeMambro, Victoria E; Le, Phuong T; Nagano, Kenichi; Baron, Roland; Mohan, Subburaman; Rosen, Clifford J

2017-01-01

Insulin-like growth factor-1 (IGF-1) and its binding proteins are critical mediators of skeletal growth. Insulin-like growth factor-binding protein 4 (IGFBP-4) is highly expressed in osteoblasts and inhibits IGF-1 actions in vitro. Yet, in vivo studies suggest that it could potentiate IGF-1 and IGF-2 actions. In this study, we hypothesized that IGFBP-4 might potentiate the actions of IGF-1 on the skeleton. To test this, we comprehensively studied 8- and 16-week-old Igfbp4−/− mice. Both male and female adult Igfbp4−/− mice had marked growth retardation with reductions in body weight, body and femur lengths, fat proportion and lean mass at 8 and 16 weeks. Marked reductions in aBMD and aBMC were observed in 16-week-old Igfbp4−/− females, but not in males. Femoral trabecular BV/TV and thickness, cortical fraction and thickness in 16-week-old Igfbp4−/− females were significantly reduced. However, surprisingly, males had significantly more trabeculae with higher connectivity density than controls. Concordantly, histomorphometry revealed higher bone resorption and lower bone formation in Igfbp4−/− females. In contrast, Igfbp4−/− males had lower mineralized surface/bone surface. Femoral expression of Sost and circulating levels of sclerostin were reduced but only in Igfbp4−/− males. Bone marrow stromal cultures from mutants showed increased osteogenesis, whereas osteoclastogenesis was markedly increased in cells from Igfbp4−/− females but decreased in males. In sum, our results indicate that loss of Igfbp4 affects mesenchymal stromal cell differentiation, regulates osteoclastogenesis and influences both skeletal development and adult bone maintenance. Thus, IGFBP-4 modulates the skeleton in a gender-specific manner, acting as both a cell autonomous and cell non-autonomous factor. PMID:28184001

Immobilization and Application of Electrospun Nanofiber Scaffold-based Growth Factor in Bone Tissue Engineering.

PubMed

Chen, Guobao; Lv, Yonggang

2015-01-01

Electrospun nanofibers have been extensively used in growth factor delivery and regenerative medicine due to many advantages including large surface area to volume ratio, high porosity, excellent loading capacity, ease of access and cost effectiveness. Their relatively large surface area is helpful for cell adhesion and growth factor loading, while storage and release of growth factor are essential to guide cellular behaviors and tissue formation and organization. In bone tissue engineering, growth factors are expected to transmit signals that stimulate cellular proliferation, migration, differentiation, metabolism, apoptosis and extracellular matrix (ECM) deposition. Bolus administration is not always an effective method for the delivery of growth factors because of their rapid diffusion from the target site and quick deactivation. Therefore, the integration of controlled release strategy within electrospun nanofibers can provide protection for growth factors against in vivo degradation, and can manipulate desired signal at an effective level with extended duration in local microenvironment to support tissue regeneration and repair which normally takes a much longer time. In this review, we provide an overview of growth factor delivery using biomimetic electrospun nanofiber scaffolds in bone tissue engineering. It begins with a brief introduction of different kinds of polymers that were used in electrospinning and their applications in bone tissue engineering. The review further focuses on the nanofiber-based growth factor delivery and summarizes the strategies of growth factors loading on the nanofiber scaffolds for bone tissue engineering applications. The perspectives on future challenges in this area are also pointed out.

Growth patterns and life-history strategies in Placodontia (Diapsida: Sauropterygia)

PubMed Central

Klein, Nicole; Neenan, James M.; Scheyer, Torsten M.; Griebeler, Eva Maria

2015-01-01

Placodontia is a clade of durophagous, near shore marine reptiles from Triassic sediments of modern-day Europe, Middle East and China. Although much is known about their primary anatomy and palaeoecology, relatively little has been published regarding their life history, i.e. ageing, maturation and growth. Here, growth records derived from long bone histological data of placodont individuals are described and modelled to assess placodont growth and life-history strategies. Growth modelling methods are used to confirm traits documented in the growth record (age at onset of sexual maturity, age when asymptotic length was achieved, age at death, maximum longevity) and also to estimate undocumented traits. Based on these growth models, generalized estimates of these traits are established for each taxon. Overall differences in bone tissue types and resulting growth curves indicate different growth patterns and life-history strategies between different taxa of Placodontia. Psephoderma and Paraplacodus grew with lamellar-zonal bone tissue type and show growth patterns as seen in modern reptiles. Placodontia indet. aff. Cyamodus and some Placodontia indet. show a unique combination of fibrolamellar bone tissue regularly stratified by growth marks, a pattern absent in modern sauropsids. The bone tissue type of Placodontia indet. aff. Cyamodus and Placodontia indet. indicates a significantly increased basal metabolic rate when compared with modern reptiles. Double lines of arrested growth, non-annual rest lines in annuli, and subcycles that stratify zones suggest high dependence of placodont growth on endogenous and exogenous factors. Histological and modelled differences within taxa point to high individual developmental plasticity but sexual dimorphism in growth patterns and the presence of different taxa in the sample cannot be ruled out. PMID:26587259

Collagenase and tissue plasminogen activator production in developing rat calvariae: normal progression despite fetal exposure to microgravity

NASA Technical Reports Server (NTRS)

Davis, B. A.; Sipe, B.; Gershan, L. A.; Fiacco, G. J.; Lorenz, T. C.; Jeffrey, J. J.; Partridge, N. C.

1998-01-01

Exposure to zero gravity has been shown to cause a decrease in bone formation. This implicates osteoblasts as the gravity-sensing cell in bone. Osteoblasts also are known to produce neutral proteinases, including collagenase and tissue plasminogen activator (tPA), which are thought to be important in bone development and remodeling. The present study investigated the effects of zero gravity on development of calvariae and their expression of collagenase and tPA. After in utero exposure to zero gravity for 9 days on the NASA STS-70 space shuttle mission, the calvariae of rat pups were examined by immunohistochemistry for the presence and location of these two proteinases. The ages of the pups were from gestational day 20 (G20) to postnatal (PN) day 35. Both collagenase and tPA were found to be present at all ages examined, with the greatest amount of both proteinases present in the PN14 rats. At later ages, high amounts were maintained for tPA but collagenase decreased substantially between ages PN21 to PN35. The location of collagenase was found to be associated with bone-lining cells, osteoblasts, osteocytes, and in the matrix along cement lines. In contrast, tPA was associated with endothelial cells lining the blood vessels entering bone. The presence and developmental expression of these two proteinases appeared to be unaffected by the exposure to zero gravity. The calvarial thickness of the pups was also examined; again the exposure to zero gravity showed little to no effect on the growth of the calvariae. Notably, from G20 to PN14, calvarial thickness increased dramatically, reaching a plateau after this age. It was apparent that elevated collagenase expression correlated with rapid bone growth in the period from G20 to PN14. To conclude, collagenase and tPA are present during the development of rat calvariae. Despite being produced by the same cell in vitro, i.e., the osteoblast, they are located in distinctly different places in bone in vivo. Their presence, developmental expression, and quantity do not seem to be affected by a brief exposure to zero gravity in utero.

Follow-up of bone lesions in an experimental multiple myeloma mouse model: description of an in vivo technique using radiography dedicated for mammography.

PubMed Central

Vanderkerken, K.; Goes, E.; De Raeve, H.; Radl, J.; Van Camp, B.

1996-01-01

The evolution of bone lesions in transplantable C57BL/KaLwRjj 5T mouse myeloma (MM) has been followed in vivo. Mice were anaesthetised and a radiograph of the pelvis and hind legs was performed by a radiograph dedicated for mammography. This is the first description of an in vivo technique under experimental conditions whereby the development of bone lesions owing to the MM growth was demonstrated. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 6 PMID:8664113

A novel osteogenic oxysterol compound for therapeutic development to promote bone growth: activation of hedgehog signaling and osteogenesis through smoothened binding.

PubMed

Montgomery, Scott R; Nargizyan, Taya; Meliton, Vicente; Nachtergaele, Sigrid; Rohatgi, Rajat; Stappenbeck, Frank; Jung, Michael E; Johnson, Jared S; Aghdasi, Bayan; Tian, Haijun; Weintraub, Gil; Inoue, Hirokazu; Atti, Elisa; Tetradis, Sotirios; Pereira, Renata C; Hokugo, Akishige; Alobaidaan, Raed; Tan, Yanlin; Hahn, Theodor J; Wang, Jeffrey C; Parhami, Farhad

2014-08-01

Osteogenic factors are often used in orthopedics to promote bone growth, improve fracture healing, and induce spine fusion. Osteogenic oxysterols are naturally occurring molecules that were shown to induce osteogenic differentiation in vitro and promote spine fusion in vivo. The purpose of this study was to identify an osteogenic oxysterol more suitable for clinical development than those previously reported, and evaluate its ability to promote osteogenesis in vitro and spine fusion in rats in vivo. Among more than 100 oxysterol analogues synthesized, Oxy133 induced significant expression of osteogenic markers Runx2, osterix (OSX), alkaline phosphatase (ALP), bone sialoprotein (BSP), and osteocalcin (OCN) in C3H10T1/2 mouse embryonic fibroblasts and in M2-10B4 mouse marrow stromal cells. Oxy133-induced activation of an 8X-Gli luciferase reporter, its direct binding to Smoothened, and the inhibition of Oxy133-induced osteogenic effects by the Hedgehog (Hh) pathway inhibitor, cyclopamine, demonstrated the role of Hh pathway in mediating osteogenic responses to Oxy133. Oxy133 did not stimulate osteogenesis via BMP or Wnt signaling. Oxy133 induced the expression of OSX, BSP, and OCN, and stimulated robust mineralization in primary human mesenchymal stem cells. In vivo, bilateral spine fusion occurred through endochondral ossification and was observed in animals treated with Oxy133 at the fusion site on X-ray after 4 weeks and confirmed with manual assessment, micro-CT (µCT), and histology after 8 weeks, with equal efficiency to recombinant human bone morphogenetic protein-2 (rhBMP-2). Unlike rhBMP-2, Oxy133 did not induce adipogenesis in the fusion mass and resulted in denser bone evidenced by greater bone volume/tissue volume (BV/TV) ratio and smaller trabecular separation. Findings here suggest that Oxy133 has significant potential as an osteogenic molecule with greater ease of synthesis and improved time to fusion compared to previously studied oxysterols. Small molecule osteogenic oxysterols may serve as the next generation of bone anabolic agents for therapeutic development. © 2014 American Society for Bone and Mineral Research.

Effects of sex steroids on bones and muscles: similarities, parallels, and putative interactions in health and disease

PubMed Central

Carson, James A.; Manolagas, Stavros C.

2015-01-01

Estrogens and androgens influence the growth and maintenance of bones and muscles and are responsible for their sexual dimorphism. A decline in their circulating levels leads to loss of mass and functional integrity in both tissues. In the article, we highlight the similarities of the molecular and cellular mechanisms of action of sex steroids in the two tissues; the commonality of a critical role of mechanical forces on tissue mass and function; emerging evidence for an interplay between mechanical forces and hormonal and growth factor signals in both bones and muscles; as well as the current state of evidence for or against a cross-talk between muscles and bone. In addition, we review evidence for the parallels in the development of osteoporosis and sarcopenia with advancing age and the potential common mechanisms responsible for the age-dependent involution of these two tissues. Lastly, we discuss the striking difference in the availability of several drug therapies for the prevention and treatment of osteoporosis, as compared to none for sarcopenia. PMID:26453497

[Role of growth hormone underproduction and support load deficit in development of muscle atrophy and osteopenia in tail-suspended rats].

PubMed

Kaplanskiĭ, A S; Durnova, G N; Ili'ina-Kakueva, E I; Loginov, V I

1999-01-01

In a 20-day experiment with tail-suspended male rats histological and histomorphometric techniques were used to study the effects of growth hormone, thyroxin, and graded support loads on the progress of atrophy in soleus and gastrocnemius m.m., tibial metaphyses spongiosis, and growth of tibiae. Daily injections of growth hormone at a dose of 0.5 mg/kg of the body mass were found to restore the longitudinal growth of tibiae and to suppress osteopenia in the spongiosis of metaphyses; however, they did not have any noteworthy effect on the muscular atrophy in the suspended rats. Support loading of the hind limbs for 2 hours a day in parallel to the treatment with growth hormone and thyroxin (0.02 mg/kg of the body mass per a day) suppressed the atrophy in soleus m. but not in gastrocnemius m. They were not able to oppose to osteoporosis in tibial metaphyses spongiosis; tibial growth was not normalized. Thyroxin did not appear to markedly influence muscle and bone atrophies; moreover, it made hypofunctioning of the thyroid more intense and, when combined with the growth hormone, masked the positive effect of the latter on the rats' bones.

Effects of growth hormone and low dose estrogen on bone growth and turnover in long bones of hypophysectomized rats

NASA Technical Reports Server (NTRS)

Kidder, L. S.; Schmidt, I. U.; Evans, G. L.; Turner, R. T.

1997-01-01

Pituitary hormones are recognized as critical to longitudinal growth, but their role in the radial growth of bone and in maintaining cancellous bone balance are less clear. This investigation examines the histomorphometric effects of hypophysectomy (Hx) and ovariectomy (OVX) and the subsequent replacement of growth hormone (GH) and estrogen (E), in order to determine the effects and possible interactions between these two hormones on cortical and cancellous bone growth and turnover. The replacement of estrogen is of interest since Hx results in both pituitary and gonadal hormone insufficiencies, with the latter being caused by the Hx-associated reduction in follicle stimulating hormone (FSH). All hypophysectomized animals received daily supplements of hydrocortisone (500 microg/kg) and L-thyroxine (10 microg/kg), whereas intact animals received daily saline injections. One week following surgery, hypophysectomized animals received either daily injections of low-dose 17 beta-estradiol (4.8 microg/kg s.c.), 3 X/d recombinant human GH (2 U/kg s.c.), both, or saline for a period of two weeks. Flurochromes were administered at weekly intervals to label bone matrix undergoing mineralization. Whereas Hx resulted in reductions in body weight, uterine weight, and tibial length, OVX significantly increased body weight and tibial length, while reducing uterine weight. The combination of OVX and Hx resulted in values similar to Hx alone. Treatment with GH normalized body weight and bone length, while not affecting uterine weight in hypophysectomized animals. Estrogen increased uterine weight, while not impacting longitudinal bone growth and reduced body weight. Hypophysectomy diminished tibial cortical bone area through reductions in both mineral appositional rate (MAR) and bone formation rate (BFR). While E had no effect, GH increased both MAR and BFR, though not to sham-operated (control) levels. Hypophysectomy reduced proximal tibial trabecular number and cancellous bone area, and increased trabecular separation. Both GH and E reduced cancellous osteopenia, although employing different mechanisms. GH reduced the decrease in trabecular thickness, whereas E reduced the decrease in trabecular number and the increase in trabecular separation. Hypophysectomy reduced both Tb.MAR and Tb.BFR while treatment with GH enhanced them. This investigation has shown that Hx and GH have a dramatic impact on selected static and dynamic indices of rat cortical and cancellous histomorphometry. Furthermore, the mechanisms of action of GH and E differ, and suggest that some of the skeletal changes associated with Hx are caused by deficiencies in estrogen as well as deficiencies in growth hormone.

Role of TGF-β in breast cancer bone metastases

PubMed Central

Chiechi, Antonella; Waning, David L.; Stayrook, Keith R.; Buijs, Jeroen T.; Guise, Theresa A.; Mohammad, Khalid S.

2014-01-01

Breast cancer is the most prevalent cancer among females worldwide leading to approximately 350,000 deaths each year. It has long been known that cancers preferentially metastasize to particular organs, and bone metastases occur in ~70% of patients with advanced breast cancer. Breast cancer bone metastases are predominantly osteolytic and accompanied by increased fracture risk, pain, nerve compression and hypercalcemia, causing severe morbidity. In the bone matrix, transforming growth factor-β (TGF-β) is one of the most abundant growth factors, which is released in active form upon tumor-induced osteoclastic bone resorption. TGF-β, in turn, stimulates bone metastatic tumor cells to secrete factors that further drive osteolytic bone destruction adjacent to the tumor. Thus, TGF-β is a crucial factor responsible for driving the feed-forward vicious cycle of cancer growth in bone. Moreover, TGF-β activates epithelial-to-mesenchymal transition, increases tumor cell invasiveness and angiogenesis and induces immunosuppression. Blocking the TGF-β signaling pathway to interrupt this vicious cycle between breast cancer and bone offers a promising target for therapeutic intervention to decrease skeletal metastasis. This review will describe the role of TGF-β in breast cancer and bone metastasis, and pre-clinical and clinical data will be evaluated for the potential use of TGF-β inhibitors in clinical practice to treat breast cancer bone metastases. PMID:24558636

Bone growth and turnover in progesterone receptor knockout mice.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rickard, David J.; Iwaniec, Urszula T.; Evans, Glenda

2008-05-01

The role of progesterone receptor (PR) signaling in skeletal metabolism is controversial. To address whether signaling through the PR is necessary for normal bone growth and turnover, we performed histomorphometric and mCT analyses of bone from homozygous female PR knockout (PRKO) mice at 6, 12, and 26 weeks of age. These mice possess a null mutation of the PR locus, which blocks the gene expression of A and B isoforms of PR. Body weight gain, uterine weight gain and tibia longitudinal bone growth was normal in PRKO mice. In contrast, total and cortical bone mass were increased in long bonesmore » of post-pubertal (12 and 26-week-old) PRKO mice, whereas cancellous bone mass was normal in the tibia but increased in the humerus. The striking 57% decrease in cancellous bone from the proximal tibia metaphysis which occurred between 6 and 26 weeks in WT mice was abolished in PRKO mice. The improved bone balance in aging PRKO mice was associated with elevated bone formation and a tendency toward reduced osteoclast perimeter. Taken together, these findings suggest that PR signaling in mice attenuates the accumulation of cortical bone mass during adolescence and is required for early age-related loss of cancellous bone.« less

Genetically engineered flavonol enriched tomato fruit modulates chondrogenesis to increase bone length in growing animals.

PubMed

Choudhary, Dharmendra; Pandey, Ashutosh; Adhikary, Sulekha; Ahmad, Naseer; Bhatia, Chitra; Bhambhani, Sweta; Trivedi, Prabodh Kumar; Trivedi, Ritu

2016-02-26

Externally visible body and longitudinal bone growth is a result of proliferation of chondrocytes. In growth disorder, there is delay in the age associated increase in height. The present study evaluates the effect of extract from transgenic tomato fruit expressing AtMYB12 transcription factor on bone health including longitudinal growth. Constitutive expression of AtMYB12 in tomato led to a significantly enhanced biosynthesis of flavonoids in general and the flavonol biosynthesis in particular. Pre-pubertal ovary intact BALB/c mice received daily oral administration of vehicle and ethanolic extract of wild type (WT-TOM) and transgenic AtMYB12-tomato (MYB12-TOM) fruits for six weeks. Animal fed with MYB12-TOM showed no inflammation in hepatic tissues and normal sinusoidal Kupffer cell morphology. MYB12-TOM extract significantly increased tibial and femoral growth and subsequently improved the bone length as compared to vehicle and WT-TOM. Histomorphometry exhibited significantly wider distal femoral and proximal tibial growth plate, increased number and size of hypertrophic chondrocytes in MYB12-TOM which corroborated with micro-CT and expression of BMP-2 and COL-10, marker genes for hypertrophic cells. We conclude that metabolic reprogramming of tomato by AtMYB12 has the potential to improve longitudinal bone growth thus helping in achievement of greater peak bone mass during adolescence.

The relation of microdamage to fracture and material property degradation in human cortical bone tissue

NASA Astrophysics Data System (ADS)

Akkus, Ozan

This dissertation investigates the relation of microdamage to fracture and material property degradation of human cortical bone tissue. Fracture resistance and fatigue crack growth of microcracks were examined experimentally and material property degradation was examined through theoretical modeling. To investigate the contribution of microdamage to static fracture resistance, fracture toughness tests were conducted in the transverse and longitudinal directions to the osteonal orientation of normal bone tissue. Damage accumulation was monitored by acoustic emission during testing and was spatially observed by histological observation following testing. The results suggested that the propagation of the main crack involved weakening of the tissue by diffuse damage at the fracture plane and by formation of linear microcracks away from the fracture plane for the transverse specimens. For the longitudinal specimens, growth of the main crack occurred in the form of separations at lamellar interfaces. Acoustic emission results supported the histological observations. To investigate the contribution of ultrastructure to static fracture resistance, fracture toughness tests were conducted after altering the collagen phase of the bone tissue by gamma radiation. A significant decrease in the fracture toughness, Work-to-Fracture and the amount damage was observed due to irradiation in both crack growth directions. For cortical bone irradiated at 27.5kGy, fracture toughness is reduced due to the inhibition of damage formation at and near the crack tip. Microcrack fatigue crack growth and arrest were investigated through observations of surface cracks during cyclic loading. At the applied cyclic stresses, the microcracks propagated and arrested in less than 10,000 cycles. In addition, the microcracks were observed not to grow beyond a length of 150mum and a DeltaK of 0.5MNm-3/2, supporting a microstructural barrier concept. Finally, the contribution of linear microcracks to material property degradation was examined by developing a theoretical micromechanical damage model. The model was compared to experimentally induced damage in bone tissue. The percent contribution of linear microcracks to the total degradation was predicted to be less than 5%, indicating that diffuse damage or an unidentified form of damage is primarily responsible for material property degradation in human cortical bone tissue.

Biomechanical properties of the mandible, as assessed by bending test, in rats fed a low-quality protein.

PubMed

Bozzini, Carlos E; Champin, Graciela M; Alippi, Rosa M; Bozzini, Clarisa

2013-04-01

The present study describes the effects of feeding growing rats with diets containing increasing concentrations of wheat gluten (a low quality protein, G) on both the morphometrical and the biomechanical properties of the mandible. Female rats were fed one of six diets containing different concentrations (5-30%) of G between the 30th and 90th days of life. Control rats were fed a diet containing 20% casein (C), which allows a normal growth and development of the bone. Mandibular growth was estimated directly on excised and cleaned bones by taking measurements between anatomical points. Mechanical properties of the right hemimandibles were determined by using a three-point bending mechanical test to obtain a load/deformation curve and estimate the structural properties of the bone. Bone material properties were calculated from structural and geometric properties. The left hemimandibles were ashed and the ash weight obtained. Calcium content was determined by atomic energy absorption. Results were summarised as means±SEM. Comparisons between parameters were performed by ANOVA and post-test. None of the G-fed groups could achieve a normal growth performance as compared to the C-fed control group. Like body size, age-related increments in mandibular weight, length, height and area (index of mandibular size) were negatively affected by the G diets, as was the posterior part of the bone (posterior to molar III). The cross-sectional geometry of the mandible (cross-sectional area and rectangular moment of inertia) as well as its structural properties (yielding load, fracture load, and stiffness) were also severely affected by the G diets. However, material properties (Young's modulus and maximum elastic stress) and calcium concentration in ashes and the degree of mineralisation were unaffected. The differences in strength and stiffness between treated and control rats seemed to be the result of an induced loss of gain in bone growth and mass, in the absence of changes in the quality of the bone mineralised material. Copyright © 2012 Elsevier Ltd. All rights reserved.

Analysis of the effects of growth hormone, exercise and food restriction on cancellous bone in different bone sites in middle-aged female rats.

PubMed

Banu, J; Orhii, P B; Okafor, M C; Wang, L; Kalu, D N

2001-06-01

The aim of this study is to determine the effects of growth hormone (GH), exercise (EX), GH+EX and food restriction on cancellous bone in middle-aged female rats. Female F344 rats aged 13 months were divided into (1) age-matched controls; (2) GH treated (2.5 mg/kg. 5 day/week); (3) EX (voluntary wheel running); (4) GH+EX; and (5) food restricted (FR) (fed 60% of the ad libitum food intake). The animals were treated for 18 weeks, at the end of which they were sacrificed. Cancellous bone and cortical bone in the fourth lumbar vertebra, proximal tibial metaphysis (PTM), distal femoral metaphysis (DFM) and femoral neck (NF) were analyzed using peripheral quantitative computerized tomography (pQCT) densitometry. Growth hormone increased cancellous bone area, cancellous bone mineral content, cortical bone area and cortical bone mineral content in the vertebra, PTM, DFM and NF. The tibial muscle wet weight was increased significantly after GH treatment. Exercise increased the cancellous bone area in the vertebra, PTM and DFM. Cortical bone area and cortical bone mineral content increased after EX in the vertebra, PTM, DFM and NF. No significant change was seen in the tibial muscle wet weight after EX. Growth hormone+EX increased cancellous bone area in the vertebra PTM and DFM but had no effect in neck of the femur. Cancellous bone mineral content, cortical bone area and cortical bone mineral content increased with GH+EX in the vertebra, PTM, DFM and NF. The tibial muscle wet weight was increased significantly with GH+EX. Food restriction decreased cancellous bone area and cancellous bone mineral content in all the bones studied. The decrease was statistically significant only at the distal femoral metaphysis. The tibial muscle wet weight decreased when compared with the age-matched control, but this decrease was not statistically significant. We conclude that the effect of the dose of GH used and the levels of voluntary wheel running EX used increased cancellous bone in intact rats; the effect of GH is much greater and different bones respond with varying intensities. The effects of combined treatment of GH and EX on cancellous bone are not always significantly higher than those of GH alone. FR at the level studied has a mostly negative effect on cancellous bone.

Value of Osteoblast-Derived Exosomes in Bone Diseases.

PubMed

Ge, Min; Wu, Yingzhi; Ke, Ronghu; Cai, Tianyi; Yang, Junyi; Mu, Xiongzheng

2017-06-01

The authors' purpose is to reveal the value of osteoblast-derived exosomes in bone diseases. Microvesicles from supernatants of mouse Mc3t3 were isolated by ultracentrifugation and then the authors presented the protein profile by proteomics analysis. The authors detected a total number of 1536 proteins by mass spectrometry and found 172 proteins overlap with bone database. The Ingenuity Pathway Analysis shows network of "Skeletal and Muscular System Development and Function, Developmental Disorder, Hereditary Disorder" and pathway about osteogenesis. EFNB1 and transforming growth factor beta receptor 3 in the network, LRP6, bone morphogenetic protein receptor type-1, and SMURF1 in the pathway seemed to be valuable in the exosome research of related bone disease. The authors' study unveiled the content of osteoblast-derived exosome and discussed valuable protein in it which might provide novel prospective in bone diseases research.

Osteogenic Activity of Locally Applied Small Molecule Drugs in a Rat Femur Defect Model

PubMed Central

Cottrell, Jessica A.; Vales, Francis M.; Schachter, Deborah; Wadsworth, Scott; Gundlapalli, Rama; Kapadia, Rasesh; O'Connor, J. Patrick

2010-01-01

The long-term success of arthroplastic joints is dependent on the stabilization of the implant within the skeletal site. Movement of the arthroplastic implant within the bone can stimulate osteolysis, and therefore methods which promote rigid fixation or bone growth are expected to enhance implant stability and the long-term success of joint arthroplasty. In the present study, we used a simple bilateral bone defect model to analyze the osteogenic activity of three small-molecule drug implants via microcomputerized tomography (micro-CT) and histomorphometry. In this study, we show that local delivery of alendronate, but not lovastatin or omeprazole, led to significant new bone formation at the defect site. Since alendronate impedes osteoclast-development, it is theorized that alendronate treatment results in a net increase in bone formation by preventing osteoclast mediated remodeling of the newly formed bone and upregulating osteoblasts. PMID:20625499

Neutral endopeptidase-resistant C-type natriuretic peptide variant represents a new therapeutic approach for treatment of fibroblast growth factor receptor 3-related dwarfism.

PubMed

Wendt, Daniel J; Dvorak-Ewell, Melita; Bullens, Sherry; Lorget, Florence; Bell, Sean M; Peng, Jeff; Castillo, Sianna; Aoyagi-Scharber, Mika; O'Neill, Charles A; Krejci, Pavel; Wilcox, William R; Rimoin, David L; Bunting, Stuart

2015-04-01

Achondroplasia (ACH), the most common form of human dwarfism, is caused by an activating autosomal dominant mutation in the fibroblast growth factor receptor-3 gene. Genetic overexpression of C-type natriuretic peptide (CNP), a positive regulator of endochondral bone growth, prevents dwarfism in mouse models of ACH. However, administration of exogenous CNP is compromised by its rapid clearance in vivo through receptor-mediated and proteolytic pathways. Using in vitro approaches, we developed modified variants of human CNP, resistant to proteolytic degradation by neutral endopeptidase, that retain the ability to stimulate signaling downstream of the CNP receptor, natriuretic peptide receptor B. The variants tested in vivo demonstrated significantly longer serum half-lives than native CNP. Subcutaneous administration of one of these CNP variants (BMN 111) resulted in correction of the dwarfism phenotype in a mouse model of ACH and overgrowth of the axial and appendicular skeletons in wild-type mice without observable changes in trabecular and cortical bone architecture. Moreover, significant growth plate widening that translated into accelerated bone growth, at hemodynamically tolerable doses, was observed in juvenile cynomolgus monkeys that had received daily subcutaneous administrations of BMN 111. BMN 111 was well tolerated and represents a promising new approach for treatment of patients with ACH. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Rho GTPase protein Cdc42 is critical for postnatal cartilage development

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nagahama, Ryo; Department of Orthodontics, School of Dentistry, Showa University, Tokyo; Yamada, Atsushi, E-mail: yamadaa@dent.showa-u.ac.jp

2016-02-19

Cdc42, a small Rho GTPase family member, has been shown to regulate multiple cellular functions in vitro, including actin cytoskeletal reorganization, cell migration, proliferation, and gene expression. However, its tissue-specific roles in vivo remain largely unknown, especially in postnatal cartilage development, as cartilage-specific Cdc42 inactivated mice die within a few days after birth. In this study, we investigated the physiological functions of Cdc42 during cartilage development after birth using tamoxifen-induced cartilage-specific inactivated Cdc42 conditional knockout (Cdc42 {sup fl/fl}; Col2-CreERT) mice, which were generated by crossing Cdc42 flox mice (Cdc42 {sup fl/fl}) with tamoxifen-induced type II collagen (Col2) Cre transgenic mice using a Cre/loxP system.more » The gross morphology of the Cdc42 cKO mice was shorter limbs and body, as well as reduced body weight as compared with the controls. In addition, severe defects were found in growth plate chondrocytes of the long bones, characterized by a shorter proliferating zone (PZ), wider hypertrophic zone (HZ), and loss of columnar organization of proliferating chondrocytes, resulting in delayed endochondral bone formation associated with abnormal bone growth. Our findings demonstrate the importance of Cdc42 for cartilage development during both embryonic and postnatal stages. - Highlights: • Tamoxifen-induced cartilage specific inactivated Cdc42 mutant mice were generated. • Cdc42 mutant mice were shorter limbs and body. • Severe defects were found in growth plate chondrocytes.« less

A metabolite of leucine (β-hydroxy-β-methylbutyrate) given to sows during pregnancy alters bone development of their newborn offspring by hormonal modulation

PubMed Central

Blicharski, Tomasz; Dobrowolski, Piotr; Hułas-Stasiak, Monika; Muszyński, Siemowit

2017-01-01

The effects of dietary β-hydroxy-β-methylbutyrate (HMB) supplementation during gestation on bone, growth plate, and articular cartilage in newborns were determined. Thermal analysis of articular cartilage was performed to examine the structural changes in collagen. At day 70 of gestation, a total of 12 sows (Large White Polish breed, at the second parity) were randomly assigned to two groups, with each group receiving either a basal diet or the same diet supplemented with 0.2 g/day HMB until the 90th day. Maternal HMB supplementation enhanced body weight, bone length, and diameter in males. It also improved geometric and mechanical properties contributing to increased bone morphology and endurance. In turn, alteration of the length was only observed in females. The positive effects were mediated by increased serum concentrations of insulin-like growth factor-1 and leptin. HMB-treatment enhanced the concentration of FSH, LH, estradiol, and testosterone. Serum TAP was enhanced by the HMB-treatment by 34% in females and 138% in males. Beneficial effects of the HMB-treatment on trabecular bone and content of proteoglycans in articular cartilage were shown. The HMB-treatment significantly changed the collagen structure in cartilages, especially in the females, which was demonstrated by the PSR analysis. Differences between the HMB-supplemented and the control females in the calorimetric peak temperatures were presumably related to different collagen fibril density in the articular cartilage structure. In summary, maternal HMB supplementation in the mid-gestation period significantly improved general growth and mechanical endurance of long bones by the influence on the somatotropic and pituitary-gonadal axes in the offspring. PMID:28617846

Chemical modification of extracellular matrix by cold atmospheric plasma-generated reactive species affects chondrogenesis and bone formation

PubMed Central

Eisenhauer, Peter; Chernets, Natalie; Song, You; Dobrynin, Danil; Pleshko, Nancy; Steinbeck, Marla J.; Freeman, Theresa A.

2017-01-01

The goal of this study was to investigate whether cold plasma generated by dielectric barrier discharge (DBD) modifies extracellular matrices (ECM) to influence chondrogenesis and endochondral ossification. Replacement of cartilage by bone during endochondral ossification is essential in fetal skeletal development, bone growth and fracture healing. Regulation of this process by the ECM occurs through matrix remodelling, involving a variety of cell attachment molecules and growth factors, which influence cell morphology and protein expression. The commercially available ECM, Matrigel, was treated with microsecond or nanosecond pulsed (µsp or nsp, respectively) DBD frequencies conditions at the equivalent frequencies (1 kHz) or power (~1 W). Recombinant human bone morphogenetic protein-2 was added and the mixture subcutaneously injected into mice to simulate ectopic endochondral ossification. Two weeks later, the masses were extracted and analysed by microcomputed tomography. A significant increase in bone formation was observed in Matrigel treated with µsp DBD compared with control, while a significant decrease in bone formation was observed for both nsp treatments. Histological and immunohistochemical analysis showed Matrigel treated with µsp plasma increased the number of invading cells, the amount of vascular endothelial growth factor and chondrogenesis while the opposite was true for Matrigel treated with nsp plasma. In support of the in vivo Matrigel study, 10 T1/2 cells cultured in vitro on µsp DBD-treated type I collagen showed increased expression of adhesion proteins and activation of survival pathways, which decreased with nsp plasma treatments. These results indicate DBD modification of ECM can influence cellular behaviours to accelerate or inhibit chondrogenesis and endochondral ossification. PMID:27510797

Effect of Daily Exposure to an Isolated Soy Protein Supplement on Body Composition, Energy and Macronutrient Intake, Bone Formation Markers, and Lipid Profile in Children in Colombia.

PubMed

Mejía, Wilson; Córdoba, Diana; Durán, Paola; Chacón, Yersson; Rosselli, Diego

2018-01-16

A soy protein-based supplement may optimize bone health, support physical growth, and stimulate bone formation. This study aimed to assess the effect of a daily soy protein supplement (SPS) on nutritional status, bone formation markers, lipid profile, and daily energy and macronutrient intake in children. One hundred seven participants (62 girls), ages 2 to 9, started the study and were randomly assigned to lunch fruit juice with (n = 57, intervention group) or without (n = 50, control group) addition of 45 g (230 Kcal) of a commercial SPS during 12 months; 84 children (51 girls, 33 boys) completed the study (45 and 39 intervention and control, respectively). Nutritional assessment included anthropometry and nutrient intakes; initial and final blood samples were taken; insulin-like growth factor-I (IGF-I), osteocalcin, bone specific alkaline phosphatase (BAP), insulin-like growth factor binding protein-3 (IGFBP-3), cholesterol, triglycerides, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) were analyzed. Statistically significant changes (p < .05) in body mass index and weight for age Z scores were observed between groups while changes in body composition were not. Changes in energy, total protein, and carbohydrate intakes were significantly higher in the intervention group (p < .01). Calorie intake changes were statistically significant between groups (p < .001), and BAP decreased in both groups, with values within normal ranges. Osteocalcin, IGFBP-3, and lipid profile were not different between groups. IGF-I levels and IGF/IGFBP-3 ratio increased significantly in both groups. In conclusion, changes in macronutrient and energy intake and nutritional status in the intervention group compared to control group may ensure harmonious and adequate bone health and development.

Growth in bone and body size among Asian and white girls in the Female Adolescent Maturation (FAM) study.

PubMed

Novotny, Rachel; Davis, James

2015-01-01

This study intends to identify differences in growth of Asian and White girls. Asian girls gained bone at similar rates to White girls. Physical activity was important to bone growth. Ethnic differences remained after adjusting for physical activity, demographics, and diet. Physical activity can improve bone gain. The purpose of this study is to examine differences in body size and bone growth of Asian, White, and Asian-White Mixed girls. Three prospective examinations of 99 Asian, 73 White, and 63 Mixed Asian and White girls, with a mean age of 11.0 years at enrollment were performed. Calcaneal bone mass, skeletal breadths, and body fat were measured. Physical activity, diet, and birth size were reported. The analyses examined the extent that body dimensions and bone size changed over time by demographic, diet, physical activity, body, and bone size parameters. White children were the most physically active yet had lower calcaneal ultrasound values for speed of sound (SOS). Based on regression models, bone mass, and subscapular skinfold thickness were greater in Asian girls compared to White and Asian-White Mixed girls at age 10 years. Asian-White Mixed girls had greater BMI compared to Asian or White girls. Asian girls gained body size more slowly than White girls, but changes in bone parameters did not differ significantly; Asian-White Mixed girls gained abdomen, hip, and weight more slowly than White girls. Among all girls, SOS and broadband ultrasound attenuation (BUA) increased significantly by level of physical activity before 12 years, but not after. Asian girls had more upper body (subscapular) fat at age 10 years and gained height and hip and abdomen circumferences more slowly than Asian-White and White girls. Asian girls had greater bone SOS and BUA at age 10 years but gained bone at similar rates to White girls. Physical activity was especially important to bone growth before age 12 years. However, ethnic differences remained after adjusting for physical activity, demographic, and dietary factors.

Growth dynamics of Australia's polar dinosaurs.

PubMed

Woodward, Holly N; Rich, Thomas H; Chinsamy, Anusuya; Vickers-Rich, Patricia

2011-01-01

Analysis of bone microstructure in ornithopod and theropod dinosaurs from Victoria, Australia, documents ontogenetic changes, providing insight into the dinosaurs' successful habitation of Cretaceous Antarctic environments. Woven-fibered bone tissue in the smallest specimens indicates rapid growth rates during early ontogeny. Later ontogeny is marked by parallel-fibered tissue, suggesting reduced growth rates approaching skeletal maturity. Bone microstructure similarities between the ornithopods and theropods, including the presence of LAGs in each group, suggest there is no osteohistologic evidence supporting the hypothesis that polar theropods hibernated seasonally. Results instead suggest high-latitude dinosaurs had growth trajectories similar to their lower-latitude relatives and thus, rapid early ontogenetic growth and the cyclical suspensions of growth inherent in the theropod and ornithopod lineages enabled them to successfully exploit polar regions.

Detection of fungi colony growth on bones by dynamic speckle

NASA Astrophysics Data System (ADS)

Vincitorio, F. M.; Budini, N.; Mulone, C.; Spector, M.; Freyre, C.; López Díaz, A. J.; Ramil, A.

2013-11-01

In this work we have studied the dynamic speckle patterns of mucor fungi colonies, which were inoculated on different samples. We were interested in analyzing the development of fungi colonies in bones, since during the last two years, a series of infections by mucor fungi have been reported on patients from different hospitals in Argentina. Coincidentally, all of these infections appeared on patients that were subjected to a surgical intervention for implantation of a titanium prosthesis. Apparently, the reason of the infection was a deficient sterilization process in conjunction with an accidental contamination. We observed that fungi growth, activity and death can be distinguished by means of the dynamic speckle technique.

Direct and indirect effects of a combination of adipose-derived stem cells and platelet-rich plasma on bone regeneration.

PubMed

Tajima, Satoshi; Tobita, Morikuni; Orbay, Hakan; Hyakusoku, Hiko; Mizuno, Hiroshi

2015-03-01

A key goal for successful bone regeneration is to bridge a bone defect using healing procedures that are stable and durable. Adipose-derived stem cells (ASCs) have the potential to differentiate into bone. Meanwhile, platelet-rich plasma (PRP) is an interesting biological means to repair tissue by inducing chemotactic, proliferative, and anabolic cellular responses. This study evaluated bone regeneration using a combination of ASCs and PRP in a rat calvarial defect model. ASCs were isolated from inguinal fat pads of F344 inbred rats, while PRP was prepared from these rats. ASCs were cultured in control medium supplemented with 10% fetal bovine serum or 5% PRP in vitro. After 1 week, levels of growth factors including insulin-like growth factor-1, transforming growth factor-β1, hepatocyte growth factor, and vascular endothelial growth factor in the culture supernatant were measured by enzyme-linked immunosorbent assays. Moreover, the ASC/PRP admixture was transplanted into the rat calvarial defect. Microcomputed tomography, histological, and immunohistochemical (osteopontin and osteocalcin) analyses were performed at 4 and 8 weeks after transplantation. The in vitro study showed that the levels of growth factors secreted by ASCs were significantly increased by the addition of PRP. Transplantation of the ASC/PRP admixture had dramatic effects on bone regeneration overtime in comparison with rats that received other transplants. Furthermore, some ASCs directly differentiated into osteogenic cells in vivo. These findings suggest that the combination of ASCs and PRP has augmentative effects on bone regeneration. The ASC/PRP admixture may be a promising source for the clinical treatment of cranial defects.

Bone Morphogenetic Protein (BMP) signaling in development and human diseases

PubMed Central

Wang, Richard N.; Green, Jordan; Wang, Zhongliang; Deng, Youlin; Qiao, Min; Peabody, Michael; Zhang, Qian; Ye, Jixing; Yan, Zhengjian; Denduluri, Sahitya; Idowu, Olumuyiwa; Li, Melissa; Shen, Christine; Hu, Alan; Haydon, Rex C.; Kang, Richard; Mok, James; Lee, Michael J.; Luu, Hue L.; Shi, Lewis L.

2014-01-01

Bone Morphogenetic Proteins (BMPs) are a group of signaling molecules that belongs to the Transforming Growth Factor-β (TGF-β) superfamily of proteins. Initially discovered for their ability to induce bone formation, BMPs are now known to play crucial roles in all organ systems. BMPs are important in embryogenesis and development, and also in maintenance of adult tissue homeostasis. Mouse knockout models of various components of the BMP signaling pathway result in embryonic lethality or marked defects, highlighting the essential functions of BMPs. In this review, we first outline the basic aspects of BMP signaling and then focus on genetically manipulated mouse knockout models that have helped elucidate the role of BMPs in development. A significant portion of this review is devoted to the prominent human pathologies associated with dysregulated BMP signaling. PMID:25401122

Clinical assessment of bone quality of human extraction sockets after conversion with growth factors.

PubMed

Ntounis, Athanasios; Geurs, Nico; Vassilopoulos, Philip; Reddy, Michael

2015-01-01

The study was conducted to evaluate the effect of mineralized freeze-dried bone allograft (FDBA), alone or in combination with growth factors in extraction sockets, on subjective assessment of bone quality during implant placement. Forty-one patients whose treatment plan involved extraction of anterior or premolar teeth were randomized into four groups: Group 1, collagen plug (control); Group 2, FDBA/β-tricalcium phosphate (β-TCP)/collagen plug; Group 3, FDBA/β-TCP/platelet-rich plasma (PRP)/collagen plug; Group 4, FDBA/β-TCP/recombinant human platelet-derived growth factor BB (rhPDGF-BB)/collagen plug. After 8 weeks of healing, implants were placed. The clinicians assessed bone quality according to the Misch classification. A benchtop calibration exercise test was conducted to evaluate agreement and accuracy of operators in recognizing different bone qualities. Differences were analyzed using one-way analysis of variance (ANOVA) or chi-square tests for continuous and categorical data. Pairwise comparisons were tested using least squares means (LS means). Spearman correlation coefficients were used to evaluate the relationship of bone growth with potential confounders. P < .05 was considered statistically significant. A simple (not weighted) kappa statistic was used to assess the agreement between raters. To assess accuracy in identifying bone quality, a chi-square test was used to compare the percent correct for each rater. The benchtop calibration exercise test demonstrated agreement among clinicians (0.75 and 0.92 between raters 1 and 2 and raters 1 and 3, respectively). Raters were more likely to identify the correct bone quality (P > .05). Inclusion of bone grafting is associated with a shift from D4 quality to D3 quality bone. Inclusion of PRP in bone grafting eliminates the incidence of D4 bone, establishing D3 and D2 quality bone as prevalent (56% vs. 42%, respectively). Inclusion of rhPDGF-BB and β-TCP in combination with the bone grafting has the same effect, although D2 quality is less prevalent. When compared to sockets grafted with FDBA/β-TCP/collagen plug alone, the sockets with growth factors demonstrated fewer residual bone graft particles. (1) Inclusion of bone grafting enhanced bone quality as assessed during implant placement. (2) Overall inclusion of PRP and rhPDGF-BB enhanced subjective bone quality, eliminating incidence of D4 quality in human extraction sockets. (3) The use of PRP or rhPDGF-BB may enhance healing within extraction sockets and decrease the healing time prior to dental implant placement.

Targeted Deletion of Autophagy Genes Atg5 or Atg7 in the Chondrocytes Promotes Caspase-Dependent Cell Death and Leads to Mild Growth Retardation.

PubMed

Vuppalapati, Karuna K; Bouderlique, Thibault; Newton, Phillip T; Kaminskyy, Vitaliy O; Wehtje, Henrik; Ohlsson, Claes; Zhivotovsky, Boris; Chagin, Andrei S

2015-12-01

Longitudinal bone growth takes place in epiphyseal growth plates located in the ends of long bones. The growth plate consists of chondrocytes traversing from the undifferentiated (resting zone) to the terminally differentiated (hypertrophic zone) stage. Autophagy is an intracellular catabolic process of lysosome-dependent recycling of intracellular organelles and protein complexes. Autophagy is activated during nutritionally depleted or hypoxic conditions in order to facilitate cell survival. Chondrocytes in the middle of the growth plate are hypoxic and nutritionally depleted owing to the avascular nature of the growth plate. Accordingly, autophagy may facilitate their survival. To explore the role of autophagy in chondrocyte survival and constitutional bone growth, we generated mice with cartilage-specific ablation of either Atg5 (Atg5cKO) or Atg7 (Atg7cKO) by crossing Atg5 or Atg7 floxed mice with cartilage-specific collagen type 2 promoter-driven Cre. Both Atg5cKO and Atg7cKO mice showed growth retardation associated with enhanced chondrocyte cell death and decreased cell proliferation. Similarly, inhibition of autophagy by Bafilomycin A1 (Baf) or 3-methyladenine (3MA) promoted cell death in cultured slices of human growth plate tissue. To delineate the underlying mechanisms we employed ex vivo cultures of mouse metatarsal bones and RCJ3.IC5.18 rat chondrogenic cell line. Baf or 3MA impaired metatarsal bone growth associated with processing of caspase-3 and massive cell death. Similarly, treatment of RCJ3.IC5.18 chondrogenic cells by Baf also showed massive cell death and caspase-3 cleavage. This was associated with activation of caspase-9 and cytochrome C release. Altogether, our data suggest that autophagy is important for chondrocyte survival, and inhibition of this process leads to stunted growth and caspase-dependent death of chondrocytes. © 2015 American Society for Bone and Mineral Research.

Human growth is associated with distinct patterns of gene expression in evolutionarily conserved networks

PubMed Central

2013-01-01

Background A co-ordinated tissue-independent gene expression profile associated with growth is present in rodent models and this is hypothesised to extend to all mammals. Growth in humans has similarities to other mammals but the return to active long bone growth in the pubertal growth spurt is a distinctly human growth event. The aim of this study was to describe gene expression and biological pathways associated with stages of growth in children and to assess tissue-independent expression patterns in relation to human growth. Results We conducted gene expression analysis on a library of datasets from normal children with age annotation, collated from the NCBI Gene Expression Omnibus (GEO) and EBI Arrayexpress databases. A primary data set was generated using cells of lymphoid origin from normal children; the expression of 688 genes (ANOVA false discovery rate modified p-value, q < 0.1) was associated with age, and subsets of these genes formed clusters that correlated with the phases of growth – infancy, childhood, puberty and final height. Network analysis on these clusters identified evolutionarily conserved growth pathways (NOTCH, VEGF, TGFB, WNT and glucocorticoid receptor – Hyper-geometric test, q < 0.05). The greatest degree of network ‘connectivity’ and hence functional significance was present in infancy (Wilcoxon test, p < 0.05), which then decreased through to adulthood. These observations were confirmed in a separate validation data set from lymphoid tissue. Similar biological pathways were observed to be associated with development-related gene expression in other tissues (conjunctival epithelia, temporal lobe brain tissue and bone marrow) suggesting the existence of a tissue-independent genetic program for human growth and maturation. Conclusions Similar evolutionarily conserved pathways have been associated with gene expression and child growth in multiple tissues. These expression profiles associate with the developmental phases of growth including the return to active long bone growth in puberty, a distinctly human event. These observations also have direct medical relevance to pathological changes that induce disease in children. Taking into account development-dependent gene expression profiles for normal children will be key to the appropriate selection of genes and pathways as potential biomarkers of disease or as drug targets. PMID:23941278

Tibial bone mineral distribution as influenced by calcium, phosphorus, and vitamin D feeding levels in the growing turkey

NASA Technical Reports Server (NTRS)

Spurrell, F. A.; Brenes, J.; Waibel, P.

1974-01-01

Roentgen signs, subperiosteal, endosteal, and trabecular bone growth are evaluated in turkeys fed phosphorus at the 0.5, 0.56, 0.68, 0.90, and 2.70 percent levels. Calcium levels of 0.30, 0.40, 0.60, 1.2, and 3.60 percent were also tested. Vitamin D levels of 0, 100, 300, 900 and 27,000 I.U. per day were likewise evaluated. Roentgen signs, bone mineral as measured by T-125 gamma ray absorption, and bone mineral growth patterns as shown by radiograph area projection are correlated with calcium, phosphorus, and vitamin D feeding levels. Differences in bone growth at the various feeding levels were observed which were not reflected by differences in other studied parameters.

Patterns of long bone growth in a mid-19th century documented sample of the urban poor from Bethnal Green, London, UK.

PubMed

Ives, Rachel; Humphrey, Louise

2017-05-01

Studies of male and female long bone growth in past populations are limited and usually constrained by the lack of personal identification. This article aimed to evaluate long bone growth in a series of mid-19 th century documented burials associated with the urban poor from Bethnal Green, London, UK. Maximum diaphyseal lengths from 74 males and 70 females (2 months to 12 years) were compared to modern reference data from North America. Diaphyseal lengths were expressed as a percentage of expected length and an average percentage value was calculated across all available long bones. An index of growth progression was introduced to explore differences in the progress of males and females towards their projected adult size. Deviation from the expected growth attainment was evident in both sexes in the archaeological series by 2-4 months of age. Only 19.4% (28/144) of the children had attained an average long bone length >90% of the predicted mean in the reference series. The percentage of expected growth attainment decreased steadily in both sexes during infancy and early childhood. Overall, females deviated further from their expected growth progression than males. Growth faltering in both males and females was established during infancy (<1 year) with no evidence for recovery in older age groups. Early weaning and inadequate artificial feeding, together with impoverished living conditions and limited sanitary provision, most likely impacted on childhood growth. © 2017 Wiley Periodicals, Inc.

The prospective opportunities offered by magnetic scaffolds for bone tissue engineering: a review

PubMed Central

ORTOLANI, ALESSANDRO; BIANCHI, MICHELE; MOSCA, MASSIMILIANO; CARAVELLI, SILVIO; FUIANO, MARIO; MARCACCI, MAURILIO; RUSSO, ALESSANDRO

2016-01-01

Magnetic scaffolds are becoming increasingly attractive in tissue engineering, due to their ability to enhance bone tissue formation by attracting soluble factors, such as growth factors, hormones and polypeptides, directly to the implantation site, as well as their potential to improve the fixation and stability of the implant. Moreover, there is increasing evidence that the synergistic effects of magnetic scaffolds and magnetic fields can promote bone repair and regeneration. In this manuscript we review the recent innovations in bone tissue engineering that exploit magnetic biomaterials combined with static magnetic fields to enhance bone cell adhesion and proliferation, and thus bone tissue growth. PMID:28217659

Bone Metabolism in Adolescent Athletes With Amenorrhea, Athletes With Eumenorrhea, and Control Subjects

PubMed Central

Christo, Karla; Prabhakaran, Rajani; Lamparello, Brooke; Cord, Jennalee; Miller, Karen K.; Goldstein, Mark A.; Gupta, Nupur; Herzog, David B.; Klibanski, Anne; Misra, Madhusmita

2011-01-01

OBJECTIVE We hypothesized that, despite increased activity, bone density would be low in athletes with amenorrhea, compared with athletes with eumenorrhea and control subjects, because of associated hypogonadism and would be associated with a decrease in bone formation and increases in bone-resorption markers. METHODS In a cross-sectional study, we examined bone-density measures (spine, hip, and whole body) and body composition by using dual-energy radiograph absorptiometry and assessed fasting levels of insulin-like growth factor I and bone-turnover markers (N-terminal propeptied of type 1 procollagen and N-telopeptide) in 21 athletes with amenorrhea, 18 athletes with eumenorrhea, and 18 control subjects. Subjects were 12 to 18 years of age and of comparable chronologic and bone age. RESULTS Athletes with amenorrhea had lower bone-density z scores at the spine and whole body, compared with athletes with eumenorrhea and control subjects, and lower hip z scores, compared with athletes with eumenorrhea. Lean mass did not differ between groups. However, athletes with amenorrhea had lower BMI z scores than did athletes with eumenorrhea and lower insulin-like growth factor I levels than did control subjects. Levels of both markers of bone turnover were lower in athletes with amenorrhea than in control subjects. BMI z scores, lean mass, insulin-like growth factor I levels, and diagnostic category were important independent predictors of bone mineral density z scores. CONCLUSIONS Although they showed no significant differences in lean mass, compared with athletes with eumenorrhea and control subjects, athletes with amenorrhea had lower bone density at the spine and whole body. Insulin-like growth factor I levels, body-composition parameters, and menstrual status were important predictors of bone density. Follow-up studies are necessary to determine whether amenorrhea in athletes adversely affects the rate of bone mass accrual and therefore peak bone mass. PMID:18519482

Bone microstructure and developmental plasticity in birds and other dinosaurs.

PubMed

Starck, J Matthias; Chinsamy, Anusuya

2002-12-01

Patterns of bone microstructure have frequently been used to deduce dynamics and processes of growth in extant and fossil tetrapods. Often, the various types of primary bone tissue have been associated with different bone deposition rates and more recently such deductions have extended to patterns observed in dinosaur bone microstructure. These previous studies are challenged by the findings of the current research, which integrates an experimental neontological approach and a paleontological comparison. We use tetracycline labeling and morphometry to study the variability of bone deposition rates in Japanese quail (Coturnix japonica) growing under different experimental conditions. We compare resulting patterns in bone microstructure with those found in fossil birds and other dinosaurs. We found that a single type of primary bone varies significantly in rates of growth in response to environmental conditions. Ranging between 10-50 microm per day, rates of growth overlap with the full range of bone deposition rates that were previously associated with different patterns of bone histology. Bone formation rate was significantly affected by environmental/experimental conditions, skeletal element, and age. In the quail, the experimental conditions did not result in formation of lines of arrested growth (LAGs). Because of the observed variation of bone deposition rates in response to variation in environmental conditions, we conclude that bone deposition rates measured in extant birds cannot simply be extrapolated to their fossil relatives. Additionally, we observe the variable incidence of LAGs and annuli among several dinosaur species, including fossil birds, extant sauropsids, as well as nonmammalian synapsids, and some extant mammals. This suggests that the ancestral condition of the response of bone to environmental conditions was variable. We propose that such developmental plasticity in modern birds may be reduced in association with the shortened developmental time during the later evolution of the ornithurine birds. Copyright 2002 Wiley-Liss, Inc.

Erythropoietin induces bone marrow and plasma fibroblast growth factor 23 during acute kidney injury.

PubMed

Toro, Luis; Barrientos, Víctor; León, Pablo; Rojas, Macarena; Gonzalez, Magdalena; González-Ibáñez, Alvaro; Illanes, Sebastián; Sugikawa, Keigo; Abarzúa, Néstor; Bascuñán, César; Arcos, Katherine; Fuentealba, Carlos; Tong, Ana María; Elorza, Alvaro A; Pinto, María Eugenia; Alzamora, Rodrigo; Romero, Carlos; Michea, Luis

2018-05-01

It is accepted that osteoblasts/osteocytes are the major source for circulating fibroblast growth factor 23 (FGF23). However, erythropoietic cells of bone marrow also express FGF23. The modulation of FGF23 expression in bone marrow and potential contribution to circulating FGF23 has not been well studied. Moreover, recent studies show that plasma FGF23 may increase early during acute kidney injury (AKI). Erythropoietin, a kidney-derived hormone that targets erythropoietic cells, increases in AKI. Here we tested whether an acute increase of plasma erythropoietin induces FGF23 expression in erythropoietic cells of bone marrow thereby contributing to the increase of circulating FGF23 in AKI. We found that erythroid progenitor cells of bone marrow express FGF23. Erythropoietin increased FGF23 expression in vivo and in bone marrow cell cultures via the homodimeric erythropoietin receptor. In experimental AKI secondary to hemorrhagic shock or sepsis in rodents, there was a rapid increase of plasma erythropoietin, and an induction of bone marrow FGF23 expression together with a rapid increase of circulating FGF23. Blockade of the erythropoietin receptor fully prevented the induction of bone marrow FGF23 and partially suppressed the increase of circulating FGF23. Finally, there was an early increase of both circulating FGF23 and erythropoietin in a cohort of patients with severe sepsis who developed AKI within 48 hours of admission. Thus, increases in plasma erythropoietin and erythropoietin receptor activation are mechanisms implicated in the increase of plasma FGF23 in AKI. Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

[Growth rate and bone maturation in celiac disease (author's transl)].

PubMed

Martínez Sopena, M J; Calvo Romero, M C; Bedate Calderón, P; Alonso Franch, M; Sánchez Villares, E

1978-05-01

The growth and bone maturation of 43 celiac patients were analyzed. A significant correlation between gluten intake and growth rate was found. The authors suggest this is a good parameter to advise the best moment to make the control biopsie and the provocation test.

Bone marrow-derived cultured mast cells and peritoneal mast cells as targets of a growth activity secreted by BALB/3T3 fibroblasts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jozaki, K.; Kuriu, A.; Hirota, S.

1991-03-01

When fibroblast cell lines were cultured in contact with bone marrow-derived cultured mast cells (CMC), both NIH/3T3 and BALB/3T3 cell lines supported the proliferation of CMC. In contrast, when contact between fibroblasts and CMC was prohibited by Biopore membranes or soft agar, only BALB/3T3 fibroblasts supported CMC proliferation, suggesting that BALB/3T3 but not NIH/3T3 cells secreted a significant amount of a mast cell growth activity. Moreover, the BALB/3T3-derived growth activity induced the incorporation of (3H)thymidine by CMC and the clonal growth of peritoneal mast cells in methylcellulose. The mast cell growth activity appeared to be different from interleukin 3 (IL-3)more » and interleukin 4 (IL-4), because mRNAs for these interleukins were not detectable in BALB/3T3 fibroblasts. Although mast cells are genetically deficient in tissues of W/Wv mice, CMC did develop when bone marrow cells of W/Wv mice were cultured with pokeweed mitogen-stimulated spleen cell-conditioned medium. Because BALB/3T3 fibroblast-conditioned medium (BALB-FCM) did not induce the incorporation of (3H)thymidine by W/Wv CMC, the growth activity in BALB-FCM appeared to be a ligand for the receptor encoded by the W (c-kit) locus. Because CMC and peritoneal mast cells are obtained as homogeneous suspensions rather easily, these cells may be potentially useful as targets for the fibroblast-derived mast cell growth activity.« less

Alterations of the Temporomandibular Joint on Magnetic Resonance Imaging according to Growth and Development in Schoolchildren

PubMed Central

Tanaka, Tatsurou; Konoo, Tetsuro; Habu, Manabu; Oda, Masafumi; Kito, Shinji; Kodama, Masaaki; Kokuryo, Shinya; Wakasugi-Sato, Nao; Matsumoto-Takeda, Shinobu; Nishida, Ikuko; Morikawa, Kazumasa; Saeki, Katsura; Maki, Kenshi; Tominaga, Kazuhiro; Masumi, Shin-ichi; Terashita, Masamichi; Morimoto, Yasuhiro

2012-01-01

The paper explains the alterations of the temporomandibular joint (TMJ) visualized by magnetic resonance imaging (MRI) according to the growth and development of schoolchildren. Appearance and disappearance of a “double contour-like structure” (DCLS) of the mandibular condyle on MRI according to the growth and development of schoolchildren were demonstrated. In addition, possible constituents of DCLS and the significance of detection of DCLS on MRI were also speculated. The relationship between red marrow and yellow marrow in the articular eminence of temporal bone, the disappearance of DCLS, and alterations of the mandibular condyle have been elucidated. PMID:23316233

Adult Rat Bones Maintain Distinct Regionalized Expression of Markers Associated with Their Development

PubMed Central

Rawlinson, Simon C. F.; McKay, Ian J.; Ghuman, Mandeep; Wellmann, Claudia; Ryan, Paul; Prajaneh, Saengsome; Zaman, Gul; Hughes, Francis J.; Kingsmill, Virginia J.

2009-01-01

The incidence of limb bone fracture and subsequent morbidity and mortality due to excessive bone loss is increasing in the progressively ageing populations of both men and women. In contrast to bone loss in the weight-bearing limb, bone mass in the protective skull vault is maintained. One explanation for this could be anatomically diverse bone matrix characteristics generated by heterogeneous osteoblast populations. We have tested the hypothesis that adult bones demonstrate site-specific characteristics, and report differences at the organ, cell and transcriptome levels. Limb bones contain greater amounts of polysulphated glycosaminoglycan stained with Alcian Blue and have significantly higher osteocyte densities than skull bone. Site-specific patterns persist in cultured adult bone-derived cells both phenotypically (proliferation rate, response to estrogen and cell volumes), and at the level of specific gene expression (collagen triple helix repeat containing 1, reelin and ras-like and estrogen-regulated growth inhibitor). Based on genome-wide mRNA expression and cluster analysis, we demonstrate that bones and cultured adult bone-derived cells segregate according to site of derivation. We also find the differential expression of genes associated with embryological development (Skull: Zic, Dlx, Irx, Twist1 and Cart1; Limb: Hox, Shox2, and Tbx genes) in both adult bones and isolated adult bone-derived cells. Together, these site-specific differences support the view that, analogous to different muscle types (cardiac, smooth and skeletal), skull and limb bones represent separate classes of bone. We assign these differences, not to mode of primary ossification, but to the embryological cell lineage; the basis and implications of this division are discussed. PMID:20027296

Intercellular signaling pathways active during and after growth and differentiation of the lumbar vertebral growth plate.

PubMed

Dahia, Chitra Lekha; Mahoney, Eric J; Durrani, Atiq A; Wylie, Christopher

2011-06-15

Vertebral growth plates at different postnatal ages were assessed for active intercellular signaling pathways. To generate a spatial and temporal map of the major signaling pathways active in the postnatal mouse lumbar vertebral growth plate. The growth of all long bones is known to occur by cartilaginous growth plates. The growth plate is composed of layers of chondrocyets that actively proliferate, differentiate, die and, are replaced by bone. The role of major cell signaling pathways has been suggested for regulation of the fetal long bones. But not much is known about the molecular or cellular signals that control the postnatal vertebral growth plate and hence postnatal vertebral bone growth. Understanding such molecular mechanisms will help design therapeutic treatments for vertebral growth disorders such as scoliosis. Antibodies against activated downstream intermediates were used to identify cells in the growth plate responding to BMP, TGFβ, and FGF in cryosections of lumbar vertebrae from different postnatal age mice to identify the zones that were responding to these signals. Reporter mice were used to identify the chondrocytes responding to hedgehog (Ihh), and Wnt signaling. We present a spatial/temporal map of these signaling pathways during growth, and differentiation of the mouse lumbar vertebral growth plate. During growth and differentiation of the vertebral growth plate, its different components respond at different times to different intercellular signaling ligands. Response to most of these signals is dramatically downregulated at the end of vertebral growth.

Core binding factor beta (Cbfβ) controls the balance of chondrocyte proliferation and differentiation by upregulating Indian hedgehog (Ihh) expression and inhibiting parathyroid hormone-related protein receptor (PPR) expression in postnatal cartilage and bone formation.

PubMed

Tian, Fei; Wu, Mengrui; Deng, Lianfu; Zhu, Guochun; Ma, Junqing; Gao, Bo; Wang, Lin; Li, Yi-Ping; Chen, Wei

2014-07-01

Core binding factor beta (Cbfβ) is essential for embryonic bone morphogenesis. Yet the mechanisms by which Cbfβ regulates chondrocyte proliferation and differentiation as well as postnatal cartilage and bone formation remain unclear. Hence, using paired-related homeobox transcription factor 1-Cre (Prx1-Cre) mice, mesenchymal stem cell-specific Cbfβ-deficient (Cbfβ(f/f) Prx1-Cre) mice were generated to study the role of Cbfβ in postnatal cartilage and bone development. These mutant mice survived to adulthood but exhibited severe sternum and limb malformations. Sternum ossification was largely delayed in the Cbfβ(f/f) Prx1-Cre mice and the xiphoid process was noncalcified and enlarged. In newborn and 7-day-old Cbfβ(f/f) Prx1-Cre mice, the resting zone was dramatically elongated, the proliferation zone and hypertrophic zone of the growth plates were drastically shortened and disorganized, and trabecular bone formation was reduced. Moreover, in 1-month-old Cbfβ(f/f) Prx1-Cre mice, the growth plates were severely deformed and trabecular bone was almost absent. In addition, Cbfβ deficiency impaired intramembranous bone formation both in vivo and in vitro. Interestingly, although the expression of Indian hedgehog (Ihh) was largely reduced, the expression of parathyroid hormone-related protein (PTHrP) receptor (PPR) was dramatically increased in the Cbfβ(f/f) Prx1-Cre growth plate, indicating that that Cbfβ deficiency disrupted the Ihh-PTHrP negative regulatory loop. Chromatin immunoprecipitation (ChIP) analysis and promoter luciferase assay demonstrated that the Runx/Cbfβ complex binds putative Runx-binding sites of the Ihh promoter regions, and also the Runx/Cbfβ complex directly upregulates Ihh expression at the transcriptional level. Consistently, the expressions of Ihh target genes, including CyclinD1, Ptc, and Pthlh, were downregulated in Cbfβ-deficient chondrocytes. Taken together, our study reveals not only that Cbfβ is essential for chondrocyte proliferation and differentiation for the growth and maintenance of the skeleton in postnatal mice, but also that it functions in upregulating Ihh expression to promoter chondrocyte proliferation and osteoblast differentiation, and inhibiting PPR expression to enhance chondrocyte differentiation. © 2014 American Society for Bone and Mineral Research.

Wnt/RANKL-mediated bone growth promoting effects of blueberries in weanling rats

USDA-ARS?s Scientific Manuscript database

We studied the effects of dietary blueberry supplementation on bone growth in weanling rats. Weanling male and female rats were fed AIN-93G semi-purified diets supplemented with 10% whole blueberry powder for 14 and 30 days beginning on PND 21. In both sexes tibial bone mineral density and content a...

Automatic segmentation of bones from digital hand radiographs

NASA Astrophysics Data System (ADS)

Liu, Brent J.; Taira, Ricky K.; Shim, Hyeonjoon; Keaton, Patricia

1995-05-01

The purpose of this paper is to develop a robust and accurate method that automatically segments phalangeal and epiphyseal bones from digital pediatric hand radiographs exhibiting various stages of growth. The algorithm uses an object-oriented approach comprising several stages beginning with the most general objects to be segmented, such as the outline of the hand from background, and proceeding in a succession of stages to the most specific object, such as a specific phalangeal bone from a digit of the hand. Each stage carries custom operators unique to the needs of that specific stage which will aid in more accurate results. The method is further aided by a knowledge base where all model contours and other information such as age, race, and sex, are stored. Shape models, 1-D wrist profiles, as well as an interpretation tree are used to map model and data contour segments. Shape analysis is performed using an arc-length orientation transform. The method is tested on close to 340 phalangeal and epiphyseal objects to be segmented from 17 cases of pediatric hand images obtained from our clinical PACS. Patient age ranges from 2 - 16 years. A pediatric radiologist preliminarily assessed the results of the object contours and were found to be accurate to within 95% for cases with non-fused bones and to within 85% for cases with fused bones. With accurate and robust results, the method can be applied toward areas such as the determination of bone age, the development of a normal hand atlas, and the characterization of many congenital and acquired growth diseases. Furthermore, this method's architecture can be applied to other image segmentation problems.

Insulin-like growth factor I has independent effects on bone matrix formation and cell replication

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hock, J.M.; Centrella, M.; Canalis, E.

1988-01-01

The effects of insulin-like growth factor-I (IGF-I) and insulin on bone matrix synthesis and bone cell replication were studied in cultured 21-day-old fetal rat calvariae. Histomorphometry techniques were developed to measure the incorporation of (2,3-/sup 3/H)proline and (methyl-/sup 3/H)thymidine into bone matrix and bone cell nuclei, respectively, using autoradiographs of sagittal sections of calvariae cultured with IGF-I, insulin, or vehicle for up to 96 h. To confirm an effect on bone formation, IGF-I was also studied for its effects on (/sup 3/H)proline incorporation into collagenase-digestible protein (CDP) and noncollagen protein and on (/sup 3/H)thymidine incorporation into acid-precipitable material (DNA). IGF-Imore » at 10(-9)-10(-7) M significantly increased the rate of bone matrix apposition and CDP after 24 h by 45-50% and increased cell labeling by 8-fold in the osteoprogenitor cell zone, by 4-fold in the osteoblast cell zone, and by 2-fold in the periosteal fibroblast zone. Insulin at 10(-9)-10(-6) M also increased matrix apposition rate and CDP by 40-50%, but increased cell labeling by 2-fold only at a concentration of 10(-7) M or higher and then only in the osteoprogenitor cell zone. When hydroxyurea was added to IGF-I-treated bones, the effects of IGF-I on DNA synthesis were abolished, but the increase in bone matrix apposition induced by IGF-I was only partly diminished. In conclusion, IGF-I stimulates matrix synthesis in calvariae, an effect that is partly, although not completely, dependent on its stimulatory effect on DNA synthesis.« less

Proteoglycan 4: A Dynamic Regulator of Skeletogenesis and Parathyroid Hormone Skeletal Anabolism

PubMed Central

Novince, Chad M; Michalski, Megan N; Koh, Amy J; Sinder, Benjamin P; Entezami, Payam; Eber, Matthew R; Pettway, Glenda J; Rosol, Thomas J; Wronski, Thomas J; Kozloff, Ken M; McCauley, Laurie K

2014-01-01

Proteoglycan 4 (Prg4), known for its lubricating and protective actions in joints, is a strong candidate regulator of skeletal homeostasis and parathyroid hormone (PTH) anabolism. Prg4 is a PTH-responsive gene in bone and liver. Prg4 null mutant mice were used to investigate the impact of proteoglycan 4 on skeletal development, remodeling, and PTH anabolic actions. Young Prg4 mutant and wild-type mice were administered intermittent PTH(1–34) or vehicle daily from 4 to 21 days. Young Prg4 mutant mice had decreased growth plate hypertrophic zones, trabecular bone, and serum bone formation markers versus wild-type mice, but responded with a similar anabolic response to PTH. Adult Prg4 mutant and wild-type mice were administered intermittent PTH(1–34) or vehicle daily from 16 to 22 weeks. Adult Prg4 mutant mice had decreased trabecular and cortical bone, and blunted PTH-mediated increases in bone mass. Joint range of motion and animal mobility were lower in adult Prg4 mutant versus wild-type mice. Adult Prg4 mutant mice had decreased marrow and liver fibroblast growth factor 2 (FGF-2) mRNA and reduced serum FGF-2, which were normalized by PTH. A single dose of PTH decreased the PTH/PTHrP receptor (PPR), and increased Prg4 and FGF-2 to a similar extent in liver and bone. Proteoglycan 4 supports endochondral bone formation and the attainment of peak trabecular bone mass, and appears to support skeletal homeostasis indirectly by protecting joint function. Bone- and liver-derived FGF-2 likely regulate proteoglycan 4 actions supporting trabeculae formation. Blunted PTH anabolic responses in adult Prg4 mutant mice are associated with altered biomechanical impact secondary to joint failure. PMID:21932346

Nuclear Receptors in Bone Physiology and Diseases

PubMed Central

Youn, Min-Young; Inoue, Kazuki; Takada, Ichiro; Kouzmenko, Alexander; Kato, Shigeaki

2013-01-01

During the last decade, our view on the skeleton as a mere solid physical support structure has been transformed, as bone emerged as a dynamic, constantly remodeling tissue with systemic regulatory functions including those of an endocrine organ. Reflecting this remarkable functional complexity, distinct classes of humoral and intracellular regulatory factors have been shown to control vital processes in the bone. Among these regulators, nuclear receptors (NRs) play fundamental roles in bone development, growth, and maintenance. NRs are DNA-binding transcription factors that act as intracellular transducers of the respective ligand signaling pathways through modulation of expression of specific sets of cognate target genes. Aberrant NR signaling caused by receptor or ligand deficiency may profoundly affect bone health and compromise skeletal functions. Ligand dependency of NR action underlies a major strategy of therapeutic intervention to correct aberrant NR signaling, and significant efforts have been made to design novel synthetic NR ligands with enhanced beneficial properties and reduced potential negative side effects. As an example, estrogen deficiency causes bone loss and leads to development of osteoporosis, the most prevalent skeletal disorder in postmenopausal women. Since administration of natural estrogens for the treatment of osteoporosis often associates with undesirable side effects, several synthetic estrogen receptor ligands have been developed with higher therapeutic efficacy and specificity. This review presents current progress in our understanding of the roles of various nuclear receptor-mediated signaling pathways in bone physiology and disease, and in development of advanced NR ligands for treatment of common skeletal disorders. PMID:23589826

Repair of bone segment defects with surface porous fiber-reinforced polymethyl methacrylate (PMMA) composite prosthesis: histomorphometric incorporation model and characterization by SEM.

PubMed

Hautamäki, Mikko P; Aho, Allan J; Alander, Pasi; Rekola, Jami; Gunn, Jarmo; Strandberg, Niko; Vallittu, Pekka K

2008-08-01

Polymer technology has provided solutions for filling of bone defects in situations where there may be technical or biological complications with autografts, allografts, and metal prostheses. We present an experimental study on segmental bone defect reconstruction using a polymethylmethacrylate-(PMMA-) based bulk polymer implant prosthesis. We concentrated on osteoconductivity and surface characteristics. A critical size segment defect of the rabbit tibia in 19 animals aged 18-24 weeks was reconstructed with a surface porous glass fiber-reinforced (SPF) prosthesis made of polymethylmethacrylate (PMMA). The biomechanical properties of SPF implant material were previously adjusted technically to mimic the properties of normal cortical bone. A plain PMMA implant with no porosity or fiber reinforcement was used as a control. Radiology, histomorphometry, and scanning electron microscopy (SEM) were used for analysis of bone growth into the prosthesis during incorporation. The radiographic and histological incorporation model showed good host bone contact, and strong formation of new bone as double cortex. Histomorphometric evaluation showed that the bone contact index (BCI) at the posterior surface interface was higher with the SPF implant than for the control. The total appositional bone growth over the posterior surface (area %) was also stronger for the SPF implant than for controls. Both bone growth into the porous surface and the BCI results were related to the quality, coverage, and regularity of the microstructure of the porous surface. Porous surface structure enhanced appositional bone growth onto the SPF implant. Under load-bearing conditions the implant appears to function like an osteoconductive prosthesis, which enables direct mobilization and rapid return to full weight bearing.

Facial growth and development in unilateral cleft lip and palate: comparison between secondary alveolar bone grafting and primary periosteoplasty.

PubMed

Cagáňová, Veronika; Borský, Jiří; Smahel, Zbyněk; Velemínská, Jana

2014-01-01

To describe the effect of secondary alveolar bone grafting in patients with unilateral cleft lip and palate by comparison with a sample of patients who have undergone primary periosteoplasty. Cephalometric analysis of lateral x-ray films in a retrospective semilongitudinal study. Lateral x-ray films of 18 secondary alveolar bone grafting patients and 48 primary periosteoplasty patients at 10 years of age and again at 15 years of age. The treatment of secondary alveolar bone grafting patients included lip repair according to Tennison, palatoplasty including retropositioning, pharyngeal flap surgery, and secondary alveolar bone grafting. The lips of primary periosteoplasty patient were repaired using the methods of Tennison and Veau, followed by primary periosteoplasty, palatoplasty including retropositioning, and pharyngeal flap surgery. Lateral radiographs were assessed using classical morphometry. There were few significant differences at 10 years of age between the secondary alveolar bone grafting and primary periosteoplasty patients. At 15 years of age, there were several significant differences. Compared with primary periosteoplasty patients, subsequent development in patients who had undergone secondary alveolar bone grafting was characterized by a significantly better position of the upper and lower dentoalveolar components in relation to the facial plane, a higher increase in the global convexity of the soft profile, a significantly better maxillary inclination, and a more favorable development of vertical intermaxillary relationships. Craniofacial development in secondary alveolar bone grafting patients was better than that in primary periosteoplasty patients due to the more marked facial convexity, the increased prominence of the nose, and better vertical intermaxillary relationships.

Active multilayered capsules for in vivo bone formation

PubMed Central

Facca, S.; Cortez, C.; Mendoza-Palomares, C.; Messadeq, N.; Dierich, A.; Johnston, A. P. R.; Mainard, D.; Voegel, J.-C.; Caruso, F.; Benkirane-Jessel, N.

2010-01-01

Interest in the development of new sources of transplantable materials for the treatment of injury or disease has led to the convergence of tissue engineering with stem cell technology. Bone and joint disorders are expected to benefit from this new technology because of the low self-regenerating capacity of bone matrix secreting cells. Herein, the differentiation of stem cells to bone cells using active multilayered capsules is presented. The capsules are composed of poly-L-glutamic acid and poly-L-lysine with active growth factors embedded into the multilayered film. The bone induction from these active capsules incubated with embryonic stem cells was demonstrated in vitro. Herein, we report the unique demonstration of a multilayered capsule-based delivery system for inducing bone formation in vivo. This strategy is an alternative approach for in vivo bone formation. Strategies using simple chemistry to control complex biological processes would be particularly powerful, as they make production of therapeutic materials simpler and more easily controlled. PMID:20160118

Prostate Cancer Cell–Stromal Cell Cross-Talk via FGFR1 Mediates Antitumor Activity of Dovitinib in Bone Metastases

PubMed Central

Wan, Xinhai; Corn, Paul G.; Yang, Jun; Palanisamy, Nallasivam; Starbuck, Michael W.; Efstathiou, Eleni; Li-Ning Tapia, Elsa M.; Zurita, Amado J.; Aparicio, Ana; Ravoori, Murali K.; Vazquez, Elba S.; Robinson, Dan R.; Wu, Yi-Mi; Cao, Xuhong; Iyer, Matthew K.; McKeehan, Wallace; Kundra, Vikas; Wang, Fen; Troncoso, Patricia; Chinnaiyan, Arul M.; Logothetis, Christopher J.; Navone, Nora M.

2015-01-01

Bone is the most common site of prostate cancer (PCa) progression to a therapy-resistant, lethal phenotype. We found that blockade of fibroblast growth factor receptors (FGFRs) with the receptor tyrosine kinase inhibitor dovitinib has clinical activity in a subset of men with castration-resistant PCa and bone metastases. Our integrated analyses suggest that FGF signaling mediates a positive feedback loop between PCa cells and bone cells and that blockade of FGFR1 in osteoblasts partially mediates the antitumor activity of dovitinib by improving bone quality and by blocking PCa cell–bone cell interaction. These findings account for clinical observations such as reductions in lesion size and intensity on bone scans, lymph node size, and tumor-specific symptoms without proportional declines in prostate-specific antigen concentration. Our findings suggest that targeting FGFR has therapeutic activity in advanced PCa and provide direction for the development of therapies with FGFR inhibitors. PMID:25186177

Prostate cancer cell-stromal cell crosstalk via FGFR1 mediates antitumor activity of dovitinib in bone metastases.

PubMed

Wan, Xinhai; Corn, Paul G; Yang, Jun; Palanisamy, Nallasivam; Starbuck, Michael W; Efstathiou, Eleni; Li Ning Tapia, Elsa M; Tapia, Elsa M Li-Ning; Zurita, Amado J; Aparicio, Ana; Ravoori, Murali K; Vazquez, Elba S; Robinson, Dan R; Wu, Yi-Mi; Cao, Xuhong; Iyer, Matthew K; McKeehan, Wallace; Kundra, Vikas; Wang, Fen; Troncoso, Patricia; Chinnaiyan, Arul M; Logothetis, Christopher J; Navone, Nora M

2014-09-03

Bone is the most common site of prostate cancer (PCa) progression to a therapy-resistant, lethal phenotype. We found that blockade of fibroblast growth factor receptors (FGFRs) with the receptor tyrosine kinase inhibitor dovitinib has clinical activity in a subset of men with castration-resistant PCa and bone metastases. Our integrated analyses suggest that FGF signaling mediates a positive feedback loop between PCa cells and bone cells and that blockade of FGFR1 in osteoblasts partially mediates the antitumor activity of dovitinib by improving bone quality and by blocking PCa cell-bone cell interaction. These findings account for clinical observations such as reductions in lesion size and intensity on bone scans, lymph node size, and tumor-specific symptoms without proportional declines in serum prostate-specific antigen concentration. Our findings suggest that targeting FGFR has therapeutic activity in advanced PCa and provide direction for the development of therapies with FGFR inhibitors. Copyright © 2014, American Association for the Advancement of Science.

Cytomegalovirus infection of the BS-1 human stroma cell line: effect on murine hemopoiesis.

PubMed

Steinberg, H N; Anderson, J; Lim, B; Chatis, P A

1993-10-01

BS-1, a stromal cell line derived from human bone marrow, can support the growth of murine erythroid (BFU-E), granulocyte-macrophage (CFU-GM), and megakaryocyte (CFU-M) progenitor cells in a short term in vitro coculture system. Exposure of BS-1 cells to cytomegalovirus (CMV) for 3 hr prior to coculture results in a marked reduction in the stroma cell's ability to support murine hemopoiesis. CMV's effect on the BS-1 cell's hematopoietic support function is dependent on the multiplicity of infection with total suppression of BFU-E observed at a 1:1 ratio of virus to bone marrow cells. A 50% loss in the ability of BS-1 cells to support BFU-E is observed at a 0.1:1 ratio. No effect of CMV is observed with further log dilutions of virus. CMV infection of BS-1 cells affects its support of erythroid progenitor cell growth to a greater extent than its influence on the development of granulocyte-macrophage colonies. Antibody to CMV or heat inactivation of the virus reverses the inhibitory affect on BS-1 cells. The results suggest that CMV can infect a cell that constitutes one of the cellular elements of the normal bone marrow microenvironment causing a decrease in the stroma's ability to support the growth and development of normal progenitor cells.

Skeletal effect of casein and whey protein intake during catch-up growth in young male Sprague-Dawley rats.

PubMed

Masarwi, Majdi; Gabet, Yankel; Dolkart, Oleg; Brosh, Tamar; Shamir, Raanan; Phillip, Moshe; Gat-Yablonski, Galia

2016-07-01

The aim of the present study was to determine whether the type of protein ingested influences the efficiency of catch-up (CU) growth and bone quality in fast-growing male rats. Young male Sprague-Dawley rats were either fed ad libitum (controls) or subjected to 36 d of 40 % food restriction followed by 24 or 40 d of re-feeding with either standard rat chow or iso-energetic, iso-protein diets containing milk proteins - casein or whey. In terms of body weight, CU growth was incomplete in all study groups. Despite their similar food consumption, casein-re-fed rats had a significantly higher body weight and longer humerus than whey-re-fed rats in the long term. The height of the epiphyseal growth plate (EGP) in both casein and whey groups was greater than that of rats re-fed normal chow. Microcomputed tomography yielded significant differences in bone microstructure between the casein and whey groups, with the casein-re-fed animals having greater cortical thickness in both the short and long term in addition to a higher trabecular bone fraction in the short term, although this difference disappeared in the long term. Mechanical testing confirmed the greater bone strength in rats re-fed casein. Bone quality during CU growth significantly depends on the type of protein ingested. The higher EGP in the casein- and whey-re-fed rats suggests a better growth potential with milk-based diets. These results suggest that whey may lead to slower bone growth with reduced weight gain and, as such, may serve to circumvent long-term complications of CU growth.