Synchrotron imaging reveals bone healing and remodelling strategies in extinct and extant vertebrates

PubMed Central

Anné, Jennifer; Edwards, Nicholas P.; Wogelius, Roy A.; Tumarkin-Deratzian, Allison R.; Sellers, William I.; van Veelen, Arjen; Bergmann, Uwe; Sokaras, Dimosthenis; Alonso-Mori, Roberto; Ignatyev, Konstantin; Egerton, Victoria M.; Manning, Phillip L.

2014-01-01

Current understanding of bone healing and remodelling strategies in vertebrates has traditionally relied on morphological observations through the histological analysis of thin sections. However, chemical analysis may also be used in such interpretations, as different elements are known to be absorbed and used by bone for different physiological purposes such as growth and healing. These chemical signatures are beyond the detection limit of most laboratory-based analytical techniques (e.g. scanning electron microscopy). However, synchrotron rapid scanning–X-ray fluorescence (SRS–XRF) is an elemental mapping technique that uniquely combines high sensitivity (ppm), excellent sample resolution (20–100 µm) and the ability to scan large specimens (decimetre scale) approximately 3000 times faster than other mapping techniques. Here, we use SRS–XRF combined with microfocus elemental mapping (2–20 µm) to determine the distribution and concentration of trace elements within pathological and normal bone of both extant and extinct archosaurs (Cathartes aura and Allosaurus fragilis). Results reveal discrete chemical inventories within different bone tissue types and preservation modes. Chemical inventories also revealed detail of histological features not observable in thin section, including fine structures within the interface between pathological and normal bone as well as woven texture within pathological tissue. PMID:24806709

Rapid isolation of bone marrow mesenchymal stromal cells using integrated centrifuge-based technology.

PubMed

Meppelink, Amanda M; Wang, Xing-Hua; Bradica, Gino; Barron, Kathryn; Hiltz, Kathleen; Liu, Xiang-Hong; Goldman, Scott M; Vacanti, Joseph P; Keating, Armand; Hoganson, David M

2016-06-01

The use of bone marrow-derived mesenchymal stromal cells (MSCs) in cell-based therapies is currently being developed for a number of diseases. Thus far, the clinical results have been inconclusive and variable, in part because of the variety of cell isolation procedures and culture conditions used in each study. A new isolation technique that streamlines the method of concentration and demands less time and attention could provide clinical and economic advantages compared with current methodologies. In this study, we evaluated the concentrating capability of an integrated centrifuge-based technology compared with standard Ficoll isolation. MSCs were concentrated from bone marrow aspirate using the new device and the Ficoll method. The isolation capabilities of the device and the growth characteristics, secretome production, and differentiation capacity of the derived cells were determined. The new MSC isolation device concentrated the bone marrow in 90 seconds and resulted in a mononuclear cell yield 10-fold higher and with a twofold increase in cell retention compared with Ficoll. The cells isolated using the device were shown to exhibit similar morphology and functional activity as assessed by growth curves and secretome production compared to the Ficoll-isolated cells. The surface marker and trilineage differentiation profile of the device-isolated cells was consistent with the known profile of MSCs. The faster time to isolation and greater cell yield of the integrated centrifuge-based technology may make this an improved approach for MSC isolation from bone marrow aspirates. Copyright © 2016 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Nanoparticles of cobalt-substituted hydroxyapatite in regeneration of mandibular osteoporotic bones.

PubMed

Ignjatović, Nenad; Ajduković, Zorica; Savić, Vojin; Najman, Stevo; Mihailović, Dragan; Vasiljević, Perica; Stojanović, Zoran; Uskoković, Vuk; Uskoković, Dragan

2013-02-01

Indications exist that paramagnetic calcium phosphates may be able to promote regeneration of bone faster than their regular, diamagnetic counterparts. In this study, analyzed was the influence of paramagnetic cobalt-substituted hydroxyapatite nanoparticles on osteoporotic alveolar bone regeneration in rats. Simultaneously, biocompatibility of the material was tested in vitro, on osteoblastic MC3T3-E1 and epithelial Caco-2 cells in culture. The material was shown to be biocompatible and nontoxic when added to epithelial monolayers in vitro, while it caused a substantial decrease in the cell viability as well as deformation of the cytoskeleton and cell morphology when incubated with the osteoblastic cells. In the course of 6 months after the implantation of the material containing different amounts of cobalt, ranging from 5 to 12 wt%, in the osteoporotic alveolar bone of the lower jaw, the following parameters were investigated: histopathological parameters, alkaline phosphatase and alveolar bone density. The best result in terms of osteoporotic bone tissue regeneration was observed for hydroxyapatite nanoparticles with the largest content of cobalt ions. The histological analysis showed a high level of reparatory ability of the nanoparticulate material implanted in the bone defect, paralleled by a corresponding increase in the alveolar bone density. The combined effect of growth factors from autologous plasma admixed to cobalt-substituted hydroxyapatite was furthermore shown to have a crucial effect on the augmented osteoporotic bone regeneration upon the implantation of the biomaterial investigated in this study.

Nanoparticles of cobalt-substituted hydroxyapatite in regeneration of mandibular osteoporotic bones

PubMed Central

Ignjatović, Nenad; Ajduković, Zorica; Savić, Vojin; Najman, Stevo; Mihailović, Dragan; Vasiljević, Perica; Stojanović, Zoran; Uskoković, Vuk; Uskoković, Dragan

2012-01-01

Indications exist that paramagnetic calcium phosphates may be able to promote regeneration of bone faster than their regular, diamagnetic counterparts. In this study, analyzed was the influence of paramagnetic cobalt-substituted hydroxyapatite nanoparticles on osteoporotic alveolar bone regeneration in rats. Simultaneously, biocompatibility of the material was tested in vitro, on osteoblastic MC3T3-E1 and epithelial Caco-2 cells in culture. The material was shown to be biocompatible and nontoxic when added to epithelial monolayers in vitro, while it caused a substantial decrease in the cell viability as well as deformation of the cytoskeleton and cell morphology when incubated with the osteoblastic cells. In the course of six months after the implantation of the material containing different amounts of cobalt, ranging from 5 – 12 wt%, in the osteoporotic alveolar bone of the lower jaw, the following parameters were investigated: histopathological parameters, alkaline phosphatase and alveolar bone density. The best result in terms of osteoporotic bone tissue regeneration was observed for hydroxyapatite nanoparticles with the largest content of cobalt ions. The histological analysis showed a high level of reparatory ability of the nanoparticulate material implanted in the bone defect, paralleled by a corresponding increase in the alveolar bone density. The combined effect of growth factors from autologous plasma admixed to cobalt-substituted hydroxyapatite was furthermore shown to have a crucial effect on the augmented osteoporotic bone regeneration upon the implantation of the biomaterial investigated in this study. PMID:23090835

Establishment and characterization of in vivo orthotopic bioluminescent xenograft models from human osteosarcoma cell lines in Swiss nude and NSG mice.

PubMed

Marques da Costa, Maria Eugenia; Daudigeos-Dubus, Estelle; Gomez-Brouchet, Anne; Bawa, Olivia; Rouffiac, Valerie; Serra, Massimo; Scotlandi, Katia; Santos, Conceição; Geoerger, Birgit; Gaspar, Nathalie

2018-03-01

Osteosarcoma is one of the most common primary bone tumors in childhood and adolescence. Metastases occurrence at diagnosis or during disease evolution is the main therapeutic challenge. New drug evaluation to improve patient survival requires the development of various preclinical models mimicking at best the complexity of the disease and its metastatic potential. We describe here the development and characteristics of two orthotopic bioluminescent (Luc/mKate2) cell-derived xenograft (CDX) models, Saos-2-B-Luc/mKate2-CDX and HOS-Luc/mKate2-CDX, in different immune (nude and NSG mouse strains) and bone (intratibial and paratibial with periosteum activation) contexts. IVIS SpectrumCT system allowed both longitudinal computed tomography (CT) and bioluminescence real-time follow-up of primary tumor growth and metastatic spread, which was confirmed by histology. The murine immune context influenced tumor engraftment, primary tumor growth, and metastatic spread to lungs, bone, and spleen (an unusual localization in humans). Engraftment in NSG mice was found superior to that found in nude mice and intratibial bone environment more favorable to engraftment compared to paratibial injection. The genetic background of the two CDX models also led to distinct primary tumor behavior observed on CT scan. Saos-2-B-Luc/mKate2-CDX showed osteocondensed, HOS-Luc/mKate2-CDX osteolytic morphology. Bioluminescence defined a faster growth of the primary tumor and metastases in Saos-2-B-Luc/mKate2-CDX than in HOS-Luc/mKate2-CDX. The early detection of primary tumor growth and metastatic spread by bioluminescence allows an improved exploration of osteosarcoma disease at tumor progression, and metastatic spread, as well as the evaluations of anticancer treatments. Our orthotopic models with metastatic spread bring complementary information to other types of existing osteosarcoma models. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Smad7 Regulates the Adult Neural Stem/Progenitor Cell Pool in a Transforming Growth Factor β- and Bone Morphogenetic Protein-Independent Manner▿

PubMed Central

Krampert, Monika; Chirasani, Sridhar Reddy; Wachs, Frank-Peter; Aigner, Robert; Bogdahn, Ulrich; Yingling, Jonathan M.; Heldin, Carl-Henrik; Aigner, Ludwig; Heuchel, Rainer

2010-01-01

Members of the transforming growth factor β (TGF-β) family of proteins modulate the proliferation, differentiation, and survival of many different cell types. Neural stem and progenitor cells (NPCs) in the adult brain are inhibited in their proliferation by TGF-β and by bone morphogenetic proteins (BMPs). Here, we investigated neurogenesis in a hypomorphic mouse model for the TGF-β and BMP inhibitor Smad7, with the hypothesis that NPC proliferation might be reduced due to increased TGF-β and BMP signaling. Unexpectedly, we found enhanced NPC proliferation as well as an increased number of label-retaining cells in vivo. The enhanced proliferation potential of mutant cells was retained in vitro in neurosphere cultures. We observed a higher sphere-forming capacity as well as faster growth and cell cycle progression. Use of specific inhibitors revealed that these effects were independent of TGF-β and BMP signaling. The enhanced proliferation might be at least partially mediated by elevated signaling via epidermal growth factor (EGF) receptor, as mutant cells showed higher expression and activation levels of the EGF receptor. Conversely, an EGF receptor inhibitor reduced the proliferation of these cells. Our data indicate that endogenous Smad7 regulates neural stem/progenitor cell proliferation in a TGF-β- and BMP-independent manner. PMID:20479122

Comparison of potentials between stem cells isolated from human anterior cruciate ligament and bone marrow for ligament tissue engineering.

PubMed

Cheng, Ming-Te; Liu, Chien-Lin; Chen, Tain-Hsiung; Lee, Oscar K

2010-07-01

We have previously isolated and identified stem cells from human anterior cruciate ligament (ACL). The purpose of this study was to evaluate the differences in proliferation, differentiation, and extracellular matrix (ECM) formation abilities between bone marrow stem cells (BMSCs) and ACL-derived stem cells (LSCs) from the same donors when cultured with different growth factors, including basic fibroblast growth factor (bFGF), epidermal growth factor, and transforming growth factor-beta 1 (TGF-beta1). Ligament tissues and bone marrow aspirate were obtained from patients undergoing total knee arthroplasty and ACL reconstruction surgeries. Proliferation, colony formation, and population doubling capacity as well as multilineage differentiation potentials of LSCs and BMSCs were compared. Gene expression and ECM production for ligament engineering were also evaluated. It was found that BMSCs possessed better osteogenic differentiation potential than LSCs, while similar adipogenic and chondrogenic differentiation abilities were observed. Proliferation rates of both LSCs and BMSCs were enhanced by bFGF and TGF-beta1. TGF-beta1 treatment significantly increased the expression of type I collagen, type III collagen, fibronectin, and alpha-smooth muscle actin in LSCs, but TGF-beta1 only upregulated type I collagen and tenascin-c in BMSCs. Protein quantification further confirmed the results of differential gene expression and suggested that LSCs and BMSCs increase ECM production upon TGF-beta1 treatment. In summary, in comparison with BMSCs, LSCs proliferate faster and maintain an undifferentiated state with bFGF treatment, whereas under TGF-beta1 treatment, LSCs upregulate major tendinous gene expression and produce a robust amount of ligament ECM protein, making LSCs a potential cell source in future applications of ACL tissue engineering.

Injection and adhesion palatoplasty: a preliminary study in a canine model.

PubMed

Martínez-Álvarez, Concepción; González-Meli, Beatriz; Berenguer-Froehner, Beatriz; Paradas-Lara, Irene; López-Gordillo, Yamila; Rodríguez-Bobada, Cruz; González, Pablo; Chamorro, Manuel; Arias, Pablo; Hilborn, Jöns; Casado-Gómez, Inmaculada; Martínez-Sanz, Elena

2013-08-01

Raising mucoperiosteal flaps in traditional palatoplasty impairs mid-facial growth. Hyaluronic acid-based hydrogels have been successfully tested for minimally invasive craniofacial bone generation in vivo as carriers of bone morphogenetic protein-2 (BMP-2). We aimed to develop a novel flapless technique for cleft palate repair by injecting a BMP-2 containing hydrogel. Dog pups with congenital cleft palate were either non-treated (n=4) or treated with two-flap palatoplasty (n=6) or with the proposed injection/adhesion technique (n=5). The experimental approach was to inject a hyaluronic acid-based hydrogel containing hydroxyapatite and BMP-2 subperiosteally at the cleft palate margins of pups aged six weeks. At week ten, a thin strip of the medial edge mucosa was removed and the margins were closed directly. Occlusal photographs and computed tomography (CT) scans were obtained up to week 20. Four weeks after the gel injection the cleft palate margins had reached the midline and engineered bone had enlarged the palatal bones. Removal of the medial edge mucosa and suturing allowed complete closure of the cleft. Compared to traditional palatoplasty, the injection/adhesion technique was easier, and the post-surgical recovery was faster. CT on week 20 revealed some overlapping or "bending" of palatal shelves in the two-flap repair group, which was not observed in the experimental nor control groups. A minimally invasive technique for cleft palate repair upon injectable scaffolds in a dog model of congenital cleft palate is feasible. Results suggest better growth of palatal bones. This represents an attractive clinical alternative to traditional palatoplasty for cleft palate patients. Copyright © 2013 Elsevier Inc. All rights reserved.

Vertebral microanatomy in squamates: structure, growth and ecological correlates

PubMed Central

Houssaye, Alexandra; Mazurier, Arnaud; Herrel, Anthony; Volpato, Virginie; Tafforeau, Paul; Boistel, Renaud; de Buffrénil, Vivian

2010-01-01

The histological study of vertebrae in extant squamates shows that the internal vertebral structure in this group differs from that of other tetrapods. Squamate vertebrae are lightly built and basically composed of two roughly concentric osseous tubes – one surrounding the neural canal and the other constituting the peripheral cortex of the vertebra – connected by few thin trabeculae. This structure, which characteristically evokes that of a tubular bone, results from a peculiar remodelling process characterised by an imbalance between local bone resorption and redeposition; in both periosteal and endosteo-endochondral territories, bone is extensively resorbed but not reconstructed in the same proportion by secondary deposits. This process is particularly intense in the deep region of the centrum, where originally compact cortices are made cancellous, and where the endochondral spongiosa is very loose. This remodelling process starts at an early stage of development and remains active throughout subsequent growth. The growth of squamate centra is also strongly asymmetrical, with the posterior (condylar) part growing much faster than the anterior (cotylar) part. Preliminary analyses testing for associations between vertebral structure and habitat use suggest that vertebrae of fossorial taxa are denser than those of terrestrial taxa, those in aquatic taxa being of intermediate density. However, phylogenetically informed analyses do not corroborate these findings, thus suggesting a strong phylogenetic signal in the data. As our analyses demonstrate that vertebrae in snakes are generally denser than those of lizards sensu stricto, this may drive the presence of a phylogenetic signal in the data. More comprehensive sampling of fossorial and aquatic lizards is clearly needed to more rigorously evaluate these patterns. PMID:21039477

Bone Shaft Revascularization After Marrow Ablation Is Dramatically Accelerated in BSP-/- Mice, Along With Faster Hematopoietic Recolonization.

PubMed

Bouleftour, Wafa; Granito, Renata Neves; Vanden-Bossche, Arnaud; Sabido, Odile; Roche, Bernard; Thomas, Mireille; Linossier, Marie Thérèse; Aubin, Jane E; Lafage-Proust, Marie-Hélène; Vico, Laurence; Malaval, Luc

2017-09-01

The bone organ integrates the activity of bone tissue, bone marrow, and blood vessels and the factors ensuring this coordination remain ill defined. Bone sialoprotein (BSP) is with osteopontin (OPN) a member of the small integrin binding ligand N-linked glycoprotein (SIBLING) family, involved in bone formation, hematopoiesis and angiogenesis. In rodents, bone marrow ablation induces a rapid formation of medullary bone which peaks by ∼8 days (d8) and is blunted in BSP-/- mice. We investigated the coordinate hematopoietic and vascular recolonization of the bone shaft after marrow ablation of 2 month old BSP+/+ and BSP-/- mice. At d3, the ablated area in BSP-/- femurs showed higher vessel density (×4) and vascular volume (×7) than BSP+/+. Vessel numbers in the shaft of ablated BSP+/+ mice reached BSP-/- values only by d8, but with a vascular volume which was twice the value in BSP-/-, reflecting smaller vessel size in ablated mutants. At d6, a much higher number of Lin - (×3) as well as LSK (Lin - IL-7Rα - Sca-1 hi c-Kit hi , ×2) and hematopoietic stem cells (HSC: Flt3 - LSK, ×2) were counted in BSP-/- marrow, indicating a faster recolonization. However, the proportion of LSK and HSC within the Lin - was lower in BSP-/- and more differentiated stages were more abundant, as also observed in unablated bone, suggesting that hematopoietic differentiation is favored in the absence of BSP. Interestingly, unablated BSP-/- femur marrow also contains more blood vessels than BSP+/+, and in both intact and ablated shafts expression of VEGF and OPN are higher, and DMP1 lower in the mutants. In conclusion, bone marrow ablation in BSP-/- mice is followed by a faster vascular and hematopoietic recolonization, along with lower medullary bone formation. Thus, lack of BSP affects the interplay between hematopoiesis, angiogenesis, and osteogenesis, maybe in part through higher expression of VEGF and the angiogenic SIBLING, OPN. J. Cell. Physiol. 232: 2528-2537, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Mapping trace element distribution in fossil teeth and bone with LA-ICP-MS

NASA Astrophysics Data System (ADS)

Hinz, E. A.; Kohn, M. J.

2009-12-01

Trace element profiles were measured in fossil bones and teeth from the late Pleistocene (c. 25 ka) Merrell locality, Montana, USA, by using laser-ablation ICP-MS. Laser-ablation ICP-MS can collect element counts along predefined tracks on a sample’s surface using a constant ablation speed allowing for rapid spatial sampling of element distribution. Key elements analyzed included common divalent cations (e.g. Sr, Zn, Ba), a suite of REE (La, Ce, Nd, Sm, Eu, Yb), and U, in addition to Ca for composition normalization and standardization. In teeth, characteristic diffusion penetration distances for all trace elements are at least a factor of 4 greater in traverses parallel to the dentine-enamel interface (parallel to the growth axis of the tooth) than perpendicular to the interface. Multiple parallel traverses in sections parallel and perpendicular to the tooth growth axis were transformed into trace element maps, and illustrate greater uptake of all trace elements along the central axis of dentine compared to areas closer to enamel, or within the enamel itself. Traverses in bone extending from the external surface, through the thickness of cortical bone and several mm into trabecular bone show major differences in trace element uptake compared to teeth: U and Sr are homogeneous, whereas all REE show a kinked profile with high concentrations on outer surfaces that decrease by several orders of magnitude within a few mm inward. The Eu anomaly increases uniformly from the outer edge of bone inward, whereas the Ce anomaly decreases slightly. These observations point to major structural anisotropies in trace element transport and uptake during fossilization, yet transport and uptake of U and REE are not resolvably different. In contrast, transport and uptake of U in bone must proceed orders of magnitude faster than REE as U is homogeneous whereas REE exhibit strong gradients. The kinked REE profiles in bone unequivocally indicate differential transport rates, consistent with a double-medium diffusion model in which microdomains with slow diffusivities are bounded by fast-diffusing pathways.

A histomorphometric study of adaptive responses of cancellous bone in different regions in the sheep mandibular condyle following experimental forward mandibular displacement.

PubMed

Ma, Bingkui; Sampson, Wayne; Wilson, David; Wiebkin, Ole; Fazzalari, Nicola

2002-07-01

Forward mandibular displacement in animal models is associated with faster and/or redirected condylar growth. Here the effect of forward displacement induced with an intraoral appliance on modelling/remodelling of the mandibular condyle was investigated in eight, 4-month-old, castrated male Merino sheep, randomly allocated to experimental and control groups (n=4 in each group). The study period was 15 weeks, during that time, (1). calcein, (2). tetracycline, and (3). alizarin red S fluorochromes were given to all animals from day 1. Midsagittal sections of the temporomandibular joints were selected for analysis. Dynamic variables of bone formation, static indices of bone-forming and -resorbing activity, and structural indices of trabecular bone were estimated histomorphometrically. The sampling site was divided into two regions for analysis: (a). a 'subchondral region' (2 and 3 labels only), believed to be the bone newly formed during the experimental period; (b). a 'central region' (labelled by all three fluorochromes), believed to be the bone that existed before the experiment. Regional differences in adaptive response were found. In the experimental group, the bone-volume fraction (BV/TV) of the subchondral regions had decreased, although the specific bone-surface and bone-formation rates had increased. This low BV/TV was associated with decreased trabecular thickness and increased trabecular separation. In the central condylar region of the experimental group, BV/TV was unchanged, but an increased osteoid surface was apparent when the eroded surface was taken into consideration. These adaptive condylar responses to forward mandibular displacement appeared to be the result of increased osteoblastic activity. Further studies are recommended to examine why the subchondral and central regions responded differently.

An overview on autologous fibrin glue in bone tissue engineering of maxillofacial surgery

PubMed Central

Khodakaram-Tafti, Azizollah; Mehrabani, Davood; Shaterzadeh-Yazdi, Hanieh

2017-01-01

The purpose of this review is to have an overview on the applications on the autologous fibrin glue as a bone graft substitute in maxillofacial injuries and defects. A search was conducted using the databases such as Medline or PubMed and Google Scholar for articles from 1985 to 2016. The criteria were “Autograft,” “Fibrin tissue adhesive,” “Tissue engineering,” “Maxillofacial injury,” and “Regenerative medicine.” Bone tissue engineering is a new promising approach for bone defect reconstruction. In this technique, cells are combined with three-dimensional scaffolds to provide a tissue-like structure to replace lost parts of the tissue. Fibrin as a natural scaffold, because of its biocompatibility and biodegradability, and the initial stability of the grafted stem cells is introduced as an excellent scaffold for tissue engineering. It promotes cell migration, proliferation, and matrix making through acceleration in angiogenesis. Growth factors in fibrin glue can stimulate and promote tissue repair. Autologous fibrin scaffolds are excellent candidates for tissue engineering so that they can be produced faster, cheaper, and in larger quantities. In addition, they are easy to use and the probability of viral or prion transmission may be decreased. Therefore, autologous fibrin glue appears to be promising scaffold in regenerative maxillofacial surgery. PMID:28584530

Higher Resolution and Faster MRI of 31Phosphorus in Bone

NASA Astrophysics Data System (ADS)

Frey, Merideth; Barrett, Sean; Sethna, Zachary; Insogna, Karl; Vanhouten, Joshua

2013-03-01

Probing the internal composition of bone on the sub-100 μm length scale is important to study normal features and to look for signs of disease. However, few useful non-destructive techniques are available to evaluate changes in the bone mineral chemical structure and functional micro-architecture on the interior of bones. MRI would be an excellent candidate, but bone is a particularly challenging tissue to study given the relatively low water density, wider linewidths of its solid components leading to low spatial resolution, and the long imaging time compared to conventional 1H MRI. Our lab has recently made advances in obtaining high spatial resolution (sub-400 μm)3 three-dimensional 31Phosphorus MRI of bone through use of the quadratic echo line-narrowing sequence (1). In this talk, we describe our current results using proton decoupling to push this technique even further towards the factor of 1000 increase in spatial resolution imposed by fundamental limits. We also discuss our work to speed up imaging through novel, faster reconstruction algorithms that can reconstruct the desired image from very sparse data sets. (1) M. Frey, et al. PNAS 109: 5190 (2012).

Effect on Clinical Outcome and Growth Factor Synthesis With Adjunctive Use of Pulsed Electromagnetic Fields for Fifth Metatarsal Nonunion Fracture: A Double-Blind Randomized Study.

PubMed

Streit, Adam; Watson, B Collier; Granata, Jaymes D; Philbin, Terrence M; Lin, Hsuan-Ni; O'Connor, J Patrick; Lin, Sheldon

2016-09-01

Electromagnetic bone growth stimulators have been found to biologically enhance the bone healing environment, with upregulation of numerous growth factors. The purpose of the study was to quantify the effect, in vivo, of pulsed electromagnetic fields (PEMFs) on growth factor expression and healing time in fifth metatarsal nonunions. This was a prospective, randomized, double-blind trial of patients, cared for by 2 fellowship-trained orthopedic foot and ankle surgeons. Inclusion criteria consisted of patients between 18 and 75 years old who had been diagnosed with a fifth metatarsal delayed or nonunion, with no progressive signs of healing for a minimum of 3 months. Eight patients met inclusion criteria and were randomized to receive either an active stimulation or placebo PEMF device. Each patient then underwent an open biopsy of the fracture site and was fitted with the appropriate PEMF device. The biopsy was analyzed for messenger-ribonucleic acid (mRNA) levels using quantitative competitive reverse transcription polymerase chain reaction (QT-RT-PCR). Three weeks later, the patient underwent repeat biopsy and open reduction and internal fixation of the nonunion site. The patients were followed at 2- to 4-week intervals with serial radiographs and were graded by the number of cortices of healing. All fractures healed, with an average time to complete radiographic union of 14.7 weeks and 8.9 weeks for the inactive and active PEMF groups, respectively. A significant increase in placental growth factor (PIGF) level was found after active PEMF treatment (P = .043). Other factors trended higher following active PEMF including brain-derived neurotrophic factor (BDNF), bone morphogenetic protein (BMP) -7, and BMP-5. The adjunctive use of PEMF for fifth metatarsal fracture nonunions produced a significant increase in local placental growth factor. PEMF also produced trends toward higher levels of multiple other factors and faster average time to radiographic union compared to unstimulated controls. Level I, prospective randomized trial. © The Author(s) 2016.

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.

Phenotypic diagnosis of dwarfism in six Friesian horses.

PubMed

Back, W; van der Lugt, J J; Nikkels, P G J; van den Belt, A J M; van der Kolk, J H; Stout, T A E

2008-05-01

An extreme form of abnormal development, dwarfism, is common in man and some animals, but has not been officially reported in horses. Within the Friesian horse breed, congenital dwarfism has been recognised for many years, but no detailed report exists on its phenotype. The most salient feature of the dwarf syndrome is the physeal growth retardation in both limbs and ribs. Affected animals have approximately 25% shorter fore- and hindlimbs and approximately 50% reduced bodyweight. Postnatal growth is still possible in these animals, albeit at a slower rate: the head and back grow faster than the limbs and ribs leading to the characteristic disproportional growth disturbance. Thus, adult dwarfs exhibit a normal, but a relatively larger head conformation, a broader chest with narrowing at the costochondral junction, a disproportionally long back, abnormally short limbs, hyperextension of the fetlocks and narrow long-toed hooves. Furthermore, a dysplastic metaphysis of the distal metacarpus and metatarsus is radiographically evident. Microscopic analysis of the growth plates at the costochondral junction shows an irregular transition from cartilage to bone, and thickening and disturbed formation of chondrocyte columns, which is similar to findings in osteochondrodysplasia.

In vitro behaviour of three biocompatible glasses in composite implants.

PubMed

Varila, Leena; Lehtonen, Timo; Tuominen, Jukka; Hupa, Mikko; Hupa, Leena

2012-10-01

Poly(L,DL-lactide) composites containing filler particles of bioactive glasses 45S5 and S53P4 were compared with a composite containing a slowly dissolving glass S68. The in vitro reactivity of the composites was studied in simulated body fluid, Tris-buffered solution, and phosphate buffered saline. The high processing temperature induced thermal degradation giving cavities in the composites containing 45S5 and S53P4, while good adhesion of S68 to the polymer was observed. The cavities partly affected the in vitro reactivity of the composites. The degradation of the composites containing the bioactive glasses was faster in phosphate buffered saline than in the two other solutions. Hydroxyapatite precipitation suggesting bone tissue bonding capability was observed on these two composites in all three solutions. The slower dissolution of S68 glass particles and the limited hydroxyapatite precipitation suggested that this glass has potential as a reinforcing composition with the capability to guide bone tissue growth in biodegradable polymer composites.

Platelet rich fibrin in jaw defects

NASA Astrophysics Data System (ADS)

Nica, Diana; Ianes, Emilia; Pricop, Marius

2016-03-01

Platelet rich fibrin (PRF) is a tissue product of autologous origin abundant in growth factors, widely used in regenerative procedures. Aim of the study: Evaluation of the regenerative effect of PRF added in the bony defects (after tooth removal or after cystectomy) Material and methods: The comparative nonrandomized study included 22 patients divided into 2 groups. The first group (the test group) included 10 patients where the bony defects were treated without any harvesting material. The second group included 12 patients where the bony defects were filled with PRF. The bony defect design was not critical, with one to two walls missing. After the surgeries, a close clinically monitoring was carried out. The selected cases were investigated using both cone beam computer tomography (CBCT) and radiographic techniques after 10 weeks postoperatively. Results: Faster bone regeneration was observed in the bony defects filled with PRF comparing with the not grafted bony defects. Conclusions: PRF added in the bony defects accelerates the bone regeneration. This simplifies the surgical procedures and decreases the economic costs.

A comparison of long bone development in historical and contemporary ducks.

PubMed

Van Wyhe, R C; Applegate, T J; Lilburn, M S; Karcher, D M

2012-11-01

The selection for growth and carcass traits in poultry meat species has contributed to increased interest in understanding and characterizing skeletal growth as the birds struggle to balance skeletal development with increased BW and muscle mass. The objective of this study was to compare the physical characteristics and mineralization of the tibia and femur from commercial Pekin ducks representing circa 1993 and 2010 commercial strains. In 1993, the femur and tibia were collected from 8 ducks at 11 ages between 11 and 53 d. A similar study was done in 2010 in which the femur and tibia were collected from 8 ducks at 12 sample ages between 10 and 49 d. All bones were weighed and the length and width at 50% of length were measured. Each bone was subsequently cut into epiphyseal (top 25% of length) and diaphyseal (midregion at 50% of length) sections. Each bone segment was extracted with ether, hot weighed, and ashed. The 2010 contemporary ducks reached market weight faster than the 1993 ducks. Therefore, statistical comparisons were made at common BW as well as at common ages. The mean tibia length of the 2010 duck was 0.75 cm greater (P < 0.05) at similar ages and similar BW. The percentage ash in the diaphyseal region of the tibia was 3% greater (P < 0.05) in the 2010 versus 1993 ducks. The percentage epiphyseal ash in the femur was 10% lower (P < 0.01) at 10 d and 14 d in the 2010 ducks but there were no significant differences by 18 d of age. The lower epiphyseal ash values at both younger ages and smaller BW in the 2010 contemporary ducks suggests that it is critical to monitor those factors that influence bone mineralization in contemporary ducklings that can achieve market BW at earlier chronological ages.

In Vitro and In Vivo Evaluation of Zinc-Modified Ca–Si-Based Ceramic Coating for Bone Implants

PubMed Central

Zheng, Xuebin; He, Dannong; Ye, Xiaojian; Wang, Meiyan

2013-01-01

The host response to calcium silicate ceramic coatings is not always favorable because of their high dissolution rates, leading to high pH within the surrounding physiological environment. Recently, a zinc-incorporated calcium silicate-based ceramic Ca2ZnSi2O7 coating, developed on a Ti-6Al-4V substrate using plasma-spray technology, was found to exhibit improved chemical stability and biocompatibility. This study aimed to investigate and compare the in vitro response of osteoblastic MC3T3-E1 cells cultured on Ca2ZnSi2O7 coating, CaSiO3 coating, and uncoated Ti-6Al-4V titanium control at cellular and molecular level. Our results showed Ca2ZnSi2O7 coating enhanced MC3T3-E1 cell attachment, proliferation, and differentiation compared to CaSiO3 coating and control. In addition, Ca2ZnSi2O7 coating increased mRNA levels of osteoblast-related genes (alkaline phosphatase, procollagen α1(I), osteocalcin), insulin-like growth factor-I (IGF-I), and transforming growth factor-β1 (TGF-β1). The in vivo osteoconductive properties of Ca2ZnSi2O7 coating, compared to CaSiO3 coating and control, was investigated using a rabbit femur defect model. Histological and histomorphometrical analysis demonstrated new bone formation in direct contact with the Ca2ZnSi2O7 coating surface in absence of fibrous tissue and higher bone-implant contact rate (BIC) in the Ca2ZnSi2O7 coating group, indicating better biocompatibility and faster osseointegration than CaSiO3 coated and control implants. These results indicate Ca2ZnSi2O7 coated implants have applications in bone tissue regeneration, since they are biocompatible and able to osseointegrate with host bone. PMID:23483914

In vitro and in vivo evaluation of zinc-modified ca-si-based ceramic coating for bone implants.

PubMed

Yu, Jiangming; Li, Kai; Zheng, Xuebin; He, Dannong; Ye, Xiaojian; Wang, Meiyan

2013-01-01

The host response to calcium silicate ceramic coatings is not always favorable because of their high dissolution rates, leading to high pH within the surrounding physiological environment. Recently, a zinc-incorporated calcium silicate-based ceramic Ca2ZnSi2O7 coating, developed on a Ti-6Al-4V substrate using plasma-spray technology, was found to exhibit improved chemical stability and biocompatibility. This study aimed to investigate and compare the in vitro response of osteoblastic MC3T3-E1 cells cultured on Ca2ZnSi2O7 coating, CaSiO3 coating, and uncoated Ti-6Al-4V titanium control at cellular and molecular level. Our results showed Ca2ZnSi2O7 coating enhanced MC3T3-E1 cell attachment, proliferation, and differentiation compared to CaSiO3 coating and control. In addition, Ca2ZnSi2O7 coating increased mRNA levels of osteoblast-related genes (alkaline phosphatase, procollagen α1(I), osteocalcin), insulin-like growth factor-I (IGF-I), and transforming growth factor-β1 (TGF-β1). The in vivo osteoconductive properties of Ca2ZnSi2O7 coating, compared to CaSiO3 coating and control, was investigated using a rabbit femur defect model. Histological and histomorphometrical analysis demonstrated new bone formation in direct contact with the Ca2ZnSi2O7 coating surface in absence of fibrous tissue and higher bone-implant contact rate (BIC) in the Ca2ZnSi2O7 coating group, indicating better biocompatibility and faster osseointegration than CaSiO3 coated and control implants. These results indicate Ca2ZnSi2O7 coated implants have applications in bone tissue regeneration, since they are biocompatible and able to osseointegrate with host bone.

Magnesium Alloys as a Biomaterial for Degradable Craniofacial Screws

PubMed Central

Henderson, Sarah E.; Verdelis, Konstantinos; Maiti, Spandan; Pal, Siladitya; Chung, William L.; Chou, Da-Tren; Kumta, Prashant N.; Almarza, Alejandro J.

2014-01-01

Recently, magnesium (Mg) alloys have received significant attention as a potential biomaterial for degradable implants, and this study was directed at evaluating the suitability of Mg for craniofacial bone screws. The objective was to implant screws fabricated from commercially available Mg-alloys (pure Mg and AZ31) in-vivo in a rabbit mandible. First, Mg-alloy screws were compared to stainless steel screws in an in-vitro pull-out test and determined to have a similar holding strength (~40N). A finite element model of the screw was created using the pull-out test data, and the model can be used for future Mg-alloy screw design. Then, Mg-alloy screws were implanted for 4, 8, and 12 weeks, with two controls of an osteotomy site (hole) with no implant and a stainless steel screw implanted for 12 weeks. MicroCT (computed tomography) was used to assess bone remodeling and Mg-alloy degradation, both visually and qualitatively through volume fraction measurements for all time points. Histologic analysis was also completed for the Mg-alloys at 12 weeks. The results showed that craniofacial bone remodeling occurred around both Mg-alloy screw types. Pure Mg had a different degradation profile than AZ31, however bone growth occurred around both screw types. The degradation rate of both Mg-alloy screw types in the bone marrow space and the muscle were faster than in the cortical bone space at 12 weeks. Furthermore, it was shown that by alloying Mg, the degradation profile could be changed. These results indicate the promise of using Mg-alloys for craniofacial applications. PMID:24384125

Controllable mineral coatings on scaffolds as carriers for growth factor release for bone tissue engineering

NASA Astrophysics Data System (ADS)

Saurez-Gonzalez, Darilis

The work presented in this document, focused on the development and characterization of mineral coatings on scaffold materials to serve as templates for growth factor binding and release. Mineral coatings were formed using a biomimetic approach that consisted in the incubation of scaffolds in modified simulated body fluids (mSBF). To modulate the properties of the mineral coating, which we hypothesized would dictate growth factor release, we used carbonate (HCO3) concentration in mSBF of 4.2 mM, 25mM, and 100mM. Analysis of the mineral coatings formed using scanning electron microscopy indicated growth of a continuous layer of mineral with different morphologies. X-ray diffraction analysis showed peaks associated with hydroxyapatite. FTIR data confirmed the substitution of HCO3 in the mineral. As the extent of HCO3 substitution increased, the coating exhibited more rapid dissolution kinetics in an environment deficient in calcium and phosphate. The mineral coatings provided an effective mechanism for bioactive growth factor binding and release. Peptide versions of vascular endothelial growth factor (VEGF) and bone morphogenetic protein 2 (BMP2) were bound with efficiencies up to 90% to mineral-coated PCL scaffolds. Recombinant human vascular endothelial growth factor (rhVEGF) also bound to mineral coated scaffolds with lower efficiency (20%) and released with faster release kinetics compared to peptides growth factor. Released rhVEGF induced human umbilical vein endothelial cell (HUVEC) proliferation in vitro and enhanced blood vessel formation in vivo in an intramuscular sheep model. In addition to the use the mineral coatings for single growth factor release, we expanded the concept and bound both an angiogenic (rhVEGF) and osteogenic (mBMP2) growth factor by a simple double dipping process. Sustained release of both growth factors was demonstrated for over 60 days. Released rhVEGF enhanced blood vessel formation in vivo in sheep and its biological activity was not affected by the presence of mBMP2. The approach for growth factor binding and release from mineral coatings can be adapted to different materials and medical devices and provide a simple and adaptable mechanism for sustained release of single or dual growth factors.

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.

The effect of strontium ranelate on the healing of a fractured ulna with bone gap in rabbit.

PubMed

Ibrahim, Mohd Rafiq Mohd; Singh, Simmrat; Merican, Azhar Mahmood; Raghavendran, Hanumantha Rao Balaji; Murali, Malliga Raman; Naveen, Sangeetha Vasudevaraj; Kamarul, Tunku

2016-06-16

Fracture healing in bone gap is one of the major challenges encountered in Orthopedic Surgery. At present, the treatment includes bone graft, employing either internal or external fixation which has a significant impact on the patient, family and even society. New drugs are emerging in the markets such as anabolic bone-forming agents including teriparatide and strontium ranelate to stimulate bone growth. Based on the mechanism of their actions, we embarked on a study on the healing of a fractured ulna with bone gap in a rabbit model. We segregated ten rabbits into two groups: five rabbits in the test group and five rabbits in the control group. We created a 5 mm bone gap in the ulna bone, removing the periosteum as well. Rabbits in the test group received 450 mg/kg of strontium ranelate via oral administration, daily, for six weeks. The x-rays, CT scans and blood tests were performed every two weeks. At the end of six weeks, the rabbits were sacrificed, and the radius and ulna bones harvested for histopathological examination. Based on the x-rays and CT scans, fracture healing or bone formation was observed to be faster in the control group. From the x-ray findings, 80 % of the fracture united and by CT scan, 60 % of the fracture united in the control group at the end of the six-week study. None of the fractures united in the test group. However, the histopathology report showed that a callus of different stages was being formed in both groups, consisting of 80 % of bone. The serum levels of osteocalcin and alkaline phosphatase initially remained similar up to three weeks and changed slightly at the end of six weeks. We conclude that the strontium effect begins slowly, and while it may not interfere with bone cell proliferation it may interfere in the mineralization and delay the acute stage of fracture healing. We recommend that a larger sample size and a longer duration of the study period be implemented to confirm our finding.

Platelet released growth factors boost expansion of bone marrow derived CD34(+) and CD133(+) endothelial progenitor cells for autologous grafting.

PubMed

Lippross, Sebastian; Loibl, Markus; Hoppe, Sven; Meury, Thomas; Benneker, Lorin; Alini, Mauro; Verrier, Sophie

2011-01-01

Stem cell based autologous grafting has recently gained mayor interest in various surgical fields for the treatment of extensive tissue defects. CD34(+) and CD133(+) cells that can be isolated from the pool of bone marrow mononuclear cells (BMC) are capable of differentiating into mature endothelial cells in vivo. These endothelial progenitor cells (EPC) are believed to represent a major portion of the angiogenic regenerative cells that are released from bone marrow when tissue injury has occurred. In recent years tissue engineers increasingly looked at the process of vessel neoformation because of its major importance for successful cell grafting to replace damaged tissue. Up to now one of the greatest problems preventing a clinical application is the large scale of expansion that is required for such purpose. We established a method to effectively enhance the expansion of CD34(+) and CD133(+) cells by the use of platelet-released growth factors (PRGF) as a media supplement. PRGF were prepared from thrombocyte concentrates and used as a media supplement to iscove's modified dulbecco's media (IMDM). EPC were immunomagnetically separated from human bone morrow monocyte cells and cultured in IMDM + 10% fetal calf serum (FCS), IMDM + 5%, FCS + 5% PRGF and IMDM + 10% PRGF. We clearly demonstrate a statistically significant higher and faster cell proliferation rate at 7, 14, 21, and 28 days of culture when both PRGF and FCS were added to the medium as opposed to 10% FCS or 10% PRGF alone. The addition of 10% PRGF to IMDM in the absence of FCS leads to a growth arrest from day 14 on. In histochemical, immunocytochemical, and gene-expression analysis we showed that angiogenic and precursor markers of CD34(+) and CD133(+) cells are maintained during long-term culture. In summary, we established a protocol to boost the expansion of CD34(+) and CD133(+) cells. Thereby we provide a technical step towards the clinical application of autologous stem cell transplantation.

Impact of skeletal unloading on bone formation: Role of systemic and local factors

NASA Astrophysics Data System (ADS)

Bikle, Daniel D.; Halloran, Bernard P.; Morey-Holton, Emily

We have developed a model of skeletal unloading using growing rats whose hindlimbs are unweighted by tail suspension. The bones in the hindlimbs undergo a transient cessation of bone growth; when reloaded bone formation is accelerated until bone mass is restored. These changes do not occur in the normally loaded bones of the forelimbs. Associated with the fall in bone formation is a fall in 1,25(OH) 2D 3 production and osteocalcin levels. In contrast, no changes in parathyroid hormone, calcium, or corticosterone levels are seen. To examine the role of locally produced growth factors, we have measured the mRNA and protein levels of insulin like growth factor-1 (IGF-1) in bone during tail suspension. Surprisingly, both the mRNA and protein levels of IGF-1 increase during tail suspension as bone formation is reduced. Furthermore, the bones in the hindlimbs of the suspended animals develop a resistance to the growth promoting effects of both growth hormone and IGF-1 when given parenterally. Thus, the cessation of bone growth with skeletal unloading is apparently associated with a resistance to rather than failure to produce local growth factors. The cause of this resistance remains under active investigation.

Effect of a freeze-dried CMC/PLGA microsphere matrix of rhBMP-2 on bone healing.

PubMed

Schrier, J A; Fink, B F; Rodgers, J B; Vasconez, H C; DeLuca, P P

2001-10-07

The hypothesis of this research was that implants of poly(lactide-co-glycolide) (PLGA) microspheres loaded with bone morphogenetic protein-2 (rhBMP-2) and distributed in a freeze-dried carboxymethylcellulose (CMC) matrix would produce more new bone than would matrix implants of non-protein-loaded microspheres or matrix implants of only CMC. To test this hypothesis it was necessary to fashion microsphere-loaded CMC implants that were simple to insert, fit precisely into a defect, and would not elicit swelling. Microspheres were produced via a water-in-oil-in-water double-emulsion system and were loaded with rhBMP-2 by soaking them in a buffered solution of the protein at a concentration of 5.4 mg protein per gram of PLGA. Following recovery of the loaded microspheres by lyophilization, matrices for implantation were prepared by lyophilizing a suspension of the microspheres in 2% CMC in flat-bottom tissue culture plates. Similar matrices were made with 2% CMC and with 2% CMC containing blank microspheres. A full-thickness calvarial defect model in New Zealand white rabbits was used to assess bone growth. Implants fit the defect well, allowing for direct application. Six weeks postsurgery, defects were collected and processed for undecalcified histology. In vitro, 60% of the loaded rhBMP-2 released from devices or microspheres in 5 to 7 days, with the unembedded microspheres releasing faster than those embedded in CMC. In vivo, the rhBMP-2 microspheres greatly enhanced bone healing, whereas nonloaded PLGA microspheres in the CMC implants had little effect. The results showed that a lyophilized device of rhBMP-2/PLGA microspheres in CMC was an effective implantable protein-delivery system for use in bone repair.

Ethnic and sex differences in skeletal maturation among the Birth to Twenty cohort in South Africa

PubMed Central

Cole, Tim J; Rousham, Emily K; Hawley, Nicola L; Cameron, Noel; Norris, Shane A; Pettifor, John M

2015-01-01

Aim To examine ethnic and sex differences in the pattern of skeletal maturity from adolescence to adulthood using a novel longitudinal analysis technique (SuperImposition by Translation And Rotation (SITAR)). Setting Johannesburg, South Africa. Participants 607 boys and girls of black as well as white ethnicity from the Birth to Twenty bone health study, assessed annually from 9 to 20 years of age. Outcome measure Bone maturity scores (Tanner–Whitehouse III radius, ulna, and short bones (TW3 RUS)) assessed longitudinally from hand-wrist radiographs were used to produce individual and mean growth curves of bone maturity and analysed by the SITAR method. Results The longitudinal analysis showed that black boys matured later by 7.0 SE 1.6 months (p<0.0001) but at the same rate as white boys, whereas black girls matured at the same age but at a faster rate than white girls (by 8.7% SE 2.6%, p=0.0007). The mean curves for bone maturity score consistently showed a midpubertal double kink, contrasting with the quadratic shape of the commonly used reference centile curves for bone maturity (TW3). Conclusions Skeletal maturity was reached 1.9 years earlier in girls than boys, and the pattern of maturation differed between the sexes. Within girls, there were no ethnic differences in the pattern or timing of skeletal maturity. Within boys, however, skeletal maturity was delayed by 7 months in black compared with white ethnicity. Skeletal maturation, therefore, varies differentially by sex and ethnicity. The delayed maturity of black boys, but not black girls, supports the hypothesis that boys have greater sensitivity to environmental constraints than girls. PMID:25409981

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.

Osseoconductivity of a Specific Streptavidin-Biotin-Fibronectin Surface Coating of Biotinylated Titanium Implants - A Rabbit Animal Study.

PubMed

Kämmerer, Peer W; Lehnert, Michael; Al-Nawas, Bilal; Kumar, Vinay V; Hagmann, Sebastien; Alshihri, Abdulmonem; Frerich, Bernhard; Veith, Michael

2015-10-01

Biofunctionalized implant surfaces may accelerate bony integration and increase long-term stability. The aim of the study was to evaluate the osseous reaction toward biomimetic titanium implants surfaces coated with quasicovalent immobilized fibronectin in an in vivo animal model. A total of 84 implants (uncoated [control 1, n = 36], streptavidin-biotin coated [test 1, n = 24], streptavidin-biotin-fibronectin coated [test 2, n = 24]) were inserted 1 mm supracortically in the proximal tibia of 12 rabbits. The samples were examined after 3 and 6 weeks. Total bone-implant contact (tBIC; %), bone-implant contact in the cortical (cBIC; %) and in the spongious bone (sBIC; %) as well as the percentage of linear bone fill (PLF; %) were evaluated. After 3 weeks, streptavidin-biotin-fibronectin implants had a significant higher sBIC (p = .043) and PLF (p = .007) compared with the uncoated samples. After 6 weeks, this difference was significant for tBIC (p = .016) and cBIC (p < .001). Additionally, uncoated screws showed a significant higher sBIC when compared with the fibronectin coating (p < .001). Streptavidin-biotin-coated implants showed less bone growth at both time points of all examined parameters when compared with their counterparts (all p < .001). Quasicovalent immobilization of biotinylated fibronectin with the streptavidin-biotin-fibronectin system on smooth surface titanium shows a beneficial faster osseous healing in vivo. Besides, an antifouling effect of the streptavidin-biotin coating was proven. © 2015 Wiley Periodicals, Inc.

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.

Socket Preservation using Enzyme-treated Equine Bone Granules and an Equine Collagen Matrix: A Case Report with Histological and Histomorphometrical Assessment.

PubMed

Leonida, Alessandro; Todeschini, Giovanni; Lomartire, Giovanni; Cinci, Lorenzo; Pieri, Laura

2016-11-01

To histologically assess the effectiveness of a socket-preservation technique using enzyme-treated equine bone granules as a bone-graft material in combination with an equine collagen matrix as a scaffold for soft-tissue regeneration. Enzyme-treated equine bone granules and equine collagen matrix recently have been developed to help overcome alveolar bone deficiencies that develop in the wake of edentulism. The patient had one mandibular molar extracted and the socket grafted with equine bone granules. The graft was covered with the equine collagen matrix, placed in a double layer. No flap was prepared, and the gingival margins were stabilized with a single stitch, leaving the matrix partially exposed and the site to heal by secondary intention. The adjacent molar was extracted 1 month later, and that socket was left to heal by secondary intention without any further treatment. Three months after each surgery, an implant was placed and a biopsy was collected. The two biopsies underwent histological processing and qualitative evaluation. Histomorphometric analysis was also performed to calculate the percentage of newly formed bone (NFB) in the two cores. Healing at both sites was uneventful, and no inflammation or other adverse reactions were observed in the samples. Soft-tissue healing by secondary intention appeared to occur faster at the grafted site. The corresponding core showed a marked separation between soft and hard tissue that was not observed in the core from the nongrafted site, where soft-tissue hypertrophy could be observed. Newly formed bone at the grafted and nongrafted sites was not significantly different (27.2 ± 7.1 and 29.4 ± 6.2% respectively, p = 0.45). The surgical technique employed in this case appeared to facilitate postextraction soft-tissue healing by second intention and simplify soft-tissue management. Using a collagen-based matrix to cover a postextraction grafted site may facilitate second intention soft-tissue healing and proper soft-tissue growth.

Discrete tomography in an in vivo small animal bone study.

PubMed

Van de Casteele, Elke; Perilli, Egon; Van Aarle, Wim; Reynolds, Karen J; Sijbers, Jan

2018-01-01

This study aimed at assessing the feasibility of a discrete algebraic reconstruction technique (DART) to be used in in vivo small animal bone studies. The advantage of discrete tomography is the possibility to reduce the amount of X-ray projection images, which makes scans faster and implies also a significant reduction of radiation dose, without compromising the reconstruction results. Bone studies are ideal for being performed with discrete tomography, due to the relatively small number of attenuation coefficients contained in the image [namely three: background (air), soft tissue and bone]. In this paper, a validation is made by comparing trabecular bone morphometric parameters calculated from images obtained by using DART and the commonly used standard filtered back-projection (FBP). Female rats were divided into an ovariectomized (OVX) and a sham-operated group. In vivo micro-CT scanning of the tibia was done at baseline and at 2, 4, 8 and 12 weeks after surgery. The cross-section images were reconstructed using first the full set of projection images and afterwards reducing them in number to a quarter and one-sixth (248, 62, 42 projection images, respectively). For both reconstruction methods, similar changes in morphometric parameters were observed over time: bone loss for OVX and bone growth for sham-operated rats, although for DART the actual values were systematically higher (bone volume fraction) or lower (structure model index) compared to FBP, depending on the morphometric parameter. The DART algorithm was, however, more robust when using fewer projection images, where the standard FBP reconstruction was more prone to noise, showing a significantly bigger deviation from the morphometric parameters obtained using all projection images. This study supports the use of DART as a potential alternative method to FBP in X-ray micro-CT animal studies, in particular, when the number of projections has to be drastically minimized, which directly reduces scanning time and dose.

[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.

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.

The synergistic effect of VEGF and biomorphic silicon carbides topography on in vivo angiogenesis and human bone marrow derived mesenchymal stem cell differentiation.

PubMed

Díaz-Rodríguez, P; Gómez-Amoza, J L; Landin, M

2015-08-04

Topographical features of biomaterials are able to modulate cell attachment, spreading and differentiation. The addition of growth factors to implantable biomaterials can modify these cellular responses, enhancing their therapeutic potential. The aim of this research is to establish the influence of biomorphic silicon carbide ceramics (bioSiCs) surface topography on the proliferation and osteoblastic differentiation of mesenchymal stem cells and the potential synergistic effect of the ceramic porous structure together with vascular endothelial growth factor loading (VEGF) on the surface mediated osteoblastic differentiation. Three porous bioSiCs with important differences in their microstructure were obtained from different natural precursors. Samples loaded with or without VEGF through ionic interactions were cultured with human umbilical vein endothelial cells (HUVEC) or bone marrow derived mesenchymal stem cells (hMSCs). Cell behaviour and protein activity with regard to bioSiC porous structure and surface properties were analysed. An in vivo model (Chick Chorioallantoic Membrane; CAM) was used to assess the capability of the VEGF loaded systems to promote angiogenesis. Experimental data show that loaded systems were able to control the release of VEGF for up to 15 d ensuring the activity of the protein, increasing the proliferation of HUVECs and the formation of new blood vessels in the CAM. It was found that the selection of bioSiCs with a higher pore size promoted a higher concentration of osteoblastic differentiation markers of MSCs cultured on the surface of bioSiCs. Furthermore, the addition of VEGF to the systems was able to promote a faster osteoblastic differentiation according to the qPCR results, suggesting a synergy between both the surface properties and the controlled release of the growth factor. The VEGF loaded sapelli bioSiC was found to be the most promising material for bone tissue engineering applications.

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

PubMed Central

Esteve-Altava, Borja; Rasskin-Gutman, Diego

2014-01-01

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. PMID:24975579

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.

Growth Hormone and Craniofacial Tissues. An update

PubMed Central

Litsas, George

2015-01-01

Growth hormone is an important regulator of bone homeostasis. In childhood, it determines the longitudinal bone growth, skeletal maturation, and acquisition of bone mass. In adulthood, it is necessary to maintain bone mass throughout life. Although an association between craniofacial and somatic development has been clearly established, craniofacial growth involves complex interactions of genes, hormones and environment. Moreover, as an anabolic hormone seems to have an important role in the regulation of bone remodeling, muscle enhancement and tooth development. In this paper the influence of growth hormone on oral tissues is reviewed. PMID:25674165

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.

Influence of Exercise and Training on Critical Stages of Bone Growth and Development.

PubMed

Klentrou, Panagiota

2016-05-01

Although osteoporosis is considered a geriatric disease, factors affecting bone strength are most influential during child growth and development. This article reviews what is known and still unclear in terms of bone growth, development and adaptation relative to physical activity before and during puberty. Bone is responsive to certain exercise protocols early in puberty and less so in postpubertal years, where bone strength, rather than bone mass, being the outcome of interest. Mechanical loading and high impact exercise promote bone strength. Intense training before and during puberty, however, may negatively affect bone development. Future research should focus on increasing our mechanistic understanding of the manner by which diverse physical stressors alter the integrity of bone. Longitudinal studies that examine the extent to which muscle and bone are comodulated by growth in children are also recommended.

DMP-1-mediated Ghr gene recombination compromises skeletal development and impairs skeletal response to intermittent PTH.

PubMed

Liu, Zhongbo; Kennedy, Oran D; Cardoso, Luis; Basta-Pljakic, Jelena; Partridge, Nicola C; Schaffler, Mitchell B; Rosen, Clifford J; Yakar, Shoshana

2016-02-01

Bone minerals are acquired during growth and are key determinants of adult skeletal health. During puberty, the serum levels of growth hormone (GH) and its downstream effector IGF-1 increase and play critical roles in bone acquisition. The goal of the current study was to determine how bone cells integrate signals from the GH/IGF-1 to enhance skeletal mineralization and strength during pubertal growth. Osteocytes, the most abundant bone cells, were shown to orchestrate bone modeling during growth. We used dentin matrix protein (Dmp)-1-mediated Ghr knockout (DMP-GHRKO) mice to address the role of the GH/IGF axis in osteocytes. We found that DMP-GHRKO did not affect linear growth but compromised overall bone accrual. DMP-GHRKO mice exhibited reduced serum inorganic phosphate and parathyroid hormone (PTH) levels and decreased bone formation indices and were associated with an impaired response to intermittent PTH treatment. Using an osteocyte-like cell line along with in vivo studies, we found that PTH sensitized the response of bone to GH by increasing Janus kinase-2 and IGF-1R protein levels. We concluded that endogenously secreted PTH and GHR signaling in bone are necessary to establish radial bone growth and optimize mineral acquisition during growth. © FASEB.

Dual Delivery of EPO and BMP2 from a Novel Modular Poly-ɛ-Caprolactone Construct to Increase the Bone Formation in Prefabricated Bone Flaps

PubMed Central

Patel, Janki Jayesh; Modes, Jane E.; Flanagan, Colleen L.; Krebsbach, Paul H.; Edwards, Sean P.

2015-01-01

Poly-ɛ-caprolactone (PCL) is a biocompatible polymer that has mechanical properties suitable for bone tissue engineering; however, it must be integrated with biologics to stimulate bone formation. Bone morphogenetic protein-2 (BMP2) delivered from PCL produces bone when implanted subcutaneously, and erythropoietin (EPO) works synergistically with BMP2. In this study, EPO and BMP2 are adsorbed separately on two 3D-printed PCL scaffold modules that are assembled for codelivery on a single scaffold structure. This assembled modular PCL scaffold with dual BMP2 and EPO delivery was shown to increase bone growth in an ectopic location when compared with BMP2 delivery along a replicate scaffold structure. EPO (200 IU/mL) and BMP2 (65 μg/mL) were adsorbed onto the outer and inner portions of a modular scaffold, respectively. Protein binding and release studies were first quantified. Subsequently, EPO+BMP2 and BMP2 scaffolds were implanted subcutaneously in mice for 4 and 8 weeks, and the regenerated bone was analyzed with microcomputed tomography and histology; 8.6±1.4 μg BMP2 (22%) and 140±29 IU EPO (69.8%) bound to the scaffold and <1% BMP2 and 83% EPO was released in 7 days. Increased endothelial cell proliferation on EPO-adsorbed PCL discs indicated protein bioactivity. At 4 and 8 weeks, dual BMP2 and EPO delivery regenerated more bone (5.1±1.1 and 5.5±1.6 mm3) than BMP2 alone (3.8±1.1 and 4.3±1.7 mm3). BMP2 and EPO scaffolds had more ingrowth (1.4%±0.6%) in the outer module when compared with BMP2 (0.8%±0.3%) at 4 weeks. Dual delivery produced more dense cellular marrow, while BMP2 had more fatty marrow. Dual EPO and BMP2 delivery is a potential method to regenerate bone faster for prefabricated flaps. PMID:25809081

Dual Delivery of EPO and BMP2 from a Novel Modular Poly-ɛ-Caprolactone Construct to Increase the Bone Formation in Prefabricated Bone Flaps.

PubMed

Patel, Janki Jayesh; Modes, Jane E; Flanagan, Colleen L; Krebsbach, Paul H; Edwards, Sean P; Hollister, Scott J

2015-09-01

Poly-ɛ-caprolactone (PCL) is a biocompatible polymer that has mechanical properties suitable for bone tissue engineering; however, it must be integrated with biologics to stimulate bone formation. Bone morphogenetic protein-2 (BMP2) delivered from PCL produces bone when implanted subcutaneously, and erythropoietin (EPO) works synergistically with BMP2. In this study, EPO and BMP2 are adsorbed separately on two 3D-printed PCL scaffold modules that are assembled for codelivery on a single scaffold structure. This assembled modular PCL scaffold with dual BMP2 and EPO delivery was shown to increase bone growth in an ectopic location when compared with BMP2 delivery along a replicate scaffold structure. EPO (200 IU/mL) and BMP2 (65 μg/mL) were adsorbed onto the outer and inner portions of a modular scaffold, respectively. Protein binding and release studies were first quantified. Subsequently, EPO+BMP2 and BMP2 scaffolds were implanted subcutaneously in mice for 4 and 8 weeks, and the regenerated bone was analyzed with microcomputed tomography and histology; 8.6±1.4 μg BMP2 (22%) and 140±29 IU EPO (69.8%) bound to the scaffold and <1% BMP2 and 83% EPO was released in 7 days. Increased endothelial cell proliferation on EPO-adsorbed PCL discs indicated protein bioactivity. At 4 and 8 weeks, dual BMP2 and EPO delivery regenerated more bone (5.1±1.1 and 5.5±1.6 mm(3)) than BMP2 alone (3.8±1.1 and 4.3±1.7 mm(3)). BMP2 and EPO scaffolds had more ingrowth (1.4%±0.6%) in the outer module when compared with BMP2 (0.8%±0.3%) at 4 weeks. Dual delivery produced more dense cellular marrow, while BMP2 had more fatty marrow. Dual EPO and BMP2 delivery is a potential method to regenerate bone faster for prefabricated flaps.

A strontium-incorporated nanoporous titanium implant surface for rapid osseointegration

NASA Astrophysics Data System (ADS)

Zhang, Wenjie; Cao, Huiliang; Zhang, Xiaochen; Li, Guanglong; Chang, Qing; Zhao, Jun; Qiao, Yuqin; Ding, Xun; Yang, Guangzheng; Liu, Xuanyong; Jiang, Xinquan

2016-02-01

Rapid osseointegration of dental implants will shorten the period of treatment and enhance the comfort of patients. Due to the vital role of angiogenesis played during bone development and regeneration, it might be feasible to promote rapid osseointegration by modifying the implant surface to gain a combined angiogenesis/osteogenesis inducing capacity. In this study, a novel coating (MAO-Sr) with strontium-incorporated nanoporous structures on titanium implants was generated via a new micro-arc oxidation, in an attempt to induce angiogenesis and osteogenesis to enhance rapid osseointegration. In vitro, the nanoporous structure significantly enhanced the initial adhesion of canine BMSCs. More importantly, sustained release of strontium ions also displayed a stronger effect on the BMSCs in facilitating their osteogenic differentiation and promoting the angiogenic growth factor secretion to recruit endothelial cells and promote blood vessel formation. Advanced mechanism analyses indicated that MAPK/Erk and PI3K/Akt signaling pathways were involved in these effects of the MAO-Sr coating. Finally, in the canine dental implantation study, the MAO-Sr coating induced faster bone formation within the initial six weeks and the osseointegration effect was comparable to that of the commercially available ITI implants. These results suggest that the MAO-Sr coating has the potential for future use in dental implants.Rapid osseointegration of dental implants will shorten the period of treatment and enhance the comfort of patients. Due to the vital role of angiogenesis played during bone development and regeneration, it might be feasible to promote rapid osseointegration by modifying the implant surface to gain a combined angiogenesis/osteogenesis inducing capacity. In this study, a novel coating (MAO-Sr) with strontium-incorporated nanoporous structures on titanium implants was generated via a new micro-arc oxidation, in an attempt to induce angiogenesis and osteogenesis to enhance rapid osseointegration. In vitro, the nanoporous structure significantly enhanced the initial adhesion of canine BMSCs. More importantly, sustained release of strontium ions also displayed a stronger effect on the BMSCs in facilitating their osteogenic differentiation and promoting the angiogenic growth factor secretion to recruit endothelial cells and promote blood vessel formation. Advanced mechanism analyses indicated that MAPK/Erk and PI3K/Akt signaling pathways were involved in these effects of the MAO-Sr coating. Finally, in the canine dental implantation study, the MAO-Sr coating induced faster bone formation within the initial six weeks and the osseointegration effect was comparable to that of the commercially available ITI implants. These results suggest that the MAO-Sr coating has the potential for future use in dental implants. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr08580b

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.

Restrain of bone growth by estrogen-mimetic peptide-1 (EMP-1): a micro-computed tomographic study.

PubMed

Kasher, Roni; Bajayo, Alon; Gabet, Yankel; Nevo, Nava; Fridkin, Mati; Katchalski-Katzir, Ephraim; Kohen, Fortune; Bab, Itai

2009-06-01

Estrogen has a key role in the regulation of skeletal growth and maintenance of bone mass. Recently, we developed peptides having estrogen-like activity as potential estrogen-based new drugs. The aim of the present study was to evaluate the influence of long-term administration of the most efficacious of these peptides, the hexapeptide EMP-1 (VSWFFE), on bone mass and development. EMP-1 was injected daily to ovariectomized (OVX) and intact young, sexually mature female mice for 10 weeks. Whole femora, including the cartilaginous growth plates were analyzed by micro-computed tomography (microCT). We found that peptide EMP-1 restrains bone growth in OVX mice: it inhibited dramatically bone longitudinal growth (40%), and decreased femoral diaphyseal diameter. Peptide EMP-1 had no effect on bone growth in normal mice, and did not influence the OVX-induced bone loss. We then developed a new microCT methodology to evaluate uncalcified and calcified growth plate parameters. In the OVX mice, peptide EMP-1 reduced volume and thickness of the uncalcified growth plate, a possible cause for the inhibition of bone longitudinal growth. Peptide EMP-1 may be used as a lead compound for the development of drugs to treat acromegalic patients.

Reconstruction of goat femur segmental defects using triphasic ceramic-coated hydroxyapatite in combination with autologous cells and platelet-rich plasma.

PubMed

Nair, Manitha B; Varma, H K; Menon, K V; Shenoy, Sachin J; John, Annie

2009-06-01

Segmental bone defects resulting from trauma or pathology represent a common and significant clinical problem. In this study, a triphasic ceramic (calcium silicate, hydroxyapatite and tricalcium phosphate)-coated hydroxyapatite (HASi) having the benefits of both HA (osteointegration, osteoconduction) and silica (degradation) was used as a bone substitute for the repair of segmental defect (2 cm) created in a goat femur model. Three experimental goat femur implant groups--(a) bare HASi, (b) osteogenic-induced goat bone marrow-derived mesenchymal stem cells cultured HASi (HASi+C) and (c) osteogenic-induced goat bone marrow-derived mesenchymal stem cells cultured HASi+platelet-rich plasma (HASi+CP)--were designed and efficacy performance in the healing of the defect was evaluated. In all the groups, the material united with host bone without any inflammation and an osseous callus formed around the implant. This reflects the osteoconductivity of HASi where the cells have migrated from the cut ends of host bone. The most observable difference between the groups appeared in the mid region of the defect. In bare HASi groups, numerous osteoblast-like cells could be seen together with a portion of material. However, in HASi+C and HASi+CP, about 60-70% of that area was occupied by woven bone, in line with material degradation. The interconnected porous nature (50-500 microm), together with the chemical composition of the HASi, facilitated the degradation of HASi, thereby opening up void spaces for cellular ingrowth and bone regeneration. The combination of HASi with cells and PRP was an added advantage that could promote the expression of many osteoinductive proteins, leading to faster bone regeneration and material degradation. Based on these results, we conclude that bare HASi can aid in bone regeneration but, with the combination of cells and PRP, the sequence of healing events are much faster in large segmental bone defects in weight-bearing areas in goats.

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.

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

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.

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

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.

Developmental Regulation of the Growth Plate and Cranial Synchondrosis

PubMed Central

Wei, X.; Hu, M.; Mishina, Y.; Liu, F.

2016-01-01

Long bones and the cranial base are both formed through endochondral ossification. Elongation of long bones is primarily through the growth plate, which is a cartilaginous structure at the end of long bones made up of chondrocytes. Growth plate chondrocytes are organized in columns along the longitudinal axis of bone growth. The cranial base is the growth center of the neurocranium. Synchondroses, consisting of mirror-image growth plates, are critical for cranial base elongation and development. Over the last decade, considerable progress has been made in determining the roles of the parathyroid hormone–related protein, Indian hedgehog, fibroblast growth factor, bone morphogenetic protein, and Wnt signaling pathways in various aspects of skeletal development. Furthermore, recent evidence indicates the important role of the primary cilia signaling pathway in bone elongation. Here, we review the development of the growth plate and cranial synchondrosis and the regulation by the above-mentioned signaling pathways, highlighting the similarities and differences between these 2 structures. PMID:27250655

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.

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.

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

Effect of PDGF-BB and beta-tricalcium phosphate (β-TCP) on bone formation around dental implants: a pilot study in sheep.

PubMed

Choo, Tina; Marino, Victor; Bartold, P Mark

2013-02-01

The aim of this investigation was to examine the effect of a combination of purified recombinant human platelet-derived growth factor (rhPDGF-BB) mixed with a synthetic beta-tricalcium phosphate (β-TCP) on bone healing around dental implants with critical size circumferential defects. Three critical size circumferential defects were prepared in the ilium of six sheep. Three dental implants were placed into the centre of each defect and the 3.25 mm circumferential gap was filled with (a) blood clot alone; (b) β-TCP; (c) rhPDGF-BB (0.3 mg/ml) with β-TCP. All the defects in each group were covered with a Bio-Gide(®) resorbable barrier membrane. The sheep were sacrificed at 2 and 4 weeks and histological and histomorphometric analyses were performed to determine the percentage of new mineralized bone formation and residual β-TCP graft particles in the defects. Defects filled with rhPDGF-BB/β-TCP showed the highest rate of bone formation after 2 and 4 weeks with limited degradation of the β-TCP particles over 4 weeks. Defects filled with β-TCP showed the least bone fill after 2 and 4 weeks, and faster degradation of the β-TCP particles over 4 weeks compared with defects filled with rhPDGF-BB/β-TCP. Percentage of new mineralized bone was comparable in defects to blood clot alone and β-TCP after 4 weeks of healing, but there was a collapse in the defect area in defects with blood clot alone. In comparison, the space was maintained when β-TCP was used in defects at 4 weeks. Defects which had β-TCP alone showed an inhibition in bone healing at 2 and 4 weeks; however, the combination of rhPDGF-BB with β-TCP enhanced bone regeneration in these peri-implant bone defects at the same time intervals. © 2011 John Wiley & Sons A/S.

Bone healing and bone substitutes.

PubMed

Costantino, Peter D; Hiltzik, David; Govindaraj, Satish; Moche, Jason

2002-02-01

With the advent of new biomaterials and surgical techniques, the reconstructive surgeon has a wider range of treatment modalities for the rehabilitation and reconstruction of craniofacial skeletal deformities than ever before. These innovative substances act as true bone graft substitutes, thereby allowing the surgeon to avoid the use of autogenous bone grafts and their associated donor site morbidity. Surgeons have long been interested in producing a composite graft that can heal faster by induction, incorporate with surrounding tissues, and be remodeled to resemble native bone. Currently, there are a host of bone graft substitutes available that vary in both their composition and properties. Craniomaxillofacial surgeons must therefore become comfortable with numerous biomaterials to best tailor the treatment for each patient individually. Ongoing investigations into the next phase of tissue engineering will continue to bring us closer to the ability to regenerate or replace bone.

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.

Interface activation and surface characteristics of Ti/TiN/HA coated sintered stainless steels

NASA Astrophysics Data System (ADS)

Choe, Han-Cheol; Ko, Yeong-Mu

2006-02-01

Interface activation and surface characteristics of Ti/TiN/HA film coated sintered stainless steels (SSS) have been investigated by electrochemical and biocompatibility tests. HA (hydroxyapatite), Ti, and Ti/TiN film coatings were applied using electron-beam deposition method (EB-PVD). Ti, Ti/TiN, and Ti/TiN/HA film coated surfaces and layers were investigated by SEM and XPS. The coated films showed micro-columnar structure, and Ti/TiN/HA films were denser than Ti or HA-only film. The corrosion resistance of the HA coating was similar to that of Ti/TiN/HA film coating when Cu content reached 4 wt.%, but the corrosion resistance of the HA coating decreased when Cu content increased from 4 wt.% in 0.9% NaCl solution. Therefore, HA-only coating could ensure corrosion resistance when Cu content does not exceed 4 wt.%. The results of biocompatibility tests of SSS on dogs showed that bone formation and biocompatibility were favorable when Cu content did not exceed 4 wt.%. The biocompatibility with bone was generally favorable in Ti/TiN/HA film coating and HA-only coating, while bone formation was somewhat faster for the HA film coated surface than for the Ti/TiN/HA film coating. Also, good cell growth and osseointegration without toxicity were observed.

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

Disturbances of bone growth and development

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

Ledesma-Medina, J.; Newman, B.; Oh, K.S.

1988-03-01

''What is growth anyway. Can one talk about positive growth in childhood, neutral growth in maturity, and negative growth in old age. Our goal is to help promote normal positive growth in infants and children. To achieve this, we must be cognizant of the morphologic changes of both normal and abnormal bone formation as they are reflected in the radiographic image of the skeleton. The knowledge of the various causes and the pathophysiologic mechanisms of the disturbances of bone growth and development allows us to recognize the early radiographic manifestations. Endocrine and metabolic disorders affect the whole skeleton, but themore » early changes are best seen in the distal ends of the femurs, where growth rate is most rapid. In skeletal infections and in some vascular injuries two-or three-phase bone scintigraphy supercedes radiography early in the course of the disease. MRI has proved to be very helpful in the early detection of avascular bone necrosis, osteomyelitis, and tumor. Some benign bone tumors and many bone dysplasias have distinct and diagnostic radiographic findings that may preclude further studies. In constitutional diseases of bone, including chromosomal aberrations, skeletal surveys of the patient and all family members together with biochemical and cytogenetic studies are essential for both diagnosis and genetic counseling. Our role is to perform the least invasive and most informative diagnostic imaging modalities that corroborate the biochemical and histologic findings to establish the definitive diagnosis. Unrecognized, misdiagnosed, or improperly treated disturbance of bone growth can result in permanent deformity usually associated with disability. 116 references.« less

Crown Release Promotes Faster Diameter Growth of Pole-Size Black Walnut

Treesearch

Robert E. Phares; Robert D. Williams

1971-01-01

Complete crown release more than doubles the diameter growth of pole-size black walnut trees in southern Indiana over a 10-year period. Partially released trees gew about 50 percent more than unreleased trees. The faster growth of the released trees was directly related to increases in crown-area expansion. Most of the study trees produced bole sprouts; however, the...

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.

The roles of vascular endothelial growth factor in bone repair and regeneration

PubMed Central

Hu, Kai; Olsen, Bjorn R.

2016-01-01

Vascular endothelial growth factor-A (VEGF) is one of the most important growth factors for regulation of vascular development and angiogenesis. Since bone is a highly vascularized organ and angiogenesis plays an important role in osteogenesis, VEGF also influences skeletal development and postnatal bone repair. Compromised bone repair and regeneration in many patients can be attributed to impaired blood supply; thus, modulation of VEGF levels in bones represents a potential strategy for treating compromised bone repair and improving bone regeneration. This review (i) summarizes the roles of VEGF at different stages of bone repair, including the phases of inflammation, endochondral ossification, intramembranous ossification during callus formation and bone remodeling; (ii) discusses different mechanisms underlying the effects of VEGF on osteoblast function, including paracrine, autocrine and intracrine signaling during bone repair; (iii) summarizes the role of VEGF in the bone regenerative procedure, distraction osteogenesis; and (iv) reviews evidence for the effects of VEGF in the context of repair and regeneration techniques involving the use of scaffolds, skeletal stem cells and growth factors. PMID:27353702

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.

Modeling Vascularized Bone Regeneration Within a Porous Biodegradable CaP Scaffold Loaded with Growth Factors

PubMed Central

Sun, X; Kang, Y; Bao, J; Zhang, Y; Yang, Y; Zhou, X

2013-01-01

Osteogenetic microenvironment is a complex constitution in which extracellular matrix (ECM) molecules, stem cells and growth factors each interact to direct the coordinate regulation of bone tissue development. Importantly, angiogenesis improvement and revascularization are critical for osteogenesis during bone tissue regeneration processes. In this study, we developed a three-dimensional (3D) multi-scale system model to study cell response to growth factors released from a 3D biodegradable porous calcium phosphate (CaP) scaffold. Our model reconstructed the 3D bone regeneration system and examined the effects of pore size and porosity on bone formation and angiogenesis. The results suggested that scaffold porosity played a more dominant role in affecting bone formation and angiogenesis compared with pore size, while the pore size could be controlled to tailor the growth factor release rate and release fraction. Furthermore, a combination of gradient VEGF with BMP2 and Wnt released from the multi-layer scaffold promoted angiogenesis and bone formation more readily than single growth factors. These results demonstrated that the developed model can be potentially applied to predict vascularized bone regeneration with specific scaffold and growth factors. PMID:23566802

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.

[Donor age affects on the «behavior» and the sensibility bone marrow cells in on copper ion of the primary culture].

PubMed

Bozhkov, A I; Ohiienko, S L; Kuznetsova, Yu A; Bondar', A Yu; Marchenko, V P; Gumennaya, M S

2017-01-01

The changes of bone marrow cells (BMC) number in the primary culture from 0 to 96 hours, the pattern (the distribution of cells) of cells morphotypes and «lifespan» (the time of cell life after isolation) of myelocytes, metamyelocytes, band and segmented neutrophils, isolated of the young (3 months) and old (20months) animals, were investigated. The number of the BMC obtained from intact old animals increased faster in primary culture, than from young animals. The Cu induced fibrosis had different influence on the rate of BMC culture growth of old and young animals. The adding of 4 mM and 8 mM CuSO4x5H2O in the BMC culture of young and old animals resulted in a dose-dependent inhibition of growth rate of young animal cells. If copper ions were added into the culture of BMC of old animals, the decreased of the BMC number was described less than for cells of young animals. The adding of 8 mM CuSO4x5H2O inhibited proliferation less, than the adding of 4 mM CuSO4x5H2O. The Cu-induced liver fibrosis had accelerated the BMC rate death of both old and young animals. However, this effect was more pronounced in young animals. It is suggested, that during the ontogenesis the BMC undergo such epigenetic changes, which change functional properties.

The Efficacy of Plasma Rich in Growth Factors for the Treatment of Alveolar Osteitis: A Randomized Controlled Trial.

PubMed

King, Elizabeth M; Cerajewska, Tanya L; Locke, Matthew; Claydon, Nicholas C A; Davies, Maria; West, Nicola X

2018-06-01

To investigate the efficacy of plasma rich in growth factors (PRGF; BTI Biotechnology Institute, San Antonio, Spain) for the treatment of alveolar osteitis compared with a positive control (Alvogyl; Septodont, Maidstone, Kent, UK). This single-center, single-blinded, randomized, 2-treatment, parallel study was conducted in a UK dental hospital. All healthy adults who presented with alveolar osteitis after tooth extraction over a 3-month period were invited to participate. Each socket was randomized and treated with 1 of 2 treatment modalities, a test treatment (PRGF) or a positive control (Alvogyl). After treatment, patients were reviewed at 3 and 7 days by a second clinician blinded to the treatment given. Outcome measures included pain, exposed bone, inflammation, halitosis, dysgeusia, and quality-of-life assessment. Thirty-eight patients with data from 44 sockets (22 in the PRGF group and 22 in the Alvogyl group) were analyzed. The PRGF group showed significantly faster bone coverage and significantly decreased inflammation and halitosis (P < .05) compared with the control group receiving Alvogyl. There was no significant difference for pain, quality-of-life measures, or dysgeusia between groups. PRGF predictably treated alveolar osteitis after tooth extraction compared with the conventional standard treatment of Alvogyl, which has been used for many years. PRGF could be considered an alternative treatment for alveolar osteitis and indeed appears to have considerable advantages over Alvogyl. Copyright © 2018 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

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 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.

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

Growth after late-preterm birth and adult cognitive, academic, and mental health outcomes.

PubMed

Sammallahti, Sara; Heinonen, Kati; Andersson, Sture; Lahti, Marius; Pirkola, Sami; Lahti, Jari; Pesonen, Anu-Katriina; Lano, Aulikki; Wolke, Dieter; Eriksson, Johan G; Kajantie, Eero; Raikkonen, Katri

2017-05-01

Late-preterm birth (at 34 0⁄7 -36 6⁄7 wk gestation) increases the risk of early growth faltering, poorer neurocognitive functioning, and lower socio-economic attainment. Among early-preterm individuals, faster early growth benefits neurodevelopment, but it remains unknown whether these benefits extend to late-preterm individuals. In 108 late-preterm individuals, we examined if weight, head, or length growth between birth, 5 and 20 months' corrected age, and 56 mo, predicted grade point average and special education in comprehensive school, or neurocognitive abilities and psychiatric diagnoses/symptoms at 24-26 y of age. For every 1 SD faster weight and head growth from birth to 5 mo, and head growth from 5 to 20 mo, participants had 0.19-0.41 SD units higher IQ, executive functioning score, and grade point average (95% confidence intervals (CI) 0.002-0.59 SD), and lower odds of special education (odds ratio (OR) = 0.49-0.59, 95% CIs 0.28-0.97), after adjusting for sex, gestational age, follow-up age, and parental education. Faster head growth from 20 to 56 mo was associated with less internalizing problems; otherwise we found no consistent associations with mental health outcomes. Faster growth during the critical early period after late-preterm birth is associated with better adult neurocognitive functioning, but not consistently with mental health outcomes.

Ethnic and sex differences in skeletal maturation among the Birth to Twenty cohort in South Africa.

PubMed

Cole, Tim J; Rousham, Emily K; Hawley, Nicola L; Cameron, Noel; Norris, Shane A; Pettifor, John M

2015-02-01

To examine ethnic and sex differences in the pattern of skeletal maturity from adolescence to adulthood using a novel longitudinal analysis technique (SuperImposition by Translation And Rotation (SITAR)). Johannesburg, South Africa. 607 boys and girls of black as well as white ethnicity from the Birth to Twenty bone health study, assessed annually from 9 to 20 years of age. Bone maturity scores (Tanner-Whitehouse III radius, ulna, and short bones (TW3 RUS)) assessed longitudinally from hand-wrist radiographs were used to produce individual and mean growth curves of bone maturity and analysed by the SITAR method. The longitudinal analysis showed that black boys matured later by 7.0 SE 1.6 months (p<0.0001) but at the same rate as white boys, whereas black girls matured at the same age but at a faster rate than white girls (by 8.7% SE 2.6%, p=0.0007). The mean curves for bone maturity score consistently showed a midpubertal double kink, contrasting with the quadratic shape of the commonly used reference centile curves for bone maturity (TW3). Skeletal maturity was reached 1.9 years earlier in girls than boys, and the pattern of maturation differed between the sexes. Within girls, there were no ethnic differences in the pattern or timing of skeletal maturity. Within boys, however, skeletal maturity was delayed by 7 months in black compared with white ethnicity. Skeletal maturation, therefore, varies differentially by sex and ethnicity. The delayed maturity of black boys, but not black girls, supports the hypothesis that boys have greater sensitivity to environmental constraints than girls. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Immortalized porcine mesenchymal cells derived from nasal mucosa, lungs, lymph nodes, spleen and bone marrow retain their stemness properties and trigger the expression of siglec-1 in co-cultured blood monocytic cells

PubMed Central

Garba, Abubakar; Desmarets, Lowiese M. B.; Acar, Delphine D.; Devriendt, Bert; Nauwynck, Hans J.

2017-01-01

Mesenchymal stromal cells have been isolated from different sources. They are multipotent cells capable of differentiating into many different cell types, including osteocytes, chondrocytes and adipocytes. They possess a therapeutic potential in the management of immune disorders and the repair of damaged tissues. Previous work in our laboratory showed an increase of the percentages of CD172a+, CD14+, CD163+, Siglec-1+, CD4+ and CD8+ hematopoietic cells, when co-cultured with immortalized mesenchymal cells derived from bone marrow. The present work aimed to demonstrate the stemness properties of SV40-immortalized mesenchymal cells derived from nasal mucosa, lungs, spleen, lymph nodes and red bone marrow and their immunomodulatory effect on blood monocytes. Mesenchymal cells from nasal mucosa, lungs, spleen, lymph nodes and red bone marrow were isolated and successfully immortalized using simian virus 40 large T antigen (SV40LT) and later, co-cultured with blood monocytes, in order to examine their differentiation stage (expression of Siglec-1). Flow cytometric analysis revealed that the five mesenchymal cell lines were positive for mesenchymal cell markers CD105, CD44, CD90 and CD29, but lacked the expression of myeloid cell markers CD16 and CD11b. Growth analysis of the cells demonstrated that bone marrow derived-mesenchymal cells proliferated faster compared with those derived from the other tissues. All five mesenchymal cell lines co-cultured with blood monocytes for 1, 2 and 7 days triggered the expression of siglec-1 in the monocytes. In contrast, no siglec-1+ cells were observed in monocyte cultures without mesenchymal cell lines. Mesenchymal cells isolated from nasal mucosa, lungs, spleen, lymph nodes and bone marrow were successfully immortalized and these cell lines retained their stemness properties and displayed immunomodulatory effects on blood monocytes. PMID:29036224

Immortalized porcine mesenchymal cells derived from nasal mucosa, lungs, lymph nodes, spleen and bone marrow retain their stemness properties and trigger the expression of siglec-1 in co-cultured blood monocytic cells.

PubMed

Garba, Abubakar; Desmarets, Lowiese M B; Acar, Delphine D; Devriendt, Bert; Nauwynck, Hans J

2017-01-01

Mesenchymal stromal cells have been isolated from different sources. They are multipotent cells capable of differentiating into many different cell types, including osteocytes, chondrocytes and adipocytes. They possess a therapeutic potential in the management of immune disorders and the repair of damaged tissues. Previous work in our laboratory showed an increase of the percentages of CD172a+, CD14+, CD163+, Siglec-1+, CD4+ and CD8+ hematopoietic cells, when co-cultured with immortalized mesenchymal cells derived from bone marrow. The present work aimed to demonstrate the stemness properties of SV40-immortalized mesenchymal cells derived from nasal mucosa, lungs, spleen, lymph nodes and red bone marrow and their immunomodulatory effect on blood monocytes. Mesenchymal cells from nasal mucosa, lungs, spleen, lymph nodes and red bone marrow were isolated and successfully immortalized using simian virus 40 large T antigen (SV40LT) and later, co-cultured with blood monocytes, in order to examine their differentiation stage (expression of Siglec-1). Flow cytometric analysis revealed that the five mesenchymal cell lines were positive for mesenchymal cell markers CD105, CD44, CD90 and CD29, but lacked the expression of myeloid cell markers CD16 and CD11b. Growth analysis of the cells demonstrated that bone marrow derived-mesenchymal cells proliferated faster compared with those derived from the other tissues. All five mesenchymal cell lines co-cultured with blood monocytes for 1, 2 and 7 days triggered the expression of siglec-1 in the monocytes. In contrast, no siglec-1+ cells were observed in monocyte cultures without mesenchymal cell lines. Mesenchymal cells isolated from nasal mucosa, lungs, spleen, lymph nodes and bone marrow were successfully immortalized and these cell lines retained their stemness properties and displayed immunomodulatory effects on blood monocytes.

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.

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.

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.

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

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.

A novel three-dimensional bone chip organ culture.

PubMed

Kuttenberger, Johannes; Polska, Elzbieta; Schaefer, Birgit M

2013-07-01

The objective of this study was to develop a 3D bone chip organ culture model. We aimed to collect in vitro evidence of the ability of vital bone chips to promote new bone formation. We developed a 3D in vitro hypoxic bone chip organ culture model. Histology of the bone chips was performed before and after culture and immunohistochemistry after 3-week culture. The 3D culture supernatants were tested for the presence of pro-angiogenic growth factors, TGFβ1, GADPH, bone alkaline phosphatase, osteocalcin, osteonectin, osteopontin, bone sialoprotein and collagen type I. Histology after culture revealed bone chips in a matrix of fibrin remnants and a fibrous-appearing matter. Collagen type I- and IV-positive structures were also identified. Cells could be seen on the surface of the bone chips, with spindle-shaped cells bridging the bone chip particles. Pro-angiogenic growth factors and TGFβ1were detected in the 3D cell culture supernatants. The transcripts for osteocalcin, bone sialoprotein and collagen type I were revealed only via PCR. Our results indicate that bone chips in our 3D organ culture remain vital and may stimulate the growth of a bone-forming matrix. The use of autogenous bone chips for oral and maxillofacial bone augmentation procedures is widespread in clinical practice. The rationale for this is that if bone chips remain vital in vivo, they could provide an environment promoting new bone formation through growth factors and cells. This 3D culture method is an essential tool for investigating the behaviour of bone chips.

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.

The Impact of Accelerating Faster than Exponential Population Growth on Genetic Variation

PubMed Central

Reppell, Mark; Boehnke, Michael; Zöllner, Sebastian

2014-01-01

Current human sequencing projects observe an abundance of extremely rare genetic variation, suggesting recent acceleration of population growth. To better understand the impact of such accelerating growth on the quantity and nature of genetic variation, we present a new class of models capable of incorporating faster than exponential growth in a coalescent framework. Our work shows that such accelerated growth affects only the population size in the recent past and thus large samples are required to detect the models’ effects on patterns of variation. When we compare models with fixed initial growth rate, models with accelerating growth achieve very large current population sizes and large samples from these populations contain more variation than samples from populations with constant growth. This increase is driven almost entirely by an increase in singleton variation. Moreover, linkage disequilibrium decays faster in populations with accelerating growth. When we instead condition on current population size, models with accelerating growth result in less overall variation and slower linkage disequilibrium decay compared to models with exponential growth. We also find that pairwise linkage disequilibrium of very rare variants contains information about growth rates in the recent past. Finally, we demonstrate that models of accelerating growth may substantially change estimates of present-day effective population sizes and growth times. PMID:24381333

The impact of accelerating faster than exponential population growth on genetic variation.

PubMed

Reppell, Mark; Boehnke, Michael; Zöllner, Sebastian

2014-03-01

Current human sequencing projects observe an abundance of extremely rare genetic variation, suggesting recent acceleration of population growth. To better understand the impact of such accelerating growth on the quantity and nature of genetic variation, we present a new class of models capable of incorporating faster than exponential growth in a coalescent framework. Our work shows that such accelerated growth affects only the population size in the recent past and thus large samples are required to detect the models' effects on patterns of variation. When we compare models with fixed initial growth rate, models with accelerating growth achieve very large current population sizes and large samples from these populations contain more variation than samples from populations with constant growth. This increase is driven almost entirely by an increase in singleton variation. Moreover, linkage disequilibrium decays faster in populations with accelerating growth. When we instead condition on current population size, models with accelerating growth result in less overall variation and slower linkage disequilibrium decay compared to models with exponential growth. We also find that pairwise linkage disequilibrium of very rare variants contains information about growth rates in the recent past. Finally, we demonstrate that models of accelerating growth may substantially change estimates of present-day effective population sizes and growth times.

NF-κB RelB Negatively Regulates Osteoblast Differentiation and Bone Formation

PubMed Central

Yao, Zhenqiang; Li, Yanyun; Yin, Xiaoxiang; Dong, Yufeng; Xing, Lianping; Boyce, Brendan F.

2013-01-01

RelA-mediated NF-κB canonical signaling promotes mesenchymal progenitor cell (MPC) proliferation, but inhibits differentiation of mature osteoblasts (OBs) and thus negatively regulates bone formation. Previous studies suggest that NF-κB RelB may also negatively regulate bone formation through non-canonical signaling, but they involved a complex knockout mouse model and the molecular mechanisms involved were not investigated. Here, we report that RelB−/− mice develop age-related increased trabecular bone mass associated with increased bone formation. RelB−/− bone marrow stromal cells expanded faster in vitro and have enhanced OB differentiation associated with increased expression of the osteoblastogenic transcription factor, Runx2. In addition, RelB directly targeted the Runx2 promoter to inhibit its activation. Importantly, RelB−/− bone-derived MPCs formed bone more rapidly than wild-type cells after they were injected into a murine tibial bone defect model. Our findings indicate that RelB negatively regulates bone mass as mice age and limits bone formation in healing bone defects, suggesting that inhibition of RelB could reduce age-related bone loss and enhance bone repair. PMID:24115294

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.

Quantification 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

1996-01-01

Our stated primary objective is to quantify the growth rate variability of rat lamellar bone exposed to micro 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.

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.

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.

Shanghai: a study on the spatial growth of population and economy in a Chinese metropolitan area.

PubMed

Zhu, J

1995-01-01

In this study of the growth in population and industry in Shanghai, China, between the 1982 and 1990 censuses, data on administrative divisions was normalized through digitization and spatial analysis. Analysis focused on spatial units, intensity of growth, time period, distance, rate of growth, and direction of spatial growth. The trisection method divided the city into city proper, outskirts, and suburbs. The distance function method considered the distance from center city as a function: exponential, power, trigonometric, logarithmic, and polynomial. Population growth and employment in all sectors increased in the outskirts and suburbs and decreased in the city proper except tertiary sectors. Primary sector employment decreased in all three sections. Employment in the secondary increased faster in the outskirts and suburbs than the total rate of growth of population and employment. In the city secondary sector employment rates decreased faster than total population and employment rates. The tertiary sector had the highest rate of growth in all sections, and employment grew faster than secondary sector rates. Tertiary growth was highest in real estate, finance, and insurance. Industrial growth in the secondary sector was 160.2% in the suburbs, 156.6% in the outskirts, and 80.9% in the city. In the distance function analysis, industry expanded further out than the entire secondary sector. Commerce grew the fastest in areas 15.4 km from center city. Economic growth was faster after economic reforms in 1978. Growth was led by industry and followed by the secondary sector, the tertiary sector, and population. Industrial expansion resulted from inner pressure, political factors controlling size, the social and economic system, and the housing construction and distribution system. Initially sociopsychological factors affected urban concentration.

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.

National Health Expenditure Projections, 2015-25: Economy, Prices, And Aging Expected To Shape Spending And Enrollment.

PubMed

Keehan, Sean P; Poisal, John A; Cuckler, Gigi A; Sisko, Andrea M; Smith, Sheila D; Madison, Andrew J; Stone, Devin A; Wolfe, Christian J; Lizonitz, Joseph M

2016-08-01

Health spending growth in the United States for 2015-25 is projected to average 5.8 percent-1.3 percentage points faster than growth in the gross domestic product-and to represent 20.1 percent of the total economy by 2025. As the initial impacts associated with the Affordable Care Act's coverage expansions fade, growth in health spending is expected to be influenced by changes in economic growth, faster growth in medical prices, and population aging. Projected national health spending growth, though faster than observed in the recent history, is slower than in the two decades before the recent Great Recession, in part because of trends such as increasing cost sharing in private health insurance plans and various Medicare payment update provisions. In addition, the share of total health expenditures paid for by federal, state, and local governments is projected to increase to 47 percent by 2025. Project HOPE—The People-to-People Health Foundation, Inc.

National health expenditure projections, 2013-23: faster growth expected with expanded coverage and improving economy.

PubMed

Sisko, Andrea M; Keehan, Sean P; Cuckler, Gigi A; Madison, Andrew J; Smith, Sheila D; Wolfe, Christian J; Stone, Devin A; Lizonitz, Joseph M; Poisal, John A

2014-10-01

In 2013 health spending growth is expected to have remained slow, at 3.6 percent, as a result of the sluggish economic recovery, the effects of sequestration, and continued increases in private health insurance cost-sharing requirements. The combined effects of the Affordable Care Act's coverage expansions, faster economic growth, and population aging are expected to fuel health spending growth this year and thereafter (5.6 percent in 2014 and 6.0 percent per year for 2015-23). However, the average rate of increase through 2023 is projected to be slower than the 7.2 percent average growth experienced during 1990-2008. Because health spending is projected to grow 1.1 percentage points faster than the average economic growth during 2013-23, the health share of the gross domestic product is expected to rise from 17.2 percent in 2012 to 19.3 percent in 2023. Project HOPE—The People-to-People Health Foundation, Inc.

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.

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.

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

Biochemical Bone Turnover Markers and Osteoporosis in Older Men: Where Are We?

PubMed Central

Szulc, Pawel

2011-01-01

In men aged less than 60, the association of serum and urinary levels of biochemical bone turnover markers (BTMs) and bone mineral density (BMD) is weak or not significant. After this age, higher BTM levels are correlated weakly, but significantly, with lower BMD and faster bone loss. Limited data from the cohort studies suggest that BTM measurement does not improve the prediction of fragility fractures in older men in comparison with age, BMD, history of falls and fragility fractures. Testosterone replacement therapy (TRT) decreases bone resorption. During TRT, bone formation markers slightly increase (direct effect on osteoblasts), then decrease (slowdown of bone turnover). Bisphosphonates (alendronate, risedronate, ibandronate, zoledronate) induce a rapid decrease in bone resorption followed by a milder decrease in bone formation. In men receiving antiresorptive therapy for prostate cancer, zoledronate, denosumab and toremifene decrease significantly levels of bone resorption and bone formation markers. Teriparatide induced a rapid increase in serum concentrations of bone formation markers followed by an increase in bone resorption. We need more studies on the utility of BTM measurement for the improvement of the persistence and adherence to the anti-osteoporotic treatment in men. PMID:22220284

Growth plate stress distribution implications during bone development: a simple framework computational approach.

PubMed

Guevara, J M; Moncayo, M A; Vaca-González, J J; Gutiérrez, M L; Barrera, L A; Garzón-Alvarado, D A

2015-01-01

Mechanical stimuli play a significant role in the process of long bone development as evidenced by clinical observations and in vivo studies. Up to now approaches to understand stimuli characteristics have been limited to the first stages of epiphyseal development. Furthermore, growth plate mechanical behavior has not been widely studied. In order to better understand mechanical influences on bone growth, we used Carter and Wong biomechanical approximation to analyze growth plate mechanical behavior, and explore stress patterns for different morphological stages of the growth plate. To the best of our knowledge this work is the first attempt to study stress distribution on growth plate during different possible stages of bone development, from gestation to adolescence. Stress distribution analysis on the epiphysis and growth plate was performed using axisymmetric (3D) finite element analysis in a simplified generic epiphyseal geometry using a linear elastic model as the first approximation. We took into account different growth plate locations, morphologies and widths, as well as different epiphyseal developmental stages. We found stress distribution during bone development established osteogenic index patterns that seem to influence locally epiphyseal structures growth and coincide with growth plate histological arrangement. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Healing of osteotomy sites applying either piezosurgery or two conventional saw blades: a pilot study in rabbits.

PubMed

Ma, Li; Stübinger, Stefan; Liu, Xi Ling; Schneider, Urs A; Lang, Niklaus P

2013-08-01

The purpose of this study was to compare bone healing of experimental osteotomies applying either piezosurgery or two different oscillating saw blades in a rabbit model. The 16 rabbits were randomly assigned into four groups to comply with observation periods of one, two, three and five weeks. In all animals, four osteotomy lines were performed on the left and right nasal bone using a conventional saw blade, a novel saw blade and piezosurgery. All three osteotomy techniques revealed an advanced gap healing starting after one week. The most pronounced new bone formation took place between two and three weeks, whereby piezoelectric surgery revealed a tendency to faster bone formation and remodelling. Yet, there were no significant differences between the three modalities. The use of a novel as well as the piezoelectric bone-cutting instrument revealed advanced bone healing with a favourable surgical performance compared to a traditional saw.

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

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

Bone Histology in Dysalotosaurus lettowvorbecki (Ornithischia: Iguanodontia) – Variation, Growth, and Implications

PubMed Central

Hübner, Tom R.

2012-01-01

Background Dysalotosaurus lettowvorbecki is a small ornithopod dinosaur known from thousands of bones and several ontogenetic stages. It was found in a single locality within the Tendaguru Formation of southeastern Tanzania, possibly representing a single herd. Dysalotosaurus provides an excellent case study for examining variation in bone microstructure and life history and helps to unravel the still mysterious growth pattern of small ornithopods. Methodology/Principal Findings Five different skeletal elements were sampled, revealing microstructural variation between individuals, skeletal elements, cross sectional units, and ontogenetic stages. The bone wall consists of fibrolamellar bone with strong variability in vascularization and development of growth cycles. Larger bones with a high degree of utilization have high relative growth rates and seldom annuli/LAGs, whereas small and less intensively used bones have lower growth rates and a higher number of these resting lines. Due to the scarcity of annuli/LAGs, the reconstruction of the life history of Dysalotosaurus was carried out using regularly developed and alternating slow and fast growing zones. Dysalotosaurus was a precocial dinosaur, which experienced sexual maturity at ten years, had an indeterminate growth pattern, and maximum growth rates comparable to a large kangaroo. Conclusions/Significance The variation in the bone histology of Dysalotosaurus demonstrates the influence of size, utilization, and shape of bones on relative growth rates. Annuli/LAGs are not the only type of annual growth cycles that can be used to reconstruct the life history of fossil vertebrates, but the degree of development of these lines may be of importance for the reconstruction of paleobehavior. The regular development of annuli/LAGs in subadults and adults of large ornithopods therefore reflects higher seasonal stress due to higher food demands, migration, and altricial breeding behavior. Small ornithopods often lack regularly developed annuli/LAGs due to lower food demands, no need for migration, and precocial behavior. PMID:22238683

Repair of osteochondral defects with hyaluronan- and polyester-based scaffolds.

PubMed

Solchaga, Luis A; Temenoff, Johnna S; Gao, Jizong; Mikos, Antonios G; Caplan, Arnold I; Goldberg, Victor M

2005-04-01

The natural repair of osteochondral defects can be enhanced with biocompatible, biodegradable materials that support the repair process. It is our hypothesis that hyaluronan-based scaffolds are superior to synthetic scaffolds because they provide biological cues. We tested this thesis by comparing two hyaluronan-based scaffolds [auto cross-linked polysaccharide polymer (ACP) and HYAFF-11] to polyester-based scaffolds [poly(DL-lactic-co-glycolic acid) (PLGA) and poly(L-lactic acid) (PLLA)] with similar pore size, porosity and degradation times. Fifty-four rabbits received bilateral osteochondral defects. One defect received a hyaluronan-based scaffold and the contralateral defect received the corresponding polyester-based scaffold. Rabbits were euthanized 4, 12 and 20 weeks after surgery and the condyles dissected and processed for histology. Only ACP-treated defects presented bone at the base of the defect at 4 weeks. At 12 weeks, only defects treated with rapidly dissolving implants (ACP and PLGA) presented bone reconstitution consistently, while bone was present in only one third of those treated with slowly dissolving scaffolds (HYAFF-11 and PLLA). After 20 weeks, the articular surface of PLGA-treated defects presented fibrillation more frequently than in ACP-treated defects. The surface of defects treated with slowly dissolving scaffolds presented more cracks and fissures. The degradation rate of the scaffolds is critical for the repair process. Slowly dissolving scaffolds sustain thicker cartilage at the surface but, it frequently presents cracks and discontinuities. These scaffolds also delay bone formation at the base of the defects. Hyaluronan-based scaffolds appear to allow faster cell infiltration leading to faster tissue formation. The degradation of ACP leads to rapid bone formation while the slow degradation of HYAFF-11 prolongs the presence of cartilage and delays endochondral bone formation.

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.

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.

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

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

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

Overexpression of TIMP-3 in Chondrocytes Produces Transient Reduction in Growth Plate Length but Permanently Reduces Adult Bone Quality and Quantity

PubMed Central

Plumb, Darren; Vo, Phoung; Shah, Mittal; Staines, Katherine; Sampson, Alexandra; Shefelbine, Sandra; Pitsillides, Andrew A.; Bou-Gharios, George

2016-01-01

Bone development and length relies on the growth plate formation, which is dependent on degradative enzymes such as MMPs. Indeed, deletion of specific members of this enzyme family in mice results in important joint and bone abnormalities, suggesting a role in skeletal development. As such, the control of MMP activity is vital in the complex process of bone formation and growth. We generated a transgenic mouse line to overexpress TIMP3 in mouse chondrocytes using the Col2a1-chondrocyte promoter. This overexpression in cartilage resulted in a transient shortening of growth plate in homozygote mice but bone length was restored at eight weeks of age. However, tibial bone structure and mechanical properties remained compromised. Despite no transgene expression in adult osteoblasts from transgenic mice in vitro, their differentiation capacity was decreased. Neonates, however, did show transgene expression in a subset of bone cells. Our data demonstrate for the first time that transgene function persists in the chondro-osseous lineage continuum and exert influence upon bone quantity and quality. PMID:28002442

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

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

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

An essential role for IGF2 in cartilage development and glucose metabolism during postnatal long bone growth.

PubMed

Uchimura, Tomoya; Hollander, Judith M; Nakamura, Daisy S; Liu, Zhiyi; Rosen, Clifford J; Georgakoudi, Irene; Zeng, Li

2017-10-01

Postnatal bone growth involves a dramatic increase in length and girth. Intriguingly, this period of growth is independent of growth hormone and the underlying mechanism is poorly understood. Recently, an IGF2 mutation was identified in humans with early postnatal growth restriction. Here, we show that IGF2 is essential for longitudinal and appositional murine postnatal bone development, which involves proper timing of chondrocyte maturation and perichondrial cell differentiation and survival. Importantly, the Igf2 null mouse model does not represent a simple delay of growth but instead uncoordinated growth plate development. Furthermore, biochemical and two-photon imaging analyses identified elevated and imbalanced glucose metabolism in the Igf2 null mouse. Attenuation of glycolysis rescued the mutant phenotype of premature cartilage maturation, thereby indicating that IGF2 controls bone growth by regulating glucose metabolism in chondrocytes. This work links glucose metabolism with cartilage development and provides insight into the fundamental understanding of human growth abnormalities. © 2017. Published by The Company of Biologists Ltd.

Towards the synthesis of hydroxyapatite/protein scaffolds with controlled porosities: bulk and interfacial shear rheology of a hydroxyapatite suspension with protein additives.

PubMed

Maas, Michael; Bodnar, Pedro Marcus; Hess, Ulrike; Treccani, Laura; Rezwan, Kurosch

2013-10-01

The synthesis of porous hydroxyapatite scaffolds is essential for biomedical applications such as bone tissue engineering and replacement. One way to induce macroporosity, which is needed to support bone in-growth, is to use protein additives as foaming agents. Another reason to use protein additives is the potential to introduce a specific biofunctionality to the synthesized scaffolds. In this work, we study the rheological properties of a hydroxyapatite suspension system with additions of the proteins bovine serum albumin (BSA), lysozyme (LSZ) and fibrinogen (FIB). Both the rheology of the bulk phase as well as the interfacial shear rheology are studied. The bulk rheological data provides important information on the setting behavior of the thixotropic suspension, which we find to be faster with the addition of FIB and LSZ and much slower with BSA. Foam bubble stabilization mechanisms can be rationalized via interfacial shear rheology and we show that it depends on the growth of interfacial films at the suspension/air interface. These interfacial films support the stabilization of bubbles within the ceramic matrix and thereby introduce macropores. Due to the weak interaction of the protein molecules with the hydroxyapatite particles of the suspension, we find that BSA forms the most stable interfacial films, followed by FIB. LSZ strongly interacts with the hydroxyapatite particles and thus only forms thin films with very low elastic moduli. In summary, our study provides fundamental rheological insights which are essential for tailoring hydroxyapatite/protein suspensions in order to synthesize scaffolds with controlled porosities. Copyright © 2013 Elsevier Inc. All rights reserved.

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.

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.

Growth rate effects on the formation of dislocation loops around deep helium bubbles in Tungsten

DOE PAGES

Sandoval, Luis; Perez, Danny; Uberuaga, Blas P.; ...

2016-11-15

Here, the growth process of spherical helium bubbles located 6 nm below a (100) surface is studied using molecular dynamics and parallel replica dynamics simulations, over growth rates from 10 6 to 10 12 helium atoms per second. Slower growth rates lead to a release of pressure and lower helium content as compared with fast growth cases. In addition, at slower growth rates, helium bubbles are not decorated by multiple dislocation loops, as these tend to merge or emit given sufficient time. At faster rates, dislocation loops nucleate faster than they can emit, leading to a more complicated dislocation structuremore » around the bubble.« less

Parathyroid hormone induces the Nrna family of nuclear orphan receptors in vivo

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

Pirih, Flavia Q.; Aghaloo, Tara L.; Bezouglaia, Olga

2005-07-01

Parathyroid hormone (PTH) has both anabolic and catabolic effects on bone metabolism, although the molecular mechanisms mediating these effects are largely unknown. Among the transcription factors induced by Pth in osteoblasts are the nerve growth factor-inducible factor B (NR4A; NGFI-B) family of orphan nuclear receptors: Nurr1, Nur77, and NOR-1. PTH induces NR4A members through the cAMP-protein kinase A (PKA) pathway in vitro. We report here that PTH rapidly and transiently induced expression of all three NR4A genes in PTH-target tissues in vivo. In calvaria, long bones, and kidneys, NR4A induction was maximal 0.5-1 h after a single intraperitoneal (i.p.) injectionmore » of 80 {mu}g/kg PTH. Nur77 demonstrated the highest expression, followed, in order, by Nurr1 and NOR-1. In calvaria and long bone, PTH-induced expression of each NR4A gene was detectable at 10 {mu}g/kg i.p. with maximum induction at 40-80 {mu}g/kg. PTH (3-34) did not induce NR4A mRNA levels in calvaria, long bone, and kidney in vivo, confirming our in vitro results that NR4A genes are induced primarily through the cAMP-PKA pathway. The magnitude of PTH-induced NR4A expression was comparable in vivo and in vitro. However, NR4A mRNA levels peaked and returned to baseline faster in vivo. Both in vivo and in vitro, PTH induced NR4A pre-mRNA levels suggesting that induction of these genes is, at least in part, through activation of mRNA synthesis. The in vivo induction of the NR4A family members by PTH suggests their involvement in, at least some, PTH-induced changes in bone metabolism.« 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

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

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.

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

MEASURING ECONOMIC GROWTH FROM OUTER SPACE.

PubMed

Henderson, J Vernon; Storeygard, Adam; Weil, David N

2012-04-01

GDP growth is often measured poorly for countries and rarely measured at all for cities or subnational regions. We propose a readily available proxy: satellite data on lights at night. We develop a statistical framework that uses lights growth to augment existing income growth measures, under the assumption that measurement error in using observed light as an indicator of income is uncorrelated with measurement error in national income accounts. For countries with good national income accounts data, information on growth of lights is of marginal value in estimating the true growth rate of income, while for countries with the worst national income accounts, the optimal estimate of true income growth is a composite with roughly equal weights. Among poor-data countries, our new estimate of average annual growth differs by as much as 3 percentage points from official data. Lights data also allow for measurement of income growth in sub- and supranational regions. As an application, we examine growth in Sub Saharan African regions over the last 17 years. We find that real incomes in non-coastal areas have grown faster by 1/3 of an annual percentage point than coastal areas; non-malarial areas have grown faster than malarial ones by 1/3 to 2/3 annual percent points; and primate city regions have grown no faster than hinterland areas. Such applications point toward a research program in which "empirical growth" need no longer be synonymous with "national income accounts."

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.

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.

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

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.

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.

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.

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

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

[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.

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

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.

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

Determinants of infant growth: Evidence from Hong Kong's "Children of 1997" birth cohort.

PubMed

Hui, L L; Leung, Gabriel M; Cowling, Benjamin J; Lam, T H; Schooling, C Mary

2010-11-01

A high rate of infant growth may be associated with adult cardiovascular disease. We investigated factors associated with infant weight growth in a large sample from the recently transitioned population of Hong Kong. We used a nonlinear shape invariant model with random effects among 5949 term, singletons (77% follow-up) from a population-representative Hong Kong Chinese birth cohort "Children of 1997" to investigate factors associated with weight growth in the first year of life. Overall birth weight was lower but infant growth was more rapid than the 2006 WHO standards. Shorter gestation and lower birth order were associated with lower birth weight and faster infant growth. Female sex, maternal smoking in pregnancy, and a mother born in Hong Kong were associated with lower birth weight, but not with faster growth. Higher maternal education was associated with faster infant growth, grades 10-11 (1.03, 95% confidence interval [CI] = 1.03-1.05), greater than or equal to grade12 (1.07, CI = 1.04-1.09) compared with less than or equal to grade 9. Infant growth may respond more rapidly to socio-economic development than birth weight. Whether mother's education is associated with rapid infant growth via current conditions or her own "constitution" is unclear, nevertheless we believe this study illustrates the importance of contextually specific research for understanding the determinants of population health. Copyright © 2010 Elsevier Inc. All rights reserved.

[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.

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

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

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

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.

Mechanobiological simulations of peri-acetabular bone ingrowth: a comparative analysis of cell-phenotype specific and phenomenological algorithms.

PubMed

Mukherjee, Kaushik; Gupta, Sanjay

2017-03-01

Several mechanobiology algorithms have been employed to simulate bone ingrowth around porous coated implants. However, there is a scarcity of quantitative comparison between the efficacies of commonly used mechanoregulatory algorithms. The objectives of this study are: (1) to predict peri-acetabular bone ingrowth using cell-phenotype specific algorithm and to compare these predictions with those obtained using phenomenological algorithm and (2) to investigate the influences of cellular parameters on bone ingrowth. The variation in host bone material property and interfacial micromotion of the implanted pelvis were mapped onto the microscale model of implant-bone interface. An overall variation of 17-88 % in peri-acetabular bone ingrowth was observed. Despite differences in predicted tissue differentiation patterns during the initial period, both the algorithms predicted similar spatial distribution of neo-tissue layer, after attainment of equilibrium. Results indicated that phenomenological algorithm, being computationally faster than the cell-phenotype specific algorithm, might be used to predict peri-prosthetic bone ingrowth. The cell-phenotype specific algorithm, however, was found to be useful in numerically investigating the influence of alterations in cellular activities on bone ingrowth, owing to biologically related factors. Amongst the host of cellular activities, matrix production rate of bone tissue was found to have predominant influence on peri-acetabular bone ingrowth.

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

Heterochrony in fringeheads (Neoclinus) and amplification of an extraordinary aggressive display in the Sarcastic Fringehead (Teleostei: Blenniiformes).

PubMed

Hongjamrassilp, Watcharapong; Summers, Adam P; Hastings, Philip A

2018-05-01

The Sarcastic Fringehead (Neoclinus blanchardi, Teleostei) exhibits an extreme version of a common aggressive display, the "gaping display," in which an open mouth is presented toward an opponent. Males of this species have extremely long jaws that extend posteriorly well past the posterior margin of the head and are flared laterally during the gaping display. In this study, we explored morphological traits related to this extraordinary display in this and related species of blennies. Morphological modifications include enlargement of the buccopalatal membrane, elongation of the maxilla via an uncalcified posterior extension, and evolution of a novel hinge between the anterior maxilla and lacrimal bones permitting lateral movement of the upper jaw. Geometric morphometry using the truss network system, thin-plate spline, and PCA of three closely related species of Neoclinus indicate that the elongate maxilla of N. blanchardi most likely evolved via acceleration (faster growth compared to outgroups) and hypermorphosis (continued growth to a larger body size), both forms of peramorphic heterochrony. Coloration and fluorescence of the buccopalatal membrane may also serve to amplify the extraordinary gaping display of the Sarcastic Fringehead. © 2018 Wiley Periodicals, Inc.

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.

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

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.

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

Biocompatibility and biodegradation studies of PCL/β-TCP bone tissue scaffold fabricated by structural porogen method.

PubMed

Lu, Lin; Zhang, Qingwei; Wootton, David; Chiou, Richard; Li, Dichen; Lu, Bingheng; Lelkes, Peter; Zhou, Jack

2012-09-01

Three-dimensional printer (3DP) (Z-Corp) is a solid freeform fabrication system capable of generating sub-millimeter physical features required for tissue engineering scaffolds. By using plaster composite materials, 3DP can fabricate a universal porogen which can be injected with a wide range of high melting temperature biomaterials. Here we report results toward the manufacture of either pure polycaprolactone (PCL) or homogeneous composites of 90/10 or 80/20 (w/w) PCL/beta-tricalcium phosphate (β-TCP) by injection molding into plaster composite porogens fabricated by 3DP. The resolution of printed plaster porogens and produced scaffolds was studied by scanning electron microscopy. Cytotoxicity test on scaffold extracts and biocompatibility test on the scaffolds as a matrix supporting murine osteoblast (7F2) and endothelial hybridoma (EAhy 926) cells growth for up to 4 days showed that the porogens removal process had only negligible effects on cell proliferation. The biodegradation tests of pure PCL and PCL/β-TCP composites were performed in DMEM with 10 % (v/v) FBS for up to 6 weeks. The PCL/β-TCP composites show faster degradation rate than that of pure PCL due to the addition of β-TCP, and the strength of 80/20 PCL/β-TCP composite is still suitable for human cancellous bone healing support after 6 weeks degradation. Combining precisely controlled porogen fabrication structure, good biocompatibility, and suitable mechanical properties after biodegradation, PCL/β-TCP scaffolds fabricated by 3DP porogen method provide essential capability for bone tissue engineering.

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.

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)

Environment determines evolutionary trajectory in a constrained phenotypic space

PubMed Central

Fraebel, David T; Mickalide, Harry; Schnitkey, Diane; Merritt, Jason; Kuhlman, Thomas E; Kuehn, Seppe

2017-01-01

Constraints on phenotypic variation limit the capacity of organisms to adapt to the multiple selection pressures encountered in natural environments. To better understand evolutionary dynamics in this context, we select Escherichia coli for faster migration through a porous environment, a process which depends on both motility and growth. We find that a trade-off between swimming speed and growth rate constrains the evolution of faster migration. Evolving faster migration in rich medium results in slow growth and fast swimming, while evolution in minimal medium results in fast growth and slow swimming. In each condition parallel genomic evolution drives adaptation through different mutations. We show that the trade-off is mediated by antagonistic pleiotropy through mutations that affect negative regulation. A model of the evolutionary process shows that the genetic capacity of an organism to vary traits can qualitatively depend on its environment, which in turn alters its evolutionary trajectory. DOI: http://dx.doi.org/10.7554/eLife.24669.001 PMID:28346136

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.

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

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

Decreased bone turnover with balanced resorption and formation prevent cortical bone loss during disuse (hibernation) in grizzly bears (Ursus arctos horribilis).

PubMed

McGee, Meghan E; Maki, Aaron J; Johnson, Steven E; Nelson, O Lynne; Robbins, Charles T; Donahue, Seth W

2008-02-01

Disuse uncouples bone formation from resorption, leading to increased porosity, decreased bone geometrical properties, and decreased bone mineral content which compromises bone mechanical properties and increases fracture risk. However, black bear bone properties are not adversely affected by aging despite annual periods of disuse (i.e., hibernation), which suggests that bears either prevent bone loss during disuse or lose bone and subsequently recover it at a faster rate than other animals. Here we show decreased cortical bone turnover during hibernation with balanced formation and resorption in grizzly bear femurs. Hibernating grizzly bear femurs were less porous and more mineralized, and did not demonstrate any changes in cortical bone geometry or whole bone mechanical properties compared to active grizzly bear femurs. The activation frequency of intracortical remodeling was 75% lower during hibernation than during periods of physical activity, but the normalized mineral apposition rate was unchanged. These data indicate that bone turnover decreases during hibernation, but osteons continue to refill at normal rates. There were no changes in regional variation of porosity, geometry, or remodeling indices in femurs from hibernating bears, indicating that hibernation did not preferentially affect one region of the cortex. Thus, grizzly bears prevent bone loss during disuse by decreasing bone turnover and maintaining balanced formation and resorption, which preserves bone structure and strength. These results support the idea that bears possess a biological mechanism to prevent disuse osteoporosis.

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.

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.

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.

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.

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.

Behavior of POP-calcium carbonate hydrogel as bone substitute with controlled release capability: a study in rat.

PubMed

Dewi, Anne Handrini; Ana, Ika Dewi; Wolke, Joop; Jansen, John

2015-10-01

Gypsum or calcium sulfate (CS) or plaster of Paris (POP) is considered as a fast degradable material that usually resorbs before the bone defect area is completely filled by new bone. In this study, the incorporation of CaCO3 hydrogel into POP in different compositions was proposed to enhance the bone biological activity of POP and to decrease its degradability. The mechanical and degradation properties of the various materials were characterized by in vitro analysis. Subsequently, the materials were inserted into cylindrically sized bone defects as created into the femoral condyle of rats and left in situ for 1, 4, and 8 weeks. Histological analysis of the retrieved specimens indicated that the addition of CaCO3 hydrogel into POP increased bone formation, angiogenesis and collagen density and resulted into faster bone formation and maturation. It was also confirmed that the degradation rate of the POP decreased by the addition of CaCO3 hydrogel. The in vivo findings did corroborate with the in vitro analysis. In conclusion, the incorporation of CaCO3 hydrogel provides a promising technology to improve the properties of POP, the oldest biomaterial used for bone grafting. © 2015 Wiley Periodicals, Inc.

National health expenditure projections, 2014-24: spending growth faster than recent trends.

PubMed

Keehan, Sean P; Cuckler, Gigi A; Sisko, Andrea M; Madison, Andrew J; Smith, Sheila D; Stone, Devin A; Poisal, John A; Wolfe, Christian J; Lizonitz, Joseph M

2015-08-01

Health spending growth in the United States is projected to average 5.8 percent for 2014-24, reflecting the Affordable Care Act's coverage expansions, faster economic growth, and population aging. Recent historically low growth rates in the use of medical goods and services, as well as medical prices, are expected to gradually increase. However, in part because of the impact of continued cost-sharing increases that are anticipated among health plans, the acceleration of these growth rates is expected to be modest. The health share of US gross domestic product is projected to rise from 17.4 percent in 2013 to 19.6 percent in 2024. Project HOPE—The People-to-People Health Foundation, Inc.

Grasping primate development: Ontogeny of intrinsic hand and foot proportions in capuchin monkeys (Cebus albifrons and Sapajus apella).

PubMed

Young, Jesse W; Heard-Booth, Amber N

2016-09-01

Young primates have relatively large hands and feet for their body size, perhaps enhancing grasping ability. We test the hypothesis that selection for improved grasping ability is responsible for these scaling trends by examining the ontogeny of intrinsic hand and foot proportions in capuchin monkeys (Cebus albifrons and Sapajus apella). If selection for improved grasping ability is responsible for the observed patterns of hand and foot growth in primates, we predicted that fingers and toes would be longer early in life and proportionally decline with age. We measured the lengths of manual and pedal metapodials and phalanges in a mixed-longitudinal radiographic sample. Bone lengths were (a) converted into phalangeal indices (summed non-distal phalangeal length/metapodial length) to test for age-related changes in intrinsic proportions and (b) fit to Gompertz models of growth to test for differences in the dynamics of phalangeal versus metapodial growth. Manual and pedal phalangeal indices nearly universally decreased with age in capuchin monkeys. Growth curve analyses revealed that metapodials generally grew at a faster rate, and for a longer duration, than corresponding phalanges. Our findings are consistent with the hypothesis that primates are under selection for increased grasping ability early in life. Relatively long digits may be functionally adaptive for growing capuchins, permitting a more secure grasp on both caregivers and arboreal supports, as well as facilitating early foraging. Additional studies of primates and other mammals, as well as tests of grasping performance, are required to fully evaluate the adaptive significance of primate hand and foot growth. © 2016 Wiley Periodicals, Inc.

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.

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.

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

MEASURING ECONOMIC GROWTH FROM OUTER SPACE

PubMed Central

Henderson, J. Vernon; Storeygard, Adam; Weil, David N.

2013-01-01

GDP growth is often measured poorly for countries and rarely measured at all for cities or subnational regions. We propose a readily available proxy: satellite data on lights at night. We develop a statistical framework that uses lights growth to augment existing income growth measures, under the assumption that measurement error in using observed light as an indicator of income is uncorrelated with measurement error in national income accounts. For countries with good national income accounts data, information on growth of lights is of marginal value in estimating the true growth rate of income, while for countries with the worst national income accounts, the optimal estimate of true income growth is a composite with roughly equal weights. Among poor-data countries, our new estimate of average annual growth differs by as much as 3 percentage points from official data. Lights data also allow for measurement of income growth in sub- and supranational regions. As an application, we examine growth in Sub Saharan African regions over the last 17 years. We find that real incomes in non-coastal areas have grown faster by 1/3 of an annual percentage point than coastal areas; non-malarial areas have grown faster than malarial ones by 1/3 to 2/3 annual percent points; and primate city regions have grown no faster than hinterland areas. Such applications point toward a research program in which “empirical growth” need no longer be synonymous with “national income accounts.” PMID:25067841

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.

[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.

Microgeographic differentiation in thermal performance curves between rural and urban populations of an aquatic insect.

PubMed

Tüzün, Nedim; Op de Beeck, Lin; Brans, Kristien I; Janssens, Lizanne; Stoks, Robby

2017-12-01

The rapidly increasing rate of urbanization has a major impact on the ecology and evolution of species. While increased temperatures are a key aspect of urbanization ("urban heat islands"), we have very limited knowledge whether this generates differentiation in thermal responses between rural and urban populations. In a common garden experiment, we compared the thermal performance curves (TPCs) for growth rate and mortality in larvae of the damselfly Coenagrion puella from three urban and three rural populations. TPCs for growth rate shifted vertically, consistent with the faster-slower theoretical model whereby the cold-adapted rural larvae grew faster than the warm-adapted urban larvae across temperatures. In line with costs of rapid growth, rural larvae showed lower survival than urban larvae across temperatures. The relatively lower temperatures hence expected shorter growing seasons in rural populations compared to the populations in the urban heat islands likely impose stronger time constraints to reach a certain developmental stage before winter, thereby selecting for faster growth rates. In addition, higher predation rates at higher temperature may have contributed to the growth rate differences between urban and rural ponds. A faster-slower differentiation in TPCs may be a widespread pattern along the urbanization gradient. The observed microgeographic differentiation in TPCs supports the view that urbanization may drive life-history evolution. Moreover, because of the urban heat island effect, urban environments have the potential to aid in developing predictions on the impact of climate change on rural populations.

Macro-structural effect of metal surfaces treated using computer-assisted yttrium-aluminum-garnet laser scanning on bone-implant fixation.

PubMed

Hirao, Makoto; Sugamoto, Kazuomi; Tamai, Noriyuki; Oka, Kunihiro; Yoshikawa, Hideki; Mori, Yusuke; Sasaki, Takatomo

2005-05-01

Porous coatings have been applied to the surface of prosthetic devices to foster stable device fixation. The coating serves as a source of mechanical interlocking and may stimulate healthy bone growth through osseointegrated load transfer in cementless arthroplasty. Joint arthroplasty by porous-coated prostheses is one of the most common surgical treatments, and has provided painless and successful joint mobility. However, long-term success is often impaired by the loss of fixation between the prosthesis and bone. Porous-coated prostheses are associated with several disadvantages, including metal debris from porous coatings (third body wear particles) and irregular micro-texture of metal surfaces. Consequently, quantitative histological analysis has been very difficult. These issues arise because the porous coating treatment is based on addition of material and is not precisely controllable. We recently developed a precisely controllable porous texture technique based on material removal by yttrium-aluminum-garnet laser. Free shapes can be applied to complex, three-dimensional hard metal surfaces using this technique. In this study, tartan check shapes made by crossing grooves and dot shapes made by forming holes were produced on titanium (Ti6A14V) or cobalt chrome (CoCr) and evaluated with computer-assisted histological analysis and measurement of bone-metal interface shear strength. Width of grooves or holes ranged from 100 to 800 mum (100, 200, 500, and 800 microm), with a depth of 500 microm. When the cylindrical porous-texture-treated metal samples (diameter, 5 mm; height, 15 mm) were implanted into a rabbit femoral condyle, bone tissue with bone trabeculae formed in the grooves and holes after 2 or 4 weeks, especially in 500-microm-wide grooves. Abundant osteoconduction was consistently observed throughout 500-microm-wide grooves in both Ti6A14V and CoCr. Speed of osteoconduction was faster in Ti6A14V than in CoCr, especially in the tartan check shape made of 500-microm-wide grooves. In pushout testing, the tartan check shape made of 500-microm-wide grooves had significantly higher bone-metal interface shear strength than the dot shape or commercial porous coating. These results indicate that the tartan check shape made of 500-microm-wide grooves on metal surfaces has potential for clinical application in artificial prosthesis design.

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.

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...

Perturbations in growth trajectory due to early diet affect age-related deterioration in performance.

PubMed

Lee, Who-Seung; Monaghan, Pat; Metcalfe, Neil B

2016-04-01

Fluctuations in early developmental conditions can cause changes in growth trajectories that subsequently affect the adult phenotype. Here, we investigated whether compensatory growth has long-term consequences for patterns of senescence.Using three-spined sticklebacks ( Gasterosteus aculeatus ), we show that a brief period of dietary manipulation in early life affected skeletal growth rate not only during the manipulation itself, but also during a subsequent compensatory phase when fish caught up in size with controls.However, this growth acceleration influenced swimming endurance and its decline over the course of the breeding season, with a faster decline in fish that had undergone faster growth compensation.Similarly, accelerated growth led to a more pronounced reduction in the breeding period (as indicated by the duration of sexual ornamentation) over the following two breeding seasons, suggesting faster reproductive senescence. Parallel experiments showed a heightened effect of accelerated growth on these age-related declines in performance if the fish were under greater time stress to complete their compensation prior to the breeding season.Compensatory growth led to a reduction in median life span of 12% compared to steadily growing controls. While life span was independent of the eventual adult size attained, it was negatively correlated with the age-related decline in swimming endurance and sexual ornamentation.These results, complementary to those found when growth trajectories were altered by temperature rather than dietary manipulations, show that the costs of accelerated growth can last well beyond the time over which growth rates differ and are affected by the time available until an approaching life-history event such as reproduction.

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.

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.

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.

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.

Rethinking the nature of fibrolamellar bone: an integrative biological revision of sauropod plexiform bone formation.

PubMed

Stein, Koen; Prondvai, Edina

2014-02-01

We present novel findings on sauropod bone histology that cast doubt on general palaeohistological concepts concerning the true nature of woven bone in primary cortical bone and its role in the rapid growth and giant body sizes of sauropod dinosaurs. By preparing and investigating longitudinal thin sections of sauropod long bones, of which transverse thin sections were published previously, we found that the amount of woven bone in the primary complex has been largely overestimated. Using comparative cellular and light-extinction characteristics in the two section planes, we revealed that the majority of the bony lamina consists of longitudinally organized primary bone, whereas woven bone is usually represented only by a layer a few cells thin in the laminae. Previous arguments on sauropod biology, which have been based on the overestimated amount, misinterpreted formation process and misjudged role of woven bone in the plexiform bone formation of sauropod dinosaurs, are thereby rejected. To explain the observed pattern in fossil bones, we review the most recent advances in bone biology concerning bone formation processes at the cellular and tissue levels. Differentiation between static and dynamic osteogenesis (SO and DO) and the revealed characteristics of SO- versus DO-derived bone tissues shed light on several questions raised by our palaeohistological results and permit identification of these bone tissues in fossils with high confidence. By presenting the methods generally used for investigating fossil bones, we show that the major cause of overestimation of the amount of woven bone in previous palaeohistological studies is the almost exclusive usage of transverse sections. In these sections, cells and crystallites of the longitudinally organized primary bone are cut transversely, thus cells appear rounded and crystallites remain dark under crossed plane polarizers, thereby giving the false impression of woven bone. In order to avoid further confusion in palaeohistological studies, we introduce new osteohistological terms as well as revise widely used but incorrect terminology. To infer the role of woven bone in the bone formation of fast-growing tetrapods, we review some aspects of the interrelationships between the vascularity of bone tissues, basal metabolic rate, body size and growth rate. By putting our findings into the context of osteogenesis, we provide a new model for the diametrical limb bone growth of sauropods and present new implications for the evolution of fast growth in vertebrates. Since biomechanical studies of bone tissues suggest that predominant collagen fibre orientation (CFO) is controlled by endogenous, functional and perhaps phylogenetic factors, the relationship between CFO and bone growth rate as defined by Amprino's rule, which has been the basis for the biological interpretation of several osteohistological features, must be revised. Our findings draw attention to the urgent need for revising widely accepted basic concepts of palaeohistological studies, and for a more integrative approach to bone formation, biomechanics and bone microstructural features of extant and extinct vertebrates to infer life history traits of long extinct, iconic animals like dinosaurs. © 2013 The Authors. Biological Reviews © 2013 Cambridge Philosophical Society.

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.

Growth promoting in vitro effect of synthetic cyclic RGD-peptides on human osteoblast-like cells attached to cancellous bone.

PubMed

Magdolen, Ursula; Auernheimer, Jörg; Dahmen, Claudia; Schauwecker, Johannes; Gollwitzer, Hans; Tübel, Jutta; Gradinger, Reiner; Kessler, Horst; Schmitt, Manfred; Diehl, Peter

2006-06-01

In tissue engineering, the application of biofunctional compounds on biomaterials such as integrin binding RGD-peptides has gained growing interest. Anchorage-dependent cells like osteoblasts bind to these peptides thus ameliorating the integration of a synthetic implant. In case sterilized bone grafts are used as substitutes for reconstruction of bone defects, the ingrowth of the implanted bone is often disturbed because of severe pretreatment such as irradiation or autoclaving, impairing the biological and mechanical properties of the bone. We report for the first time on the in vitro coating of the surface of freshly resected, cleaned bone discs with synthetic, cyclic RGD-peptides. For this approach, two different RGD-peptides were used, one containing two phosphonate anchors, the other peptide four of these binding moieties to allow efficient association of these reactive RGD-peptides to the inorganic bone matrix. Human osteoblast-like cells were cultured on RGD-coated bone discs and the adherence and growth of the cells were analyzed. Coating of bone discs with RGD-peptides did not improve the adhesion rate of osteoblast-like cells to the discs but significantly (up to 40%) accelerated growth of these cells within 8 days after attachment. This effect points to pretreatment of bone implants, especially at the critical interface area between the implanted bone and the non-resected residual bone structure, before re-implantation in order to stimulate and enhance osteointegration of a bone implant.

Identifying the Mechanism(s) Responsible for the Translational Regulation of the Stress Signaling Kinase MKK4

DTIC Science & Technology

2012-08-01

without CWR22Rv1 growth. Upper right, H&E of left femur of animal in A. Malformed bone growth along with metastatic growth in marrow space can be seen...clearly malformed . Note the growth of the bone into the marrow space, with an almost stalagmite appearance. The close-up views of the metastases

Inflammation and linear bone growth: the inhibitory role of SOCS2 on GH/IGF-1 signaling.

PubMed

Farquharson, Colin; Ahmed, S Faisal

2013-04-01

Linear bone growth is widely recognized to be adversely affected in children with chronic kidney disease (CKD) and other chronic inflammatory disorders. The growth hormone (GH)/insulin-like growth factor-1 (IGF-1) pathway is anabolic to the skeleton and inflammatory cytokines compromise bone growth through a number of different mechanisms, which include interference with the systemic as well as the tissue-level GH/IGF-1 axis. Despite attempts to promote growth and control disease, there are an increasing number of reports of the persistence of poor growth in a substantial proportion of patients receiving rhGH and/or drugs that block cytokine action. Thus, there is an urgent need to consider better and alternative forms of therapy that are directed specifically at the mechanism of the insult which leads to abnormal bone health. Suppressor of cytokine signaling 2 (SOCS2) expression is increased in inflammatory conditions including CKD, and is a recognized inhibitor of GH signaling. Therefore, in this review, we will focus on the premise that SOCS2 signaling represents a critical pathway in growth plate chondrocytes through which pro-inflammatory cytokines alter both GH/IGF-1 signaling and cellular function.

Tissue Engineering Strategies for Promoting Vascularized Bone Regeneration

PubMed Central

Almubarak, Sarah; Nethercott, Hubert; Freeberg, Marie; Beaudon, Caroline; Jha, Amit; Jackson, Wesley; Marcucio, Ralph; Miclau, Theodore; Healy, Kevin; Bahney, Chelsea

2016-01-01

This review focuses on current tissue engineering strategies for promoting vascularized bone regeneration. We review the role of angiogenic growth factors in promoting vascularized bone regeneration and discuss the different therapeutic strategies for controlled/sustained growth factor delivery. Next, we address the therapeutic uses of stem cells in vascularized bone regeneration. Specifically, this review addresses the concept of co-culture using osteogenic and vasculogenic stem cells, and how adipose derived stem cells compare to bone marrow derived mesenchymal stem cells in the promotion of angiogenesis. We conclude this review with a discussion of a novel approach to bone regeneration through a cartilage intermediate, and discuss why it has the potential to be more effective than traditional bone grafting methods. PMID:26608518

Improved bone status by the beta-blocker propranolol in an animal model of nutritional growth retardation.

PubMed

Lezón, Christian E; Olivera, María I; Bozzini, Clarisa; Mandalunis, Patricia; Alippi, Rosa M; Boyer, Patricia M

2009-06-01

The aim of the present research was to study if the beta-blocker propranolol, which is known to increase bone mass, could reverse the adverse skeletal effects of mild chronic food restriction in weanling rats. Male Wistar rats were divided into four groups: control, control+propranolol (CP), nutritional growth retardation (NGR) and nutritional growth retardation+propranolol (NGRP). Control and CP rats were fed freely with the standard diet. NGR and NGRP rats received, for 4 weeks, 80 % of the amount of food consumed by the control and CP rats, respectively. Results were expressed as mean values and sem. Food restriction induced detrimental effects on body and femur weight and length (P < 0.05) and bone structural and geometrical properties (P < 0.001), confirming results previously shown in our laboratory. However, the beta-blocker overcame the deleterious effect of nutritional stress on load-bearing capacity, yielding load, bone stiffness, cross-sectional cortical bone area and second moment of inertia of the cross-section in relation to the horizontal axis without affecting anthropometric, histomorphometric and bone morphometric parameters. The results suggest that propranolol administration to mildly chronically undernourished rats markedly attenuates the impaired bone status in this animal model of growth retardation.

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.

Strontium enhances osseointegration of calcium phosphate cement: a histomorphometric pilot study in ovariectomized rats.

PubMed

Baier, Martin; Staudt, Patric; Klein, Roman; Sommer, Ulrike; Wenz, Robert; Grafe, Ingo; Meeder, Peter Jürgen; Nawroth, Peter P; Kasperk, Christian

2013-06-07

Calcium phosphate cements are used frequently in orthopedic and dental surgeries. Strontium-containing drugs serve as systemic osteoblast-activating medication in various clinical settings promoting mechanical stability of the osteoporotic bone. Strontium-containing calcium phosphate cement (SPC) and calcium phosphate cement (CPC) were compared regarding their local and systemic effects on bone tissue in a standard animal model for osteoporotic bone. A bone defect was created in the distal femoral metaphysis of 60 ovariectomized Sprague-Dawley rats. CPC and SPC were used to fill the defects in 30 rats in each group. Local effects were assessed by histomorphometry at the implant site. Systemic effects were assessed by bone mineral density (BMD) measurements at the contralateral femur and the spine. Faster osseointegration and more new bone formation were found for SPC as compared to CPC implant sites. SPC implants exhibited more cracks than CPC implants, allowing more bone formation within the implant. Contralateral femur BMD and spine BMD did not differ significantly between the groups. The addition of strontium to calcium phosphate stimulates bone formation in and around the implant. Systemic release of strontium from the SPC implants did not lead to sufficiently high serum strontium levels to induce significant systemic effects on bone mass in this rat model.

[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.

[Calcitonin physiologically regulates the postmenopausal bone loss and possibly inhibits the bone loss in fast losers].

PubMed

Chen, J T; Shiraki, M; Katase, K; Kato, T; Hirai, Y; Hasumi, K

1994-10-01

To study the correlation between the basal serum calcitonin level and L2-4 bone mineral density (BMD), a cross sectional study of 384 healthy subjects (106 premenopausal, 88 perimenopausal and 109 postmenopausal subjects) and a longitudinal study of 42 oophorectomized subjects were conducted. A positive correlation was found in perimenopause (r = 0.219, p = 0.040) but not in premenopause (r = 0.069, p = 0.4898) and postmenopause (r = 0.141, p = 0.0554) in a cross sectional study. The percent reduction in L2-4BMD compared to the baseline also correlated with preoperative calcitonin levels at 6 months after oophorectomy (r = 0.333, p = 0.0442), but not significantly at 12 months (r = 0.224, p = 0.27). These data suggest that the basal calcitonin level correlates to L2-4BMD only at perimenopause or in the early postoophorectomized period when bone turnover is accelerated and bone resorption seems to be faster than bone formation. In addition the premenopausal basal calcitonin level may be an indicator of the fast loser after menopause.

Ricinus communis-based biopolymer and epidermal growth factor regulations on bone defect repair: A rat tibia model

NASA Astrophysics Data System (ADS)

Mendoza-Barrera, C.; Meléndez-Lira, M.; Altuzar, V.; Tomás, S. A.

2003-01-01

We report the effect of the addition of an epidermal growth factor to a Ricinus communis-based biopolymer in the healing of a rat tibia model. Bone repair and osteointegration after a period of three weeks were evaluated employing photoacoustic spectroscopy and x-ray diffraction. A parallel study was performed at 1, 2, 3, 4, 5, 6, 7, and 8 weeks with energy dispersive x-ray spectroscopy. We conclude that the use of an epidermal growth factor (group EGF) in vivo accelerates the process of bony repair in comparison with other groups, and that the employment of the Ricinus communis-based biopolymer as a bone substitute decreases bone production.

Heating or freezing bone. Effects on angiogenesis induction and growth potential in mice.

PubMed

Leunig, M; Yuan, F; Berk, D A; Gerweck, L E; Jain, R K

1996-08-01

We have characterized the effect of bone graft treatment by heating or freezing (with or without dimethyl sulfoxide (DMSO)). Tissue culture and dorsal skin-fold chambers in mice were used as sites to quantify the effect on angiogenesis, growth and calcification of neonatal femora. Fresh femora increased in both length and cartilage diameter (calcification in vivo only), but cryopreservation or heating abolished the increase in femoral dimensions. In vivo, femora of all experimental groups elicited an angiogenic response from the host tissue, which was most pronounced for fresh femora, weaker for DMSO-preserved frozen bone and poor for unprotected frozen bone and boiled femora. Freezing in the presence of a cryopreservative (DMSO) was found to preserve the angiogenic potential of frozen bone, whereas unprotected heating or freezing significantly impaired angiogenesis induction and growth potential.

Strategies for Controlled Delivery of Growth Factors and Cells for Bone Regeneration

PubMed Central

Vo, Tiffany N.; Kasper, F. Kurtis; Mikos, Antonios G.

2012-01-01

The controlled delivery of growth factors and cells within biomaterial carriers can enhance and accelerate functional bone formation. The carrier system can be designed with preprogrammed release kinetics to deliver bioactive molecules in a localized, spatiotemporal manner most similar to the natural wound healing process. The carrier can also act as an extracellular matrix-mimicking substrate for promoting osteoprogenitor cellular infiltration and proliferation for integrative tissue repair. This review discusses the role of various regenerative factors involved in bone healing and their appropriate combinations with different delivery systems for augmenting bone regeneration. The general requirements of protein, cell and gene therapy are described, with elaboration on how the selection of materials, configurations and processing affects growth factor and cell delivery and regenerative efficacy in both in vitro and in vivo applications for bone tissue engineering. PMID:22342771

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.

DETERMINATION OF THE RADIOSENSITIVITY OF DIFFERENT BONE GROWTH REGIONS USING Ca$sup 45$ METABOLISM (in German)

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

Kolar, J.; Babicky, A.

1961-02-01

The radiation sensitivity of some bone segments and especially of the growth zones of white rats was examined with the help of Ca/sup 45/. The deviations in the specific activities corresponded not only to the delivered dosage but also to the growth activity of some of the bone segments. After large radiation doses and in more activity growth zones the radiation damage was also greater. These results should give reason in the clinical practice for greater caution in radiation treatment in the area of strongly growing epiphyseal zones (in the area of knee and wrist joints). (auth)

Markers of Bone Metabolism Are Affected by Renal Function and Growth Hormone Therapy in Children with Chronic Kidney Disease

PubMed Central

Doyon, Anke; Fischer, Dagmar-Christiane; Bayazit, Aysun Karabay; Canpolat, Nur; Duzova, Ali; Sözeri, Betül; Bacchetta, Justine; Balat, Ayse; Büscher, Anja; Candan, Cengiz; Cakar, Nilgun; Donmez, Osman; Dusek, Jiri; Heckel, Martina; Klaus, Günter; Mir, Sevgi; Özcelik, Gül; Sever, Lale; Shroff, Rukshana; Vidal, Enrico; Wühl, Elke; Gondan, Matthias; Melk, Anette; Querfeld, Uwe; Haffner, Dieter; Schaefer, Franz

2015-01-01

Objectives The extent and relevance of altered bone metabolism for statural growth in children with chronic kidney disease is controversial. We analyzed the impact of renal dysfunction and recombinant growth hormone therapy on a panel of serum markers of bone metabolism in a large pediatric chronic kidney disease cohort. Methods Bone alkaline phosphatase (BAP), tartrate-resistant acid phosphatase 5b (TRAP5b), sclerostin and C-terminal FGF-23 (cFGF23) normalized for age and sex were analyzed in 556 children aged 6–18 years with an estimated glomerular filtration rate (eGFR) of 10–60 ml/min/1.73m2. 41 children receiving recombinant growth hormone therapy were compared to an untreated matched control group. Results Standardized levels of BAP, TRAP5b and cFGF-23 were increased whereas sclerostin was reduced. BAP was correlated positively and cFGF-23 inversely with eGFR. Intact serum parathormone was an independent positive predictor of BAP and TRAP5b and negatively associated with sclerostin. BAP and TRAP5B were negatively affected by increased C-reactive protein levels. In children receiving recombinant growth hormone, BAP was higher and TRAP5b lower than in untreated controls. Sclerostin levels were in the normal range and higher than in untreated controls. Serum sclerostin and cFGF-23 independently predicted height standard deviation score, and BAP and TRAP5b the prospective change in height standard deviation score. Conclusion Markers of bone metabolism indicate a high-bone turnover state in children with chronic kidney disease. Growth hormone induces an osteoanabolic pattern and normalizes osteocyte activity. The osteocyte markers cFGF23 and sclerostin are associated with standardized height, and the markers of bone turnover predict height velocity. PMID:25659076

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

Calcium phosphate ceramic systems in growth factor and drug delivery for bone tissue engineering: A review

PubMed Central

Bose, Susmita; Tarafder, Solaiman

2012-01-01

Calcium phosphates (CaPs) are the most widely used bone substitutes in bone tissue engineering due to their compositional similarities to bone mineral and excellent biocompatibility. In recent years, CaPs, especially hydroxyapatite and tricalcium phosphate, have attracted significant interest in simultaneous use as bone substitute and drug delivery vehicle, adding a new dimension to their application. CaPs are more biocompatible than many other ceramic and inorganic nanoparticles. Their biocompatibility and variable stoichiometry, thus surface charge density, functionality, and dissolution properties, make them suitable for both drug and growth factor delivery. CaP matrices and scaffolds have been reported to act as delivery vehicles for growth factors and drugs in bone tissue engineering. Local drug delivery in musculoskeletal disorder treatments can address some of the critical issues more effectively and efficiently than the systemic delivery. CaPs are used as coatings on metallic implants, CaP cements, and custom designed scaffolds to treat musculoskeletal disorders. This review highlights some of the current drug and growth factor delivery approaches and critical issues using CaP particles, coatings, cements, and scaffolds towards orthopedic and dental applications. PMID:22127225

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.

Long Bone Histology and Growth Patterns in Ankylosaurs: Implications for Life History and Evolution

PubMed Central

Stein, Martina; Hayashi, Shoji; Sander, P. Martin

2013-01-01

The ankylosaurs are one of the major dinosaur groups and are characterized by unique body armor. Previous studies on other dinosaur taxa have revealed growth patterns, life history and evolutionary mechanisms based on their long bone histology. However, to date nothing is known about long bone histology in the Ankylosauria. This study is the first description of ankylosaurian long bone histology based on several limb elements, which were sampled from different individuals from the Ankylosauridae and Nodosauridae. The histology is compared to that of other dinosaur groups, including other Thyreophora and Sauropodomorpha. Ankylosaur long bone histology is characterized by a fibrolamellar bone architecture. The bone matrix type in ankylosaurs is closest to that of Stegosaurus. A distinctive mixture of woven and parallel-fibered bone together with overall poor vascularization indicates slow growth rates compared to other dinosaurian taxa. Another peculiar characteristic of ankylosaur bone histology is the extensive remodeling in derived North American taxa. In contrast to other taxa, ankylosaurs substitute large amounts of their primary tissue early in ontogeny. This anomaly may be linked to the late ossification of the ankylosaurian body armor. Metabolically driven remodeling processes must have liberated calcium to ossify the protective osteodermal structures in juveniles to subadult stages, which led to further remodeling due to increased mechanical loading. Abundant structural fibers observed in the primary bone and even in remodeled bone may have improved the mechanical properties of the Haversian bone. PMID:23894321

Age determination in manatees using growth-layer-group counts in bone

USGS Publications Warehouse

Marmontel, M.; O'Shea, T.J.; Kochman, H.I.; Humphrey, S.R.

1996-01-01

Growth layers were observed in histological preparations of bones of known-age, known minimum-age, and tetracycline-marked free-ranging and captive Florida manatees (Trichechus manatus latirostris), substantiating earlier preliminary findings of other studies. Detailed analysis of 17 new case histories showed that growth-layer group (GLG) counts in the periotic bone were consistent with known age, or time since tetracycline administration, but were less reliable in other bones. GLG counts were also made in periotic bones of 1,196 Florida manatees of unknown age found dead from 1974 through 1991. These counts were conducted in order to assess variability and to determine relationships among estimated age, size, sex, and degree of bone resorption. Resorption can interfere with accuracy of GLG counts. This effect does not occur until ages greater than about 15 yr and body lengths greater than 300 cm are attained. GLGs were also observed in periotic bones of Antillean manatees (Trichechus manatus manatus) but were not validated against known-age specimens. Use of GLG counts in the periotic bone is suitable for application to studies of population dynamics and other age-related aspects of manatee biology.

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

National Health Spending In 2014: Faster Growth Driven By Coverage Expansion And Prescription Drug Spending.

PubMed

Martin, Anne B; Hartman, Micah; Benson, Joseph; Catlin, Aaron

2016-01-01

US health care spending increased 5.3 percent to $3.0 trillion in 2014. On a per capita basis, health spending was $9,523 in 2014, an increase of 4.5 percent from 2013. The share of gross domestic product devoted to health care spending was 17.5 percent, up from 17.3 percent in 2013. The faster growth in 2014 that followed five consecutive years of historically low growth was primarily due to the major coverage expansions under the Affordable Care Act, particularly for Medicaid and private health insurance, which contributed to an increase in the insured share of the population. Additionally, the introduction of new hepatitis C drugs contributed to rapid growth in retail prescription drug expenditures, which increased by 12.2 percent in 2014. Spending by the federal government grew at a faster rate in 2014 than spending by other sponsors of health care, leading to a 2-percentage-point increase in its share of total health care spending between 2013 and 2014. Project HOPE—The People-to-People Health Foundation, Inc.

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.

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.

Bone metastasis target redox-responsive micell for the treatment of lung cancer bone metastasis and anti-bone resorption.

PubMed

Ye, Wei-Liang; Zhao, Yi-Pu; Cheng, Ying; Liu, Dao-Zhou; Cui, Han; Liu, Miao; Zhang, Bang-Le; Mei, Qi-Bing; Zhou, Si-Yuan

2018-01-16

In order to inhibit the growth of lung cancer bone metastasis and reduce the bone resorption at bone metastasis sites, a bone metastasis target micelle DOX@DBMs-ALN was prepared. The size and the zeta potential of DOX@DBNs-ALN were about 60 nm and -15 mV, respectively. DOX@DBMs-ALN exhibited high binding affinity with hydroxyapatite and released DOX in redox-responsive manner. DOX@DBMs-ALN was effectively up taken by A549 cells and delivered DOX to the nucleus of A549 cells, which resulted in strong cytotoxicity on A549 cells. The in vivo experimental results indicated that DOX@DBMs-ALN specifically delivered DOX to bone metastasis site and obviously prolonged the retention time of DOX in bone metastasis site. Moreover, DOX@DBMs-ALN not only significantly inhibited the growth of bone metastasis tumour but also obviously reduced the bone resorption at bone metastasis sites without causing marked systemic toxicity. Thus, DOX@DBMs-ALN has great potential in the treatment of lung cancer bone metastasis.

Bioactive borate glass promotes the repair of radius segmental bone defects by enhancing the osteogenic differentiation of BMSCs.

PubMed

Zhang, Jieyuan; Guan, Junjie; Zhang, Changqing; Wang, Hui; Huang, Wenhai; Guo, Shangchun; Niu, Xin; Xie, Zongping; Wang, Yang

2015-11-20

Bioactive borate glass (BG) has emerged as a promising alternative for bone regeneration due to its high osteoinductivity, osteoconductivity, compressive strength, and biocompatibility. However, the role of BG in large segmental bone repair is unclear and little is known about the underlying mechanism of BG's osteoinductivity. In this study, we demonstrated that BG possessed pro-osteogenic effects in an experimental model of critical-sized radius defects. Transplanting BG to radius defects resulted in better repair of bone defects as compared to widely used β-TCP. Histological and morphological analysis indicated that BG significantly enhanced new bone formation. Furthermore, the degradation rate of the BG was faster than that of β-TCP, which matched the higher bone regeneration rate. In addition, ions from BG enhanced cell viability, ALP activity, and osteogenic-related genes expression. Mechanistically, the critical genes Smad1/5 and Dlx5 in the BMP pathway and p-Smad1/5 proteins were significantly elevated after BG transplantation, and these effects could be blocked by the BMP/Smad specific inhibitor. Taken together, our findings suggest that BG could repair large segmental bone defects through activating the BMP/Smad pathway and osteogenic differentiation in BMSCs.

Partial growth plate closure: apex view on bone scan

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

Howman-Giles, R.; Trochei, M.; Yeates, K.

1985-01-01

A new technique of using /sup 99m/Tc bone scan to assess partial closure of the growth plate is described. The site and degree of osseous fusion can be obtained by using the apex view. The technique has the potential of assessing serially the growth of a plate before and after surgery.

Rapid modification of the bone microenvironment following short-term treatment with Cabozantinib in vivo.

PubMed

Haider, Marie-Therese; Hunter, Keith D; Robinson, Simon P; Graham, Timothy J; Corey, Eva; Dear, T Neil; Hughes, Russell; Brown, Nicola J; Holen, Ingunn

2015-12-01

Bone metastasis remains incurable with treatment restricted to palliative care. Cabozantinib (CBZ) is targeted against multiple receptor tyrosine kinases involved in tumour pathobiology, including hepatocyte growth factor receptor (MET) and vascular endothelial growth factor receptor 2 (VEGFR-2). CBZ has demonstrated clinical activity in advanced prostate cancer with resolution of lesions visible on bone scans, implicating a potential role of the bone microenvironment as a mediator of CBZ effects. We characterised the effects of short-term administration of CBZ on bone in a range of in vivo models to determine how CBZ affects bone in the absence of tumour. Studies were performed in a variety of in vivo models including male and female BALB/c nude mice (age 6-17-weeks). Animals received CBZ (30 mg/kg, 5× weekly) or sterile H2O control for 5 or 10 days. Effects on bone integrity (μCT), bone cell activity (PINP, TRAP ELISA), osteoblast and osteoclast number/mm trabecular bone surface, area of epiphyseal growth plate cartilage, megakaryocyte numbers and bone marrow composition were assessed. Effects of longer-term treatment (15-day & 6-week administration) were assessed in male NOD/SCID and beige SCID mice. CBZ treatment had significant effects on the bone microenvironment, including reduced osteoclast and increased osteoblast numbers compared to control. Trabecular bone structure was altered after 8 administrations. A significant elongation of the epiphyseal growth plate, in particular the hypertrophic chondrocyte zone, was observed in all CBZ treated animals irrespective of administration schedule. Both male and female BALB/c nude mice had increased megakaryocyte numbers/mm(2) tissue after 10-day CBZ treatment, in addition to vascular ectasia, reduced bone marrow cellularity and extravasation of red blood cells into the extra-vascular bone marrow. All CBZ-induced effects were transient and rapidly lost following cessation of treatment. Short-term administration of CBZ induces rapid, reversible effects on the bone microenvironment in vivo highlighting a potential role in mediating treatment responses. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Defined culture medium for stem cell differentiation: applicability of serum-free conditions in the mouse embryonic stem cell test.

PubMed

Riebeling, Christian; Schlechter, Katharina; Buesen, Roland; Spielmann, Horst; Luch, Andreas; Seiler, Andrea

2011-06-01

The embryonic stem cell test (EST) is a validated method to assess the developmental toxicity potency of chemicals. It was developed to reduce animal use and allow faster testing for hazard assessment. The cells used in this method are maintained and differentiated in media containing foetal calf serum. This animal product is of considerable variation in quality, and individual batches require extensive testing for their applicability in the EST. Moreover, its production involves a large number of foetuses and possible animal suffering. We demonstrate the serum-free medium and feeder cell-free maintenance of the mouse embryonic stem cell line D3 and investigate the use of specific growth factors for induction of cardiac differentiation. Using a combination of bone morphogenetic protein-2, bone morphogenetic protein-4, activin A and ascorbic acid, embryoid bodies efficiently differentiated into contracting myocardium. Additionally, examining levels of intracellular marker proteins by flow cytometry not only confirmed differentiation into cardiomyocytes, but demonstrated significant differentiation into neuronal cells in the same time frame. Thus, this approach might allow for simultaneous detection of developmental effects on both early mesodermal and neuroectodermal differentiation. The serum-free conditions for maintenance and differentiation of D3 cells described here enhance the transferability and standardisation and hence the performance of the EST. Copyright © 2011 Elsevier Ltd. All rights reserved.

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.

Blockade of epidermal growth factor receptor signaling in tumor cells and tumor-associated endothelial cells for therapy of androgen-independent human prostate cancer growing in the bone of nude mice.

PubMed

Kim, Sun-Jin; Uehara, Hisanori; Karashima, Takashi; Shepherd, David L; Killion, Jerald J; Fidler, Isaiah J

2003-03-01

We determined whether blockade of the epidermal growth factor receptor (EGF-R) signaling pathway by oral administration of the EGF-R tyrosine kinase inhibitor (PKI 166) alone or in combination with injectable Taxol inhibits the growth of PC-3MM2 human prostate cancer cells in the bone of nude mice. Male nude mice implanted with PC-3MM2 cells in the tibia were treated with oral administrations of PKI 166 or PKI 166 plus injectable Taxol beginning 3 days after implantation. The incidence and size of bone tumors and destruction of bone were determined by digitalized radiography. Expression of epidermal growth factor (EGF), EGF-R, and activated EGF-R in tumor cells and tumor-associated endothelial cells was determined by immunohistochemistry. Oral administration of PKI 166 or PKI 166 plus injectable Taxol reduced the incidence and size of bone tumors and destruction of bone. Immunohistochemical analysis revealed that PC-3MM2 cells growing adjacent to the bone expressed high levels of EGF and activated EGF-R, whereas tumor cells in the adjacent musculature did not. Moreover, endothelial cells within the bone tumor lesions, but not in uninvolved bone or tumors in the muscle, expressed high levels of activated EGF-R. Treatment with PKI 166 and more so with PKI 166 plus Taxol significantly inhibited phosphorylation of EGF-R on tumor and endothelial cells and induced significant apoptosis and endothelial cells within tumor lesions. These data indicate that endothelial cells exposed to EGF produced by tumor cells express activated EGF-R and that targeting EGF-R can produce significant therapeutic effects against prostate cancer bone metastasis.

Shaping skeletal growth by modular regulatory elements in the Bmp5 gene.

PubMed

Guenther, Catherine; Pantalena-Filho, Luiz; Kingsley, David M

2008-12-01

Cartilage and bone are formed into a remarkable range of shapes and sizes that underlie many anatomical adaptations to different lifestyles in vertebrates. Although the morphological blueprints for individual cartilage and bony structures must somehow be encoded in the genome, we currently know little about the detailed genomic mechanisms that direct precise growth patterns for particular bones. We have carried out large-scale enhancer surveys to identify the regulatory architecture controlling developmental expression of the mouse Bmp5 gene, which encodes a secreted signaling molecule required for normal morphology of specific skeletal features. Although Bmp5 is expressed in many skeletal precursors, different enhancers control expression in individual bones. Remarkably, we show here that different enhancers also exist for highly restricted spatial subdomains along the surface of individual skeletal structures, including ribs and nasal cartilages. Transgenic, null, and regulatory mutations confirm that these anatomy-specific sequences are sufficient to trigger local changes in skeletal morphology and are required for establishing normal growth rates on separate bone surfaces. Our findings suggest that individual bones are composite structures whose detailed growth patterns are built from many smaller lineage and gene expression domains. Individual enhancers in BMP genes provide a genomic mechanism for controlling precise growth domains in particular cartilages and bones, making it possible to separately regulate skeletal anatomy at highly specific locations in the body.

Differential effects of intermittent and continuous administration of parathyroid hormone on bone histomorphometry and gene expression

NASA Technical Reports Server (NTRS)

Lotinun, Sutada; Sibonga, Jean D.; Turner, Russell T.

2002-01-01

A mechanism explaining the differential skeletal effects of intermittent and continuous elevation of serum parathyroid hormone (PTH) remains elusive. Intermittent PTH increases bone formation and bone mass and is being investigated as a therapy for osteoporosis. By contrast, chronic hyperparathyroidism results in the metabolic bone disease osteitis fibrosa characterized by osteomalacia, focal bone resorption, and peritrabecular bone marrow fibrosis. Intermittent and continuous PTH have similar effects on the number of osteoblasts and bone-forming activity. Many of the beneficial as well as detrimental effects of the hormone appear to be mediated by osteoblast-derived growth factors. This hypothesis was tested using cDNA microgene arrays to compare gene expression in tibia of rats treated with continuous and pulsatile administration of PTH. These treatments result in differential expression of many genes, including growth factors. One of the genes whose steady-state mRNA levels was increased by continuous but not pulsatile administration was platelet-derived growth factor-A (PDGF-A). Administration of a PDGF-A antagonist greatly reduced bone resorption, osteomalacia, and bone marrow fibrosis in a rat model for hyperparathyroidism, suggesting that PDGF-A is a causative agent for this disease. These findings suggest that profiling changes in gene expression can help identify the metabolic pathways responsible for the skeletal responses to the hormone.

Amodiaquine induced agranulocytosis: inhibition of colony growth in bone marrow by antimalarial agents.

PubMed Central

Rhodes, E G; Ball, J; Franklin, I M

1986-01-01

Bone marrow was cultured in vitro for colonies of granulocytes and macrophages five months after a patient had recovered from amodiaquine induced agranulocytosis. The addition of amodiaquine, chloroquine, and sulfadoxine to the culture was followed by a dose dependent inhibition of colony growth in the patient's marrow but not in normal control bone marrow. Colony growth was, however, unaffected by proguanil, pyrimethamine, and quinine. These findings show that in vitro marrow culture may have important predictive value in some cases of drug induced agranulocytosis. PMID:3082409

Reconstruction of Drug-induced Cleft Palate Using Bone Marrow Mesenchymal Stem Cell in Rodents.

PubMed

Amalraj, Julie Christy; Gangothri, Manasa; Babu, Hari

2017-01-01

Triamcinolone acetonide (TAC) (Kenacort*) is a commonly used synthetic glucocorticoid in today's medical practice. The drug is also a potential agent in inducing cleft palates in rats. This drug has been used to induce cleft palate in the fetus of the pregnant rats to bring out a suitable animal model for human cleft lip and palate. The drug was given intraperitoneally to induce congenital cleft palate in pregnant mother rats. The aim of this study is to induce congenital cleft palate in pregnant Wister albino rats and reconstruct the defect with bone marrow mesenchymal stem cells (BMSCs) isolated from the same species along with PLGA (poly lactic co glycolic acid) scaffold. Twenty female animals were divided into two groups. Each group contains 10 animals. The animals were allowed to mate with male rat during the esterase period and the day, in hich vaginal plug was noticed was taken to be day 0. The pregnant rats were given triamcinolone acetonide (Kenacort* 10 mg/1 ml intramuscularly/intravenous [IM/IV] injections) injection intraperitoneally at two different dosages as the existing literature. The injection was given on the 10, 12, and 14 th day of gestation. The clinical changes observed were recorded, and the change in the body weight was noted carefully. Group 1 which received 0.5 mg/kg body weight of TAC had many drug toxic effects. Group 2 which received 0.05 mg/kg body weight produced cleft palate in rat pups. The pups were divided into three groups. Group A control group without cell transplant, the cleft was allowed to close by itself. Group B containing palate reconstructed with plain PLGA scaffold (Bioscaffold, Singapore) without BMSC, Group C containing BMSC and PLGA scaffold (Bioscaffold, Singapore), Group C operated for the cleft palate reconstruction using BMSCs and PLGA scaffold. There was faster and efficient reconstruction of bone in the cleft defect in Group C while there was no defect closure in Group A and B. There was complete reconstruction of the cleft palate in the group of rat pups which received BMSCs along with PLGA scaffold. Bone growth in the cleft defect was faster; complete fusion of the defect was achieved. The dosage of drug used for inducing cleft palate was standardized in rodents for a definitive congenital cleft palate model. The cleft palate induced was reconstructed using BMSCs and PLGA scaffold. This was compared with a control group and the other group with plain PLGA used for reconstruction of the palate. This study will invite future research in the effect of the drug on human beings, especially on pregnant mothers.

Scaffold preferences of mesenchymal stromal cells and adipose-derived stem cells from green fluorescent protein transgenic mice influence the tissue engineering of bone.

PubMed

Wittenburg, Gretel; Flade, Viktoria; Garbe, Annette I; Lauer, Günter; Labudde, Dirk

2014-05-01

We have analysed the growth and differentiation of mesenchymal stromal cells (MSC) from bone marrow, and of adipose derived stem cells (ASC) from murine abdominal fat tissue, of green fluorescent protein (GFP) transgenic animals grown directly on two types of hydroxyapatite ceramic bone substitutes. BONITmatrix® and NanoBone® have specific mechanical and physiochemical properties such as porosity and an inner surface that influence cellular growth. Both MSC and ASC were separately seeded on 200mg of each biomaterial and cultured for 3 weeks under osteogenic differentiation conditions. The degree of mineralisation was assessed by alizarin red dye and the specific alkaline phosphatase activity of the differentiated cells. The morphology of the cells was examined by scanning electron microscopy and confocal microscopy. The osteoblastic phenotype of the cells was confirmed by analysing the expression of bone-specific genes (Runx2, osteocalcin, osteopontin, and osteonectin) by semiquantitative reverse transcriptase polymerase chain reaction (PCR). Comparison of BONITmatrix® and NanoBone® showed cell type-specific preferences in terms of osteogenic differentiation. MSC-derived osteoblast-like cells spread optimally on the surface of NanoBone® but not BONITmatrix® granules. In contrast BONITmatrix® granules conditioned the growth of osteoblast-like cells derived from ASC. The osteoblastic phenotype of the cultured cells on all matrices was confirmed by specific gene expression. Our results show that the in vitro growth and osteogenic differentiation of murine MSC or ASC of GFP transgenic mice are distinctly influenced by the ceramic substratum. While NanoBone® granules support the proliferation and differentiation of murine MSC isolated from bone marrow, the growth of murine ASC is supported by BONITmatrix® granules. NanoBone® is therefore recommended for use as scaffold in tissue engineering that requires MSC, whereas ASC can be combined with BONITmatrix® for in vitro bone engineering. Copyright © 2014 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

Growth-Associated Changes in the Periodontal Bone and Molar Teeth of Male Rats

PubMed Central

García, María F; Moreno, Hilda; Rigalli, Alfredo; Puche, Rodolfo C

2009-01-01

Here we report quantitative data associating periodontal bone variables of young conventional rats with the growth process. The hemimandibles of male rats (IIM/Fm stock, 2 to 15 wk of age.) were excised and submitted to conventional morphologic, radiologic, and histologic evaluation. The length, area, or X-ray absorbance of various regions or structures was measured on digital images of radiographs by using an image-analysis program. The sum of periodontal bone areas undergoing resorption (interproximal + intraradicular) increased until 9 or 10 wk of age and decreased thereafter. Mineral accretion rates and mineral density asymptotes were not significantly different among molars. The mineral density of resorption areas in alveolar bone fitted sinusoidal kinetics, indicative of the ‘instability’ of the tissue due to its high metabolic activity. Mineral accretion rates and mineral density asymptotes were not significantly different among molars. The proportion of root length within alveolar bone exhibited a biphasic curve (minimum at 5 wk of age), due to differences in the growth rates of variables involved in its calculation (distance between the cementoenamel junction to the apex and height of the resorption areas). The distance between the cementoenamel junction and alveolar bone crest over time fitted a sigmoidal function with a point of inflection that did not differ significantly from that of body or mandible dry weight. In summary, the growth process appears to affect periodontal bone support and the distance between the cementoenamel junction and alveolar bone crest in male rats. PMID:19807966

Bone characteristics of late-term embryonic and hatchling broilers: bone development under extreme growth rate.

PubMed

Yair, R; Uni, Z; Shahar, R

2012-10-01

The development of broilers is an extreme example of rapid growth, increasing in weight from 40 g at hatch to 2,000 g 5 to 6 wk later. Such rapid growth requires a correspondingly fast development of the skeleton. Bone development is a genetically programmed process that is modified by epigenetic factors, mainly muscle-induced stresses and strains. In this study, we describe the temporal changes in bone morphology and material properties during the prehatch period [embryonic day (E) 14, E17, E19, E21] and posthatch d 3 and 7. The bones were examined for their weight, length, ash content, mechanical properties, and cortical structure. We show that the cross-sectional shape of the tibia and femur changes during the examination period from circular to elliptical. Additionally, the changes in bone properties are time-dependent and nonuniform: from E14 to E17 and from d 3 to 7, fast bone growth was noted, with major increases in both mechanical properties (stiffness, ultimate load, and energy to fracture) and geometric properties (cross-sectional area and thickness, medullary area, and moment of inertia). On the other hand, during the last days of incubation, most mechanical and geometric properties remain unchanged or even decrease. The reasons for this finding may relate to the hatching process but also to mineral shortage during the last days of incubation. This study leads to better understanding of bone development in ovo and posthatch in fast-growing broilers.

The use of rats and mice as animal models in ex vivo bone growth and development studies

PubMed Central

Abubakar, A. A.; Noordin, M. M.; Azmi, T. I.; Kaka, U.

2016-01-01

In vivo animal experimentation has been one of the cornerstones of biological and biomedical research, particularly in the field of clinical medicine and pharmaceuticals. The conventional in vivo model system is invariably associated with high production costs and strict ethical considerations. These limitations led to the evolution of an ex vivo model system which partially or completely surmounted some of the constraints faced in an in vivo model system. The ex vivo rodent bone culture system has been used to elucidate the understanding of skeletal physiology and pathophysiology for more than 90 years. This review attempts to provide a brief summary of the historical evolution of the rodent bone culture system with emphasis on the strengths and limitations of the model. It encompasses the frequency of use of rats and mice for ex vivo bone studies, nutritional requirements in ex vivo bone growth and emerging developments and technologies. This compilation of information could assist researchers in the field of regenerative medicine and bone tissue engineering towards a better understanding of skeletal growth and development for application in general clinical medicine. Cite this article: A. A. Abubakar, M. M. Noordin, T. I. Azmi, U. Kaka, M. Y. Loqman. The use of rats and mice as animal models in ex vivo bone growth and development studies. Bone Joint Res 2016;5:610–618. DOI: 10.1302/2046-3758.512.BJR-2016-0102.R2. PMID:27965220

Human Studies of Vertical and Horizontal Alveolar Ridge Augmentation Comparing Different Types of Bone Graft Materials: A Systematic Review.

PubMed

Chavda, Suraj; Levin, Liran

2018-02-01

Alveolar ridge augmentation can be completed with various types of bone augmentation materials (autogenous, allograft, xenograft, and alloplast). Currently, autogenous bone is labeled as the "gold standard" because of faster healing times and integration between native and foreign bone. No systematic review has currently determined whether there is a difference in implant success between various bone augmentation materials. The purpose of this article was to systematically review comparative human studies of vertical and horizontal alveolar ridge augmentation comparing different types of bone graft materials (autogenous, allograft, xenograft, and alloplast). A MEDLINE search was conducted under the 3 search concepts of bone augmentation, dental implants, and alveolar ridge augmentation. Studies pertaining to socket grafts or sinus lifts were excluded. Case reports, small case series, and review papers were excluded. A bias assessment tool was applied to the final articles. Overall, 219 articles resulted from the initial search, and 9 articles were included for final analysis. There were no discernible differences in implant success between bone augmentation materials. Generally, patients preferred nonautogenous bone sources as there were fewer hospital days, less pain, and better recovery time. Two articles had industrial support; however, conclusions of whether that support influenced the outcomes could not be determined. Future comparative studies should compare nonautogenous bone sources and have longer follow-up times.

Nell-1-Induced Bone Regeneration in Calvarial Defects

PubMed Central

Aghaloo, Tara; Cowan, Catherine M.; Chou, Yu-Fen; Zhang, Xinli; Lee, Haofu; Miao, Steve; Hong, Nichole; Kuroda, Shun’ichi; Wu, Benjamin; Ting, Kang; Soo, Chia

2006-01-01

Many craniofacial birth defects contain skeletal components requiring bone grafting. We previously identified the novel secreted osteogenic molecule NELL-1, first noted to be overexpressed during premature bone formation in calvarial sutures of craniosynostosis patients. Nell-1 overexpression significantly increases differentiation and mineralization selectively in osteoblasts, while newborn Nell-1 transgenic mice significantly increase premature bone formation in calvarial sutures. In the current study, cultured calvarial explants isolated from Nell-1 transgenic newborn mice (with mild sagittal synostosis) demonstrated continuous bone growth and overlapping sagittal sutures. Further investigation into gene expression cascades revealed that fibroblast growth factor-2 and transforming growth factor-β1 stimulated Nell-1 expression, whereas bone morphogenetic protein (BMP)-2 had no direct effect. Additionally, Nell-1-induced osteogenesis in MC3T3-E1 osteoblasts through reduction in the expression of early up-regulated osteogenic regulators (OSX and ALP) but induction of later markers (OPN and OCN). Grafting Nell-1 protein-coated PLGA scaffolds into rat calvarial defects revealed the osteogenic potential of Nell-1 to induce bone regeneration equivalent to BMP-2, whereas immunohistochemistry indicated that Nell-1 reduced osterix-producing cells and increased bone sialoprotein, osteocalcin, and BMP-7 expression. Insights into Nell-1-regulated osteogenesis coupled with its ability to stimulate bone regeneration revealed a potential therapeutic role and an alternative to the currently accepted techniques for bone regeneration. PMID:16936265

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

The relationship between alkaline phosphatase and bone alkaline phosphatase activity and the growth hormone/insulin-like growth factor-1 axis and vitamin D status in children with growth hormone deficiency.

PubMed

Witkowska-Sędek, Ewelina; Stelmaszczyk-Emmel, Anna; Majcher, Anna; Demkow, Urszula; Pyrżak, Beata

2018-04-13

The relationships between bone turnover, the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis and vitamin D are complex, but still not fully explained. The GH/IGF-1 axis and vitamin D can mutually modulate each other's metabolism and influence the activation of cell proliferation, maturation, and mineralization as well as bone resorption. The aim of this study was to evaluate the reciprocal associations between bone formation markers [alkaline phosphatase (ALP), bone alkaline phosphatase (BALP)], the GH/IGF-1 axis and 25-hydroxyvitamin D [25(OH)D] in children with growth hormone deficiency at baseline and during recombinant human growth hormone (rhGH) therapy. ALP, BALP, 25(OH)D and IGF-1 levels were evaluated in 53 patients included in this prospective three-year study. ALP, BALP and IGF-1 increased during rhGH therapy. Baseline ALP activity correlated positively with baseline height velocity (HV). ALP and BALP activity at 12 months correlated positively with HV in the first year of therapy. We found positive correlations between ALP and IGF-1 at baseline and during the first year of therapy, between BALP activity at 12 months and rhGH dose in the first year of therapy, and between doses of cholecalciferol in the first year of rhGH therapy and early changes in BALP activity during rhGH therapy. Our results indicate that vitamin D supplementation enhances the effect of rhGH on bone formation process, which could improve the effects of rhGH therapy. ALP and BALP activity are useful in the early prediction of the effects of rhGH therapy, but their utility as long-term predictors seemed insufficient.

Physical activity effects on bone metabolism.

PubMed

Smith, E L; Gilligan, C

1991-01-01

The incidence of osteoporotic fractures rises exponentially with age and is increasing faster than the demographic increase in the aging population. Physical activity has great potential to reduce the risk for osteoporotic fractures. Three independent but interactive factors contribute to the risk of fractures: bone strength, the risk of falling, and the effectiveness of neuromuscular response that protects the skeleton from injury. Exercise can reduce fracture risk not only by preventing bone loss, but by decreasing the risk of falling and the force of impact by improving strength, flexibility, balance, and reaction time. Extreme inactivity causes rapid bone loss of up to 40%, while athletic activity results in bone hypertrophy of up to 40%. Exercise intervention programs have reduced bone loss or increased bone mass in both men and women of various ages and initial bone status. These benefits have been shown for arm bone mineral content, total body calcium, spine, calcium bone index, tibia, and calcaneus. In both middle-aged and elderly women, physical activity intervention reduced bone loss or increased bone mass. The mechanisms for maintenance of skeletal integrity rely on a cellular response to hormonal and mechanical load stimuli. Studies in animal models show that training affects cellular activity. In osteoporotics, cellular erosion is increased and mineral apposition rate (MAR) decreased compared with normal age-matched controls. In contrast to this, sows trained on a treadmill 20 min per day for 20 weeks had greater active periosteal surface, periosteal MAR, and osteonal MAR than untrained sows.

Accelerated and enhanced bone formation on novel simvastatin-loaded porous titanium oxide surfaces.

PubMed

Nyan, Myat; Hao, Jia; Miyahara, Takayuki; Noritake, Kanako; Rodriguez, Reena; Kasugai, Shohei

2014-10-01

With increasing application of dental implants in poor-quality bones, the need for implant surfaces ensuring accelerated osseointegration and enhanced peri-implant bone regeneration is increased. A study was performed to evaluate the osseointegration and bone formation on novel simvastatin-loaded porous titanium oxide surface. Titanium screws were treated by micro-arc oxidation to form porous oxide surface and 25 or 50 μg of simvastatin was loaded. The nontreated control, micro-arc oxidized, and simvastatin-loaded titanium screws were surgically implanted into the proximal tibia of 16-week-old male Wistar rats (n = 36). Peri-implant bone volume, bone-implant contact, and mineral apposition rates were measured at 2 and 4 weeks. Data were analyzed by one-way analysis of variance followed by Tukey's post hoc test. New bone was formed directly on the implant surface in the bone marrow cavity in simvastatin-loaded groups since 2 weeks. Bone-implant contact values were significantly higher in simvastatin-loaded groups than control and micro-arc oxidized groups at both time points (p < .05). Peri-implant bone volume and mineral apposition rate of simvastatin-loaded groups were significantly higher than control and micro-arc oxidized groups at 2 weeks (p < .05). These data suggested that simvastatin-loaded porous titanium oxide surface provides faster osseointegration and peri-implant bone formation and it would be potentially applicable in poor-quality bones. © 2013 Wiley Periodicals, Inc.

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.

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

Skeletal maturity and growth of adolescent mothers: relationship to pregnancy outcome.

PubMed

Stevens-Simon, C; McAnarney, E R

1993-09-01

The purpose of this study was to evaluate the relationship between postpartum maternal bone age and the incidence of obstetric and neonatal complications in adolescent pregnancies. Bone age determinations were obtained on 93 poor, black 12- through 18-year-old adolescents during the puerperium. Results showed maternal bone ages ranging from 15 to 18 years; bone age was less than 18 years in 64 (68.8%) of the 93 adolescent mothers we studied. Maternal bone age correlated significantly with maternal chronologic age (r = 0.70) and prepregnant body size (r = 0.25) but did not correlate with total maternal weight gain and growth during pregnancy, the incidence of obstetric and neonatal complications, or infant birth weight and gestational age. Our findings suggest that many young, pregnant adolescents have the potential to grow during and after pregnancy, but do not support the hypothesis that ongoing maternal growth is an obstetric risk factor during adolescence.

Analysis of Mouse Growth Plate Development

PubMed Central

Mangiavini, Laura; Merceron, Christophe; Schipani, Ernestina

2016-01-01

To investigate skeletal development, pathophysiological mechanisms of cartilage and bone disease, and eventually assess innovative treatments, the mouse is a very important resource. During embryonic development, mesenchymal condensations are formed, and cells within these mesenchymal condensations either directly differentiate into osteoblasts and give origin to intramembranous bone, or differentiate into chondrocytes and form a cartilaginous anlage. The cartilaginous anlage or fetal growth plate is then replaced with bone. This process is also called endochondral bone development, and it is responsible for the generation of most of our skeleton. In this Review, we will discuss in detail the most common in vivo and in vitro techniques our laboratory is currently using for the analysis of the mouse fetal growth plate during development. PMID:26928664

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.

Optimal Length of Cultivation Time for Isolation of Propionibacterium acnes in Suspected Bone and Joint Infections Is More than 7 Days.

PubMed

Bossard, Daniel A; Ledergerber, Bruno; Zingg, Patrick O; Gerber, Christian; Zinkernagel, Annelies S; Zbinden, Reinhard; Achermann, Yvonne

2016-12-01

Diagnosis of Propionibacterium acnes bone and joint infection is challenging due to the long cultivation time of up to 14 days. We retrospectively studied whether reducing the cultivation time to 7 days allows accurate diagnosis without losing sensitivity. We identified patients with at least one positive P. acnes sample between 2005 and 2015 and grouped them into "infection" and "no infection." An infection was defined when at least two samples from the same case were positive. Clinical and microbiological data, including time to positivity for different cultivation methods, were recorded. We found 70 cases of proven P. acnes infection with a significant faster median time to positivity of 6 days (range, 2 to 11 days) compared to 9 days in 47 cases with P. acnes identified as a contamination (P < 0.0001). In 15 of 70 (21.4%) patients with an infection, tissue samples were positive after day 7 and in 6 patients (8.6%) after day 10 when a blind subculture of the thioglycolate broth was performed. The highest sensitivity was detected for thioglycolate broth (66.3%) and the best positive predictive values for anaerobic agar plates (96.5%). A prolonged transportation time from the operating theater to the microbiological laboratory did not influence time to positivity of P. acnes growth. By reducing the cultivation time to 7 days, false-negative diagnoses would increase by 21.4%; thus, we recommend that biopsy specimens from bone and joint infections be cultivated to detect P. acnes for 10 days with a blind subculture at the end. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

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.

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.

Photoperiod-Induced Increases in Bone Mineral Apposition Rate in Siberian Hamsters and the Involvement of Seasonal Leptin Changes

PubMed Central

Kokolski, Marie; Ebling, Francis J.; Henstock, James R.; Anderson, Susan I.

2017-01-01

The adipokine leptin regulates energy balance, appetite, and reproductive maturation. Leptin also acts on bone growth and remodeling, but both osteogenic and anti-osteogenic effects have been reported depending on experimental conditions. Siberian hamsters (Phodopus sungorus) have natural variation in circulating leptin concentrations, where serum leptin is significantly decreased during the short day (SD)-induced winter state. In summer long day (LD) photoperiods, appetite and body adiposity increase with associated central leptin insensitivity. This natural change in leptin secretion was exploited to investigate leptin’s effect on bone growth. Hamsters were injected with calcium-chelating fluorescent dyes to measure bone mineral apposition rate (MAR). Measurements were initially obtained from 5-week and 6-month-old animals maintained in low leptin (SD) or high leptin (LD) states. A further study investigated effects of chronic administration of recombinant mouse leptin to hamsters housed in SD and LD conditions; growth plate thickness and bone density were also assessed. As expected, a reduction in body mass was seen in hamsters exposed to SD, confirming the phenotype change in all studies. Serum leptin concentrations were significantly reduced in SD animals in all studies. MAR was reproducibly and significantly increased in the femurs of SD animals in all studies. Vitamin D and growth plate thickness were significantly increased in SD animals at 6 months. No effect on bone density was observed in any study. Taken together these data suggest that bone growth is associated with the low leptin, winter, lean state. In leptin-treated animals, there was a significant interaction effect of leptin and photoperiod. In comparison to their vehicle counterparts, SD animals had decreased and LD animals had increased MAR, which was not apparent prior to leptin administration. In conclusion, increased MAR was associated with low serum leptin levels in early life and sustained over 6 months, implying that leptin has a negative effect on bone growth in this model. The unexpected finding that MAR increased after peripheral leptin administration in LD suggests that leptin exerts different effects on bone growth dependent on initial leptin status. This adds further weight to the hypothesis that leptin-treated LD animals display central leptin resistance. PMID:29312147

Photoperiod-Induced Increases in Bone Mineral Apposition Rate in Siberian Hamsters and the Involvement of Seasonal Leptin Changes.

PubMed

Kokolski, Marie; Ebling, Francis J; Henstock, James R; Anderson, Susan I

2017-01-01

The adipokine leptin regulates energy balance, appetite, and reproductive maturation. Leptin also acts on bone growth and remodeling, but both osteogenic and anti-osteogenic effects have been reported depending on experimental conditions. Siberian hamsters ( Phodopus sungorus ) have natural variation in circulating leptin concentrations, where serum leptin is significantly decreased during the short day (SD)-induced winter state. In summer long day (LD) photoperiods, appetite and body adiposity increase with associated central leptin insensitivity. This natural change in leptin secretion was exploited to investigate leptin's effect on bone growth. Hamsters were injected with calcium-chelating fluorescent dyes to measure bone mineral apposition rate (MAR). Measurements were initially obtained from 5-week and 6-month-old animals maintained in low leptin (SD) or high leptin (LD) states. A further study investigated effects of chronic administration of recombinant mouse leptin to hamsters housed in SD and LD conditions; growth plate thickness and bone density were also assessed. As expected, a reduction in body mass was seen in hamsters exposed to SD, confirming the phenotype change in all studies. Serum leptin concentrations were significantly reduced in SD animals in all studies. MAR was reproducibly and significantly increased in the femurs of SD animals in all studies. Vitamin D and growth plate thickness were significantly increased in SD animals at 6 months. No effect on bone density was observed in any study. Taken together these data suggest that bone growth is associated with the low leptin, winter, lean state. In leptin-treated animals, there was a significant interaction effect of leptin and photoperiod. In comparison to their vehicle counterparts, SD animals had decreased and LD animals had increased MAR, which was not apparent prior to leptin administration. In conclusion, increased MAR was associated with low serum leptin levels in early life and sustained over 6 months, implying that leptin has a negative effect on bone growth in this model. The unexpected finding that MAR increased after peripheral leptin administration in LD suggests that leptin exerts different effects on bone growth dependent on initial leptin status. This adds further weight to the hypothesis that leptin-treated LD animals display central leptin resistance.

Short-term effects of mineral particle sizes on cellular degradation activity after implantation of injectable calcium phosphate biomaterials and the consequences for bone substitution.

PubMed

Gauthier, O; Bouler, J M; Weiss, P; Bosco, J; Aguado, E; Daculsi, G

1999-08-01

This in vivo study investigated the influence of two calcium phosphate particle sizes (40-80 microm and 200-500 microm) on the cellular degradation activity associated with the bone substitution process of two injectable bone substitutes (IBS). The tested biomaterials were obtained by associating a biphasic calcium phosphate (BCP) ceramic mineral phase and a 3% aqueous solution of a cellulosic polymer (hydroxypropylmethylcellulose). Both were injected into osseous defects at the distal end of rabbit femurs for 2- and 3-week periods. Quantitative results for tartrate-resistant acid phosphatase (TRAP) cellular activity, new bone formation, and ceramic resorption were studied for statistical purposes. Positive TRAP-stained degradation cells were significantly more numerous for IBS 40-80 than IBS 200-500, regardless of implantation time. BCP degradation was quite marked during the first 2 weeks for IBS 40-80, and bone colonization occurred more extensively for IBS 40-80 than for IBS 200-500. The resorption-bone substitution process occurred earlier and faster for IBS 40-80 than IBS 200-500. Both tested IBS displayed similar biological efficiency, with conserved in vivo bioactivity and bone-filling ability. Differences in calcium phosphate particle sizes influenced cellular degradation activity and ceramic resorption but were compatible with efficient bone substitution.

A novel combined method of osteosynthesis in treatment of tibial fractures: a comparative study on sheep with application of rod-through-plate fixator and bone plating.

PubMed

Tralman, G; Andrianov, V; Arend, A; Männik, P; Kibur, R T; Nõupuu, K; Uksov, D; Aunapuu, M

2013-04-01

The study compares the efficiency of a new bone fixator combining periostal and intramedullary osteosynthesis to bone plating in treatment of tibial fractures in sheep. Experimental osteotomies were performed in the middle third of the left tibia. Animals were divided into two groups: in one group (four animals) combined osteosynthesis (rod-through-plate fixator, RTP fixator) was applied, and in the other group (three animals) bone plating was used. The experiments lasted for 10 weeks during which fracture union was followed by radiography, and the healing process was studied by blood serum markers reflecting bone turnover and by histological and immunohistochemical investigations. In the RTP fixator group, animals started to load body weight on the operated limbs the next day after the surgery, while in the bone plating group, this happened only on the seventh day. In the RTP fixator group, consolidation of fractures was also faster, as demonstrated by radiographical, histological, and immunohistochemical investigations and in part by blood serum markers for bone formation. It can be concluded that application of RTP fixation is more efficient than plate fixation in the treatment of experimental osteotomies of long bones in sheep. © 2012 Blackwell Verlag GmbH.

Exercise-Induced Changes in the Cortical Bone of Growing Mice Are Bone and Gender Specific

PubMed Central

Wallace, Joseph M.; Rajachar, Rupak M.; Allen, Matthew R.; Bloomfield, Susan A.; Robey, Pamela G.; Young, Marian F.; Kohn, David H.

2009-01-01

Fracture risk and mechanical competence of bone are functions of bone mass and tissue quality, which in turn are dependent on the bone’s mechanical environment. Male mice have a greater response to non weight-bearing exercise than females, resulting in larger, stronger bones compared with control animals. The aim of this study was to test the hypothesis that short-term weight-bearing running during growth (21 days starting at 8 weeks of age; 30 minutes/day; 12 meters/minute; 5° incline; 7 days/week) would similarly have a greater impact on cross sectional geometry and mechanical competence in the femora and tibiae of male mice versus females. Based on the orientation of the legs during running and the proximity of the tibia to the point of impact, this response was hypothesized to be greatest in the tibia. Exercise-related changes relative to controls were assayed by four-point bending tests, while volumetric bone mineral density and cross-sectional geometry were also assessed. The response to running was bone and gender-specific, with male tibiae demonstrating the greatest effects. In male tibiae, periosteal perimeter, endocortical perimeter, cortical area, medial-lateral width and bending moment of inertia increased versus control mice suggesting that while growth is occurring in these mice between 8 and 11 weeks of age, exercise accelerated this growth resulting in a greater increase in bone tissue over the 3 weeks of the study. Exercise increased tissue-level strain-to-failure and structural post-yield deformation in the male tibiae, but these post-yield benefits came at the expense of decreased yield deformation, structural and tissue-level yield strength and tissue-level ultimate strength. These results suggest that exercise superimposed upon growth accelerated growth-related increases in tibial cross-sectional dimensions. Exercise also influenced the quality of this forming bone, significantly impacting structural and tissue-level mechanical properties. PMID:17240210

Selective Laser Melting: a regular unit cell approach for the manufacture of porous, titanium, bone in-growth constructs, suitable for orthopedic applications.

PubMed

Mullen, Lewis; Stamp, Robin C; Brooks, Wesley K; Jones, Eric; Sutcliffe, Christopher J

2009-05-01

In this study, a novel porous titanium structure for the purpose of bone in-growth has been designed, manufactured and evaluated. The structure was produced by Selective Laser Melting (SLM); a rapid manufacturing process capable of producing highly intricate, functionally graded parts. The technique described utilizes an approach based on a defined regular unit cell to design and produce structures with a large range of both physical and mechanical properties. These properties can be tailored to suit specific requirements; in particular, functionally graded structures with bone in-growth surfaces exhibiting properties comparable to those of human bone have been manufactured. The structures were manufactured and characterized by unit cell size, strand diameter, porosity, and compression strength. They exhibited a porosity (10-95%) dependant compression strength (0.5-350 Mpa) comparable to the typical naturally occurring range. It is also demonstrated that optimized structures have been produced that possesses ideal qualities for bone in-growth applications and that these structures can be applied in the production of orthopedic devices. (c) 2008 Wiley Periodicals, Inc.

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

Fatigue crack growth in SA508-CL2 steel in a high temperature, high purity water environment

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

Gerber, T.L.; Heald, J.D.; Kiss, E.

1974-10-01

Fatigue crack growth tests were conducted with 1 in. plate specimens of SA508-CL 2 steel in room temperature air, 550$sup 0$F air and in a 550$sup 0$F, high purity, water environment. Zero-tension load controlled tests were run at cyclic frequencies as low as 0.037 CPM. Results show that growth rates in the simulated Boiling Water Reactor (BWR) water environment are faster than growth rates observed in 550$sup 0$F air and these rates are faster than the room temperature rate. In the BWR water environment, lowering the cyclic frequency from 0.37 to 0.037 CPM caused only a slight increase in themore » fatigue crack growth rate. All growth rates measured in these tests were below the upper bound design curve presented in Section XI of the ASME Code. (auth)« less

Leg lengthening - series (image)

MedlinePlus

... as Legg-Perthes disease Previous injuries or bone fractures that may stimulate excessive bone growth Abnormal spinal ... in the bone to be lengthened; usually the lower leg bone (tibia) or upper ... small steps, usually over the course of several months.

Positive effects of bisphosphonates on bone and muscle in a mouse model of Duchenne muscular dystrophy.

PubMed

Yoon, Sung-Hee; Sugamori, Kim S; Grynpas, Marc D; Mitchell, Jane

2016-01-01

Patients with Duchenne muscular dystrophy are at increased risk of decreased bone mineral density and bone fracture as a result of inactivity. To determine if antiresorptive bisphosphonates could improve bone quality and their effects on muscle we studied the Mdx mouse, treated with pamidronate during peak bone growth at 5 and 6 weeks of age, and examined the outcome at 13 weeks of age. Pamidronate increased cortical bone architecture and strength in femurs with increased resistance to fracture. While overall long bone growth was not affected by pamidronate, there was significant inhibition of remodeling in metaphyseal trabecular bone with evidence of residual calcified cartilage. Pamidronate treatment had positive effects on skeletal muscle in the Mdx mice with decreased serum and muscle creatine kinase and evidence of improved muscle histology and grip strength. Copyright © 2015 Elsevier B.V. All rights reserved.

Hyperspectral Raman imaging of bone growth and regrowth chemistry

NASA Astrophysics Data System (ADS)

Pezzuti, Jerilyn A.; Morris, Michael D.; Bonadio, Jeffrey F.; Goldstein, Steven A.

1998-06-01

Hyperspectral Raman microscopic imaging of carbonated hydroxyapatite (HAP) is used to follow the chemistry of bone growth and regrowth. Deep red excitation is employed to minimize protein fluorescence interference. A passive line generator based on Powell lens optics and a motorized translation stage provide the imaging capabilities. Raman image contrast is generated from several lines of the HAP Raman spectrum, primarily the PO4-3. Factor analysis is used to minimize the integration time needed for acceptable contrast and to explore the chemical species within the bone. Bone age is visualized as variations in image intensity. High definition, high resolution images of newly formed bone and mature bone are compared qualitatively. The technique is currently under evaluation for study of experimental therapies for fracture repair.

The Use of Recombinant Human Platelet-Derived Growth Factor for Maxillary Sinus Augmentation.

PubMed

Kubota, Atsushi; Sarmiento, Hector; Alqahtani, Mohammed Saad; Llobell, Arturo; Fiorellini, Joseph P

The maxillary sinus augmentation procedure has become a predictable treatment to regenerate bone for implant placement. The purpose of this study was to evaluate the effect of recombinant human platelet-derived growth factor BB (rhPDGF-BB) combined with a deproteinized cancellous bovine bone graft for sinus augmentation. The lateral window approach was used for maxillary sinuses with minimal residual bone. After a healing period of 4 months, dental implants were placed and then restored following a 2-month osseointegration period. The result demonstrated increased bone height and ISQ values and a 100% survival rate. This study indicates that the addition of rhPDGF-BB to deproteinized cancellous bovine bone accelerated the healing period in maxillary sinuses with minimal native bone.

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

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.

INDIRECT EFFECT OF X-RADIATION ON BONE GROWTH IN RATS

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

Conard, R.A.

1962-12-21

Effects of 200 to 600 r of x irradiation on tibial bone growth in groups of weanling male rats were studied by in vivo measurement of tibial bone growth in serial radiographs. By comparison of growth rates in shielded with unshielded legs, direct and indirect effects of radiation were demonstrated, both roughly dose dependent, but with the indirect effect being about twice that of the direct effect. Pair-feeding experiments showed that about 70% of the indirect effect was due to radiation-induced lowered food consumption. By partial-body shielding experiments, using pnir-fed controls, it was shown that the abdomen may be themore » site of a non-nutritional abscopal effect. (auth)« less

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.

[Clinical condition and therapy of bone diseases].

PubMed

Miura, Kohji; Oznono, Keiichi

2013-12-01

Skeletal dysplasia is the term which represents disorders including growth and differentiation of bone, cartilage and ligament. A lot of diseases are included, and new disorders have been added. However, the therapy of most bone diseases is less well-established. Achondroplasia, hypochondroplasia, and osteogenesis imperfecta are most frequent bone diseases. There is no curative treatment for these diseases, however, supportive therapies are available ; for example, growth-hormone therapy for achondroplasia and hypochondroplasia, and bisphosphonate therapy for osteogenesis imperfecta. In addition, enzyme replacement therapy for hypophosphatasia is now on clinical trial.

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.

Ontogenetic relationships between in vivo strain environment, bone histomorphometry and growth in the goat radius

PubMed Central

Main, Russell P

2007-01-01

Vertebrate long bone form, at both the gross and the microstructural level, is the result of many interrelated influences. One factor that is considered to have a significant effect on bone form is the mechanical environment experienced by the bone during growth. The work presented here examines the possible relationships between in vivo bone strains, bone geometry and histomorphology in the radii of three age/size groups of domestic goats. In vivo bone strain data were collected from the radii of galloping goats, and the regional cortical distribution of peak axial strain magnitudes, radial and circumferential strain gradients, and longitudinal strain rates related to regional patterns in cortical growth, porosity, remodelling and collagen fibre orientation. Although porosity and remodelling decreased and increased with age, respectively, these features showed no significant regional differences and did not correspond to regional patterns in the mechanical environment. Thicker regions of the radius's cortex were significantly related to high strain levels and higher rates of periosteal, but not endosteal, growth. However, cortical growth and strain environment were not significantly related. Collagen fibre orientation varied regionally, with a higher percentage of transverse fibres in the caudal region of the radius and primarily longitudinal fibres elsewhere, and, although consistent through growth, also did not generally correspond to regional strain patterns. Although strain magnitudes increased during ontogeny and regional strain patterns were variable over the course of a stride, mean regional strain patterns were generally consistent with growth, suggesting that regional growth patterns and histomorphology, in combination with external loads, may play some role in producing a relatively ‘predictable’ strain environment within the radius. It is further hypothesized that the absence of correlation between regional histomorphometric patterns and the measured strain environments is the result of the variable mechanical environment. However, the potential effects of other physiological and mechanical factors, such as skeletal metabolism and adjacent muscle insertions, that can influence the gross and microstructural morphology of the radius during ontogeny, cannot be ignored. PMID:17331177

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.

Comparison of six bone-graft substitutes regarding to cell seeding efficiency, metabolism and growth behaviour of human mesenchymal stem cells (MSC) in vitro.

PubMed

Seebach, Caroline; Schultheiss, Judith; Wilhelm, Kerstin; Frank, Johannes; Henrich, Dirk

2010-07-01

Various synthetic bone-graft substitutes are used commercially as osteoconductive scaffolds in the treatment of bone defects and fractures. The role of bone-graft substitutes is changing from osteoconductive conduits for growth to an delivery system for biologic fracture treatments. Achieving optimal bone regeneration requires biologics (e.g. MSC) and using the correct scaffold incorporated into a local environment for bone regeneration. The need for an unlimited supply with high quality bone-graft substitutes continue to find alternatives for bone replacement surgery. This in vitro study investigates cell seeding efficiency, metabolism, gene expression and growth behaviour of MSC sown on six commercially clinical available bone-graft substitutes in order to define their biological properties: synthetic silicate-substituted porous hydroxyapatite (Actifuse ABX), synthetic alpha-TCP (Biobase), synthetic beta-TCP (Vitoss), synthetic beta-TCP (Chronos), processed human cancellous allograft (Tutoplast) and processed bovines hydroxyapatite ceramic (Cerabone). 250,000 MSC derived from human bone marrow (n=4) were seeded onto the scaffolds, respectively. On days 2, 6 and 10 the adherence of MSC (fluorescence microscopy) and cellular activity (MTT assay) were analysed. Osteogenic gene expression (cbfa-1) was analysed by RT-PCR and scanning electron microscopy was performed. The highest number of adhering cells was found on Tutoplast (e.g. day 6: 110.0+/-24.0 cells/microscopic field; p<0.05) followed by Chronos (47.5+/-19.5, p<0.05), Actifuse ABX (19.1+/-4.4), Biobase (15.7+/-9.9), Vitoss (8.8+/-8.7) and Cerabone (8.1+/-2.2). MSC seeded onto Tutoplast showed highest metabolic activity and gene expression of cbfa-1. These data are confirmed by scanning electron microscopy. The cell shapes varied from round-shaped cells to wide spread cells and cell clusters, depending on the bone-graft substitutes. Processed human cancellous allograft is a well-structured and biocompatible scaffold for ingrowing MSC in vitro. Of all other synthetical scaffolds, beta-tricalcium phosphate (Chronos) have shown the best growth behaviour for MSC. Our results indicate that various bone-graft substitutes influence cell seeding efficiency, metabolic activity and growth behaviour of MSC in different manners. We detected a high variety of cellular integration of MSC in vitro, which may be important for bony integration in the clinical setting. 2010 Elsevier Ltd. All rights reserved.

Effects of growth hormone therapy on bone density and fracture risk in age-related osteoporosis in the absence of growth hormone deficiency: a systematic review and meta-analysis.

PubMed

Barake, Maya; Arabi, Asma; Nakhoul, Nancy; El-Hajj Fuleihan, Ghada; El Ghandour, Sarah; Klibanski, Anne; Tritos, Nicholas A

2018-01-01

In adults, growth hormone deficiency (GHD) has been associated with low bone mineral density (BMD), an effect counteracted by growth hormone (GH) replacement. Whether GH is beneficial in adults with age-related bone loss and without hypopituitarism is unclear. We conducted a systematic literature search using Medline, Embase and the Cochrane Register of Controlled Trials. We extracted and analyzed data according to the bone outcome included [bone mineral content (BMC), BMD, and bone biomarker, fracture risk]. We performed a meta-analysis when possible. We included eight studies. Seven randomized 272 post-menopausal women, 61-69 years, to GH or control, for 6-24 months, and the eighth was an extension trial. Except for one study, all women received concurrent osteoporosis therapies. There was no significant effect of GH, as compared to control, on BMD at the lumbar spine (Weighted mean difference WMD = -0.01 [-0.04, 0.02]), total hip (WMD = 0 [-0.05, 0.06]) or femoral neck (WMD = 0 [-0.03, 0.04]). Similarly, no effect was seen on BMC. GH significantly increased the bone formation marker procollagen type-I carboxy-terminal propeptide (PICP) (WMD = 14.03 [2.68, 25.38]). GH resulted in a trend for increase in osteocalcin and in bone resorption markers. Patients who received GH had a significant decrease in fracture risk as compared to control (RR = 0.63 [0.46, 0.87]). Reported adverse events were not major, mostly related to fluid retention. GH may not improve bone density in women with age-related bone loss but may decrease fracture risk. Larger studies of longer duration are needed to further explore these findings in both genders, and to investigate the effect of GH on bone quality.

Musculoskeletal Complications and Bone Metastases in Breast Cancer Patients Undergoing Estrogen Deprivation Therapy

DTIC Science & Technology

2016-10-01

are that any treatment or environmental factor that leads to bone loss (e.g., glucocorticoids, GnRH inhibitors, radiation, fracture , osteoporosis...recurrence and mortality. Previous cell culture and clinical studies have demonstrated that peripheral adipose ( fat ) tissue promotes cancer growth, yet the...contribution of increased MAT on metastatic tumor growth in bone is currently unknown. MAT, which is a historically understudied fat depot, accounts

The temporal response of bone to unloading

NASA Technical Reports Server (NTRS)

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

1984-01-01

Rats were suspended by their tails with the forelimbs bearing the weight load to simulate the weightlessness of space flight. Growth in bone mass ceased by 1 week in the hindlimbs and lumbar vertebrae in growing rats, while growth in the forelimbs and cervical vertebrae remained unaffected. The effects of selective skeletal unloading on bone formation during 2 weeks of suspension was investigated using radio iostope incorporation (with Ca-45 and H-3 proline) and histomorphometry (with tetracycline labeling). The results of these studies were confirmed by histomorphometric measurements of bone formation using triple tetracycline labeling. This model of simulated weightlessness results in an initial inhibition of bone formation in the unloaded bones. This temporary cessation of bone formation is followed in the accretion of bone mass, which then resumes at a normal rate by 14 days, despite continued skeletal unloading. This cycle of inhibition and resumption of bone formation has profound implication for understanding bone dynamics durng space flight, immobilization, or bed rest and offers an opportunity to study the hormonal and mechanical factors that regulate bone formation.

Pre-augmentation soft tissue expansion improves scaffold-based vertical bone regeneration - a randomized study in dogs.

PubMed

Kaner, Doğan; Zhao, Han; Arnold, Wolfgang; Terheyden, Hendrik; Friedmann, Anton

2017-06-01

Soft tissue (ST) dehiscence with graft exposure is a frequent complication of vertical augmentation. Flap dehiscence is caused by failure to achieve tension-free primary wound closure and by the impairment of flap microcirculation due to surgical trauma. Soft tissue expansion (STE) increases ST quality and quantity prior to reconstructive surgery. We hypothesized that flap preconditioning using STE would reduce the incidence of ST complications after bone augmentation and that optimized ST healing would improve the outcome of bone regeneration. Self-filling tissue expanders were implanted in mandibular bone defects in ten beagle dogs. After expansion, alloplastic scaffolds were placed for vertical bone augmentation in STE sites and in control sites without STE pre-treatment. ST flap microcirculation was analysed using laser Doppler flowmetry. The incidence of graft exposures was evaluated after 2 weeks. Bone formation was assessed after 2 months, using histomorphometry and immunohistochemistry. Test sites showed significantly less impairment of perfusion and faster recovery of microcirculation after bone augmentation. Furthermore, no flap dehiscences occurred in STE sites. Bone regeneration was found in both groups; however, significantly greater formation of new bone was detected in test sites with preceding STE. Preconditioning using STE improved ST healing and bone formation after vertical augmentation. The combination of STE and the subsequent placement of alloplastic scaffolds may facilitate the reconstruction of severe bone defects. © 2016 The Authors. Clinical Oral Implants Research Published by John Wiley & Sons Ltd.

A Therapeutic Potential for Marine Skeletal Proteins in Bone Regeneration

PubMed Central

Green, David W.; Padula, Matthew P.; Santos, Jerran; Chou, Joshua; Milthorpe, Bruce; Ben-Nissan, Besim

2013-01-01

A vital ingredient for engineering bone tissue, in the culture dish, is the use of recombinant matrix and growth proteins to help accelerate the growth of cultivated tissues into clinically acceptable quantities. The skeletal organic matrices of calcifying marine invertebrates are an untouched potential source of such growth inducing proteins. They have the advantage of being ready-made and retain the native state of the original protein. Striking evidence shows that skeleton building bone morphogenic protein-2/4 (BMP) and transforming growth factor beta (TGF-β) exist within various marine invertebrates such as, corals. Best practice mariculture and the latest innovations in long-term marine invertebrate cell cultivation can be implemented to ensure that these proteins are produced sustainably and supplied continuously. This also guarantees that coral reef habitats are not damaged during the collection of specimens. Potential proteins for bone repair, either extracted from the skeleton or derived from cultivated tissues, can be identified, evaluated and retrieved using chromatography, cell assays and proteomic methods. Due to the current evidence for bone matrix protein analogues in marine invertebrates, together with the methods established for their production and retrieval there is a genuine prospect that they can be used to regenerate living bone for potential clinical use. PMID:23574983

A nanoparticulate injectable hydrogel as a tissue engineering scaffold for multiple growth factor delivery for bone regeneration.

PubMed

Dyondi, Deepti; Webster, Thomas J; Banerjee, Rinti

2013-01-01

Gellan xanthan gels have been shown to be excellent carriers for growth factors and as matrices for several tissue engineering applications. Gellan xanthan gels along with chitosan nanoparticles of 297 ± 61 nm diameter, basic fibroblast growth factor (bFGF), and bone morphogenetic protein 7 (BMP7) were employed in a dual growth factor delivery system to promote the differentiation of human fetal osteoblasts. An injectable system with ionic and temperature gelation was optimized and characterized. The nanoparticle loaded gels showed significantly improved cell proliferation and differentiation due to the sustained release of growth factors. A differentiation marker study was conducted, analyzed, and compared to understand the effect of single vs dual growth factors and free vs encapsulated growth factors. Dual growth factor loaded gels showed a higher alkaline phosphatase and calcium deposition compared to single growth factor loaded gels. The results suggest that encapsulation and stabilization of growth factors within nanoparticles and gels are promising for bone regeneration. Gellan xanthan gels also showed antibacterial effects against Pseudomonas aeruginosa, Staphylococcus aureus, and Staphylococcus epidermidis, the common pathogens in implant failure.

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.

Effect of plasma-rich in platelet-derived growth factors on peri-implant bone healing: An experimental study in canines

PubMed Central

Birang, Reza; Torabi, Alireza; Shahabooei, Mohammad; Rismanchian, Mansour

2012-01-01

Background: Tissue engineering principles can be exploited to enhance alveolar and peri-implant bone reconstruction by applying such biological factors as platelet-derived growth factors. The objective of the present study is to investigate the effect of autologous plasma-rich in growth factors (on the healing of peri-implant bone in canine mandible). Materials and Methods: In this prospective experimental animal study, two healthy canines of the Iranian mix breed were selected. Three months after removing their premolar teeth on both sides of the mandible, 12 implants of the Osteo Implant Corporationsystem, 5 mm in diameter and 10 mm in length, were selected to be implanted. Plasma rich in growth factors (PRGF) were applied on six implants while the other six were used as plain implants without the plasma. The implants were installed in osteotomy sites on both sides of the mandible to be removed after 4 weeks with the surrounding bones using a trephine bur. Mesio-distal sections and implant blocks, 50 μ in diameter containing the peri-implant bone, were prepared By basic fuchin toluidine-bluefor histological and histomorphometric evaluation by optical microscope. The data were analyzed using Mann-Whitney Test (P<0.05). Results: The bone trabeculae and the type of bone generation in PRGF and control groups had no statistically significant differences (P=0.261, P=0.2) although the parameters showed higher measured values in the PRGF group. However, compared to the control, application of PRGF had significantly increased bone-to-implant contact (P=0.028) Conclusion: Based on the results, it may be concluded that application of PRGF on the surface of implant may enhance bone-to-implant contact. PMID:22363370

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

Biologic Approaches for the Treatment of Partial Tears of the Anterior Cruciate Ligament

PubMed Central

Dallo, Ignacio; Chahla, Jorge; Mitchell, Justin J.; Pascual-Garrido, Cecilia; Feagin, John A.; LaPrade, Robert F.

2017-01-01

Background: Anterior cruciate ligament reconstruction (ACLR) has been established as the gold standard for treatment of complete ruptures of the anterior cruciate ligament (ACL) in active, symptomatic individuals. In contrast, treatment of partial tears of the ACL remains controversial. Biologically augmented ACL-repair techniques are expanding in an attempt to regenerate and improve healing and outcomes of both the native ACL and the reconstructed graft tissue. Purpose: To review the biologic treatment options for partial tears of the ACL. Study Design: Review. Methods: A literature review was performed that included searches of PubMed, Medline, and Cochrane databases using the following keywords: partial tear of the ACL, ACL repair, bone marrow concentrate, growth factors/healing enhancement, platelet-rich plasma (PRP), stem cell therapy. Results: The use of novel biologic ACL repair techniques, including growth factors, PRP, stem cells, and bioscaffolds, have been reported to result in promising preclinical and short-term clinical outcomes. Conclusion: The potential benefits of these biological augmentation approaches for partial ACL tears are improved healing, better proprioception, and a faster return to sport and activities of daily living when compared with standard reconstruction procedures. However, long-term studies with larger cohorts of patients and with technique validation are necessary to assess the real effect of these approaches. PMID:28210653

Two familial cases with a lethal gracile bone dysplasia and intrauterine growth retardation.

PubMed

Korniszewski, Lech; Arbuckle, Susan; Kozlowski, Kazimierz

2003-05-01

A number of more or less distinct entities with low birth weight and abnormal radiographic appearances have been identified. We studied two sisters who were unusual because of severe intrauterine growth restriction, absence of growth after birth, decrease of pre- and postnatal spontaneous mobility, and early fatal outcome. The chondro-osseous morphology documented a distinctive osteochondrodysplasia. The radiographic examination was superficially similar to gracile bone dysplasias but was inconsistent with any known types of this group. These two patients appear to have a unique gracile bone dysplasia. Copyright 2003 Wiley-Liss, Inc.

Effect of radioactive iodine-induced hypothyroidism on longitudinal bone growth during puberty in immature female rats.

PubMed

Choi, Hyeonhae; Ryu, Ki-Young; Roh, Jaesook; Bae, Jaeman

2018-05-22

Thyroid cancer in children, the most common endocrine malignancy, shows aggressive behavior and has a high recurrence rate after surgical ablation. Radioactive iodine (RAI) treatment is the most effective primary modality for medical ablation of juvenile thyroid cancer, and leads to intentional hypothyroidism. Although several negative impacts of hypothyroidism have been reported in children in response to other antithyroid agents, the combined effects of RAI exposure and hypothyroidism, on growing bones specifically, are unknown. In this study, we investigated the effect of RAI-induced hypothyroidism on the long bones during the pubertal growth spurt using immature female rats. Female Sprague-Dawley rats were randomly divided into a control group, and an RAI-treated group fed with RAI (0.37 MBq/g body weight) twice via gavage. After 4 weeks, we observed a significantly-reduced serum free thyroxine level in the RAI group. The latter group also displayed decreased body weight gain compared to the control. In addition, the lengths of long bones, such as the leg bones and vertebral column, as well as bone mineral content, were reduced in the RAI-treated animals. Our results confirm the negative impacts of RAI-induced thyroid deficiency during puberty on longitudinal bone growth and bone mineralization.

Early bone growth on the surface of titanium implants in rat femur is enhanced by an amorphous diamond coating.

PubMed

Jaatinen, Jarkko J P; Korhonen, Rami K; Pelttari, Alpo; Helminen, Heikki J; Korhonen, Hannu; Lappalainen, Reijo; Kröger, Heikki

2011-08-01

Amorphous diamond (AD) is a durable and compatible biomaterial for joint prostheses. Knowledge regarding bone growth on AD-coated implants and their early-stage osseointegration is poor. We investigated bone growth on AD-coated cementless intramedullary implants implanted in rats. Titanium was chosen as a reference due to its well-known performance. We placed AD-coated and non-coated titanium implants (R(a) ≈ 0.2 μm) into the femoral bone marrow of 25 rats. The animals were divided in 2 groups according to implant coating and they were killed after 4 or 12 weeks. The osseointegration of the implants was examined from hard tissue specimens by measuring the new bone formation on their surface. 4 weeks after the operation, the thickness of new bone in the AD-coated group was greater than that in the non-coated group (15.3 (SD 7.1) μm vs. 7.6 (SD 6.0) μm). 12 weeks after the operation, the thickness of new bone was similar in the non-coated group and in the AD-coated group. We conclude that AD coating of femoral implants can enhance bone ongrowth in rats in the acute, early stage after the operation and might be an improvement over earlier coatings.

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

Sex differences and growth-related adaptations in bone microarchitecture, geometry, density and strength from childhood to early adulthood: a mixed longitudinal HR-pQCT study

PubMed Central

Gabel, Leigh; Macdonald, Heather M.; McKay, Heather A.

2016-01-01

Sex differences in bone strength and fracture risk are well-documented. However, we know little about bone strength accrual during growth and adaptations in bone microstructure, density and geometry that accompany gains in bone strength. Thus, our objectives are to 1) describe growth related adaptations in bone microarchitecture, geometry, density and strength at the distal tibia and radius in boys and girls; 2) compare differences in adaptations in bone microarchitecture, geometry, density and strength between boys and girls. We used HR-pQCT at the distal tibia (8% site) and radius (7% site) in 184 boys and 209 girls (9–20y at baseline). We aligned boys and girls on a common maturational landmark (age at peak height velocity; APHV) and fit a mixed effects model to these longitudinal data. Importantly, boys demonstrated 28–63% greater estimated bone strength across 12 years of longitudinal growth. Boys demonstrated 28–80% more porous cortices compared with girls at both sites across all biological ages, except at the radius at 9 years post-APHV. However, cortical density was similar between boys and girls at all ages at both sites, except at 9 years post-APHV at the tibia when girls’ values were 2% greater than boys’. Boys demonstrated 13–48% greater cortical and total bone area across growth. Load-to-strength ratio was 26–27% lower in boys at all ages, indicating lower risk of distal forearm fracture compared with girls. Contrary to previous HR-pQCT studies that did not align boys and girls at the same biological age, we did not observe sex differences in Ct.BMD. Boys’ superior bone size and strength compared with girls may confer them a protective advantage. However, boys’ consistently more porous cortices may contribute to boys’ higher fracture incidence during adolescence. Large prospective studies using HR-pQCT that target boys and girls who have sustained a fracture are needed to verify this. PMID:27556581

Growth rate differences between resident native brook trout and non-native brown trout

USGS Publications Warehouse

Carlson, S.M.; Hendry, A.P.; Letcher, B.H.

2007-01-01

Between species and across season variation in growth was examined by tagging and recapturing individual brook trout Salvelinus fontinalis and brown trout Salmo trutta across seasons in a small stream (West Brook, Massachusetts, U.S.A.). Detailed information on body size and growth are presented to (1) test whether the two species differed in growth within seasons and (2) characterize the seasonal growth patterns for two age classes of each species. Growth differed between species in nearly half of the season- and age-specific comparisons. When growth differed, non-native brown trout grew faster than native brook trout in all but one comparison. Moreover, species differences were most pronounced when overall growth was high during the spring and early summer. These growth differences resulted in size asymmetries that were sustained over the duration of the study. A literature survey also indicated that non-native salmonids typically grow faster than native salmonids when the two occur in sympatry. Taken together, these results suggest that differences in growth are not uncommon for coexisting native and non-native salmonids. ?? 2007 The Authors.

ADA-deficient SCID is associated with a specific microenvironment and bone phenotype characterized by RANKL/OPG imbalance and osteoblast insufficiency.

PubMed

Sauer, Aisha V; Mrak, Emanuela; Hernandez, Raisa Jofra; Zacchi, Elena; Cavani, Francesco; Casiraghi, Miriam; Grunebaum, Eyal; Roifman, Chaim M; Cervi, Maria C; Ambrosi, Alessandro; Carlucci, Filippo; Roncarolo, Maria Grazia; Villa, Anna; Rubinacci, Alessandro; Aiuti, Alessandro

2009-10-08

Adenosine deaminase (ADA) deficiency is a disorder of the purine metabolism leading to combined immunodeficiency and systemic alterations, including skeletal abnormalities. We report that ADA deficiency in mice causes a specific bone phenotype characterized by alterations of structural properties and impaired mechanical competence. These alterations are the combined result of an imbalanced receptor activator of nuclear factor-kappaB ligand (RANKL)/osteoprotegerin axis, causing decreased osteoclastogenesis and an intrinsic defect of osteoblast function with subsequent low bone formation. In vitro, osteoblasts lacking ADA displayed an altered transcriptional profile and growth reduction. Furthermore, the bone marrow microenvironment of ADA-deficient mice showed a reduced capacity to support in vitro and in vivo hematopoiesis. Treatment of ADA-deficient neonatal mice with enzyme replacement therapy, bone marrow transplantation, or gene therapy resulted in full recovery of the altered bone parameters. Remarkably, untreated ADA-severe combined immunodeficiency patients showed a similar imbalance in RANKL/osteoprotegerin levels alongside severe growth retardation. Gene therapy with ADA-transduced hematopoietic stem cells increased serum RANKL levels and children's growth. Our results indicate that the ADA metabolism represents a crucial modulatory factor of bone cell activities and remodeling.

Post-Traumatic Caspase-3 Expression in the Adjacent Areas of Growth Plate Injury Site: A Morphological Study

PubMed Central

Musumeci, Giuseppe; Castrogiovanni, Paola; Loreto, Carla; Castorina, Sergio; Pichler, Karin; Weinberg, Annelie Martina

2013-01-01

The epiphyseal plate is a hyaline cartilage plate that sits between the diaphysis and the epiphysis. The objective of this study was to determine the impact of an injury in the growth plate chondrocytes through the study of histological morphology, immunohistochemistry, histomorphometry and Western Blot analyses of the caspase-3 and cleaved PARP-1, and levels of the inflammatory cytokines, Interleukin-6 (IL-6) and Tumor Necrosis Factor alpha (TNF-α), in order to acquire more information about post-injury reactions of physeal cell turnover. In our results, morphological analysis showed that in experimental bones, neo-formed bone trabeculae—resulting from bone formation repair—invaded the growth plate and reached the metaphyseal bone tissue (bone bridge), and this could result in some growth arrest. We demonstrated, by ELISA, increased expression levels of the inflammatory cytokines IL-6 and TNF-α. Immunohistochemistry, histomorphometry and Western Blot analyses of the caspase-3 and cleaved PARP-1 showed that the physeal apoptosis rate of the experimental bones was significantly higher than that of the control ones. In conclusion, we could assume that the inflammation process causes stress to chondrocytes that will die as a biological defense mechanism, and will also increase the survival of new chondrocytes for maintaining cell homeostasis. Nevertheless, the exact stimulus leading to the increased apoptosis rate, observed after injury, needs additional research to understand the possible contribution of chondrocyte apoptosis to growth disturbance. PMID:23899790

Dual targeting c-met and VEGFR2 in osteoblasts suppresses growth and osteolysis of prostate cancer bone metastasis.

PubMed

Lee, Changki; Whang, Young Mi; Campbell, Preston; Mulcrone, Patrick L; Elefteriou, Florent; Cho, Sun Wook; Park, Serk In

2018-02-01

Prostate cancer characteristically induces osteoblastic bone metastasis, for which no therapies are available. A dual kinase inhibitor of c-Met and VEGFR-2 (cabozantinib) was shown to reduce prostate cancer growth in bone, with evidence for suppressing osteoblastic activity. However, c-Met and VEGFR2 signaling in osteoblasts in the context of bone metastasis remain unclear. Here we show using cultured osteoblasts that hepatocyte growth factor (HGF) and VEGF-A increased receptor activator of NFκB ligand (RANKL) and M-CSF, two essential factors for osteoclastogenesis. Insulin-like growth factor-1 (IGF1) also increased RANKL and M-CSF via c-Met transactivation. The conditioned media from IGF1-, HGF-, or VEGFA-treated osteoblasts promoted osteoclastogenesis that was reversed by inhibiting c-Met and/or VEGFR2 in osteoblasts. In vivo experiments used cabozantinib-resistant prostate cancer cells (PC-3 and C4-2B) to test the effects of c-Met/VEGFR2 inhibition specifically in osteoblasts. Cabozantinib (60 mg/kg, 3 weeks) suppressed tumor growth in bone and reduced expression of RANKL and M-CSF and subsequent tumor-induced osteolysis. Collectively, inhibition of c-Met and VEGFR2 in osteoblasts reduced RANKL and M-CSF expression, and associated with reduction of tumor-induced osteolysis, suggesting that c-Met and VEGFR2 are promising therapeutic targets in bone metastasis. Copyright © 2017 Elsevier B.V. All rights reserved.

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.

Interstitial ultrasound ablation of vertebral and paraspinal tumours: Parametric and patient-specific simulations

PubMed Central

Scott, Serena J.; Salgaonkar, Vasant; Prakash, Punit; Burdette, E. Clif; Diederich, Chris J.

2015-01-01

Purpose Theoretical parametric and patient-specific models are applied to assess the feasibility of interstitial ultrasound ablation of tumours in and near the spine and to identify potential treatment delivery strategies. Methods 3D patient-specific finite element models (n=11) of interstitial ultrasound ablation of tumours associated with spine were generated. Gaseous nerve insulation and various applicator configurations, frequencies (3 and 7 MHz), placement trajectories, and tumour locations were simulated. Parametric studies with multilayered models investigated the impacts of tumour attenuation, tumour dimension, and the thickness of bone insulating critical structures. Temperature and thermal dose were calculated to define ablation (>240 equivalent minutes at 43°C (EM43°C)) and safety margins (<45°C & <6 EM43°C), and to determine performance and required delivery parameters. Results Osteolytic tumours (≤44 mm) encapsulated by bone could be successfully ablated with 7 MHz interstitial ultrasound (8.1-16.6 W/cm2, 120-5900 J, 0.4-15 min). Ablation of tumours (94.6-100% volumetric) 0-14.5 mm from the spinal canal was achieved within 3-15 min without damaging critical nerves. 3 MHz devices provided faster ablation (390 versus 930 s) of an 18 mm diameter osteoblastic (high bone content) volume than 7 MHz devices. Critical anatomy in proximity to the tumour could be protected by selection of appropriate applicator configurations, active sectors, and applied power schemas, and through gaseous insulation. Preferential ultrasound absorption at bone surfaces facilitated faster, more effective ablations in osteolytic tumours and provided isolation of ablative energies and temperatures. Conclusions Parametric and patient-specific studies demonstrated the feasibility and potential advantages of interstitial ultrasound ablation treatment of paraspinal and osteolytic vertebral tumours. PMID:25017322

Effect of single- and double-row rotator cuff repair at the tendon-to-bone interface: preliminary results using an in vivo sheep model.

PubMed

Baums, M H; Schminke, B; Posmyk, A; Miosge, N; Klinger, H-M; Lakemeier, S

2015-01-01

The clinical superiority of the double-row technique is still a subject of controversial debate in rotator cuff repair. We hypothesised that the expression of different collagen types will differ between double-row and single-row rotator cuff repair indicating a faster healing response by the double-row technique. Twenty-four mature female sheep were randomly assembled to two different groups in which a surgically created acute infraspinatus tendon tear was fixed using either a modified single- or double-row repair technique. Shoulder joints from female sheep cadavers of identical age, bone maturity, and weight served as untreated control cluster. Expression of type I, II, and III collagen was observed in the tendon-to-bone junction along with recovering changes in the fibrocartilage zone after immunohistological tissue staining at 1, 2, 3, 6, 12, and 26 weeks postoperatively. Expression of type III collagen remained positive until 6 weeks after surgery in the double-row group, whereas it was detectable for 12 weeks in the single-row group. In both groups, type I collagen expression increased after 12 weeks. Type II collagen expression was increased after 12 weeks in the double-row versus single-row group. Clusters of chondrocytes were only visible between week 6 and 12 in the double-row group. The study demonstrates differences regarding the expression of type I and type III collagen in the tendon-to-bone junction following double-row rotator cuff repair compared to single-row repair. The healing response in this acute repair model is faster in the double-row group during the investigated healing period.

Blockade of epidermal growth factor receptor signaling leads to inhibition of renal cell carcinoma growth in the bone of nude mice.

PubMed

Weber, Kristy L; Doucet, Michele; Price, Janet E; Baker, Cheryl; Kim, Sun Jin; Fidler, Isaiah J

2003-06-01

Renal cell carcinoma (RCC) frequently produces metastases to the musculoskeletal system that are a major source of morbidity in the form of pain, immobilization, fractures, neurological compromise, and a decreased ability to perform activities of daily living. Patients with metastatic RCC therefore have a dismal prognosis because there is no effective adjuvant treatment for this disease. Because the epidermal growth factor receptor (EGF-R) signaling cascade is important in the growth and metastasis of RCC, its blockade has been hypothesized to inhibit tumor growth and hence prevent resultant bone destruction. We determined whether blockade of EGF-R by the tyrosine kinase inhibitor PKI 166 inhibited the growth of RCC in bone. We use a novel cell line, RBM1-IT4, established from a human RCC bone metastasis. Protein and mRNA expression of the ligands and receptors was assessed by Western and Northern blots. The stimulation of RBM1-IT4 cells with epidermal growth factor or transforming growth factor alpha resulted in increased cellular proliferation and tyrosine kinase autophosphorylation. PKI 166 prevented these effects. First, RBM1-IT4 cells were implanted into the tibia of nude mice, where they established lytic, progressively growing lesions, after which the mice were treated with PKI 166 alone or in combination with paclitaxel (Taxol). Immunohistochemical analysis revealed that tumor cells and tumor-associated endothelial cells in control mice expressed activated EGF-R. Treatment of mice with PKI 166 alone or in combination with Taxol produced a significant decrease in the incidence and size of bone lesions as compared with the results in control or Taxol-treated mice (P < 0.001). Treatment with PKI 166 also decreased the expression of phosphorylated EGF-R by tumor cells and tumor-associated endothelial cells, and this was even more pronounced with PKI 166 plus Taxol treatment. The PKI 166 plus Taxol combination produced apoptosis of tumor cells and tumor-associated endothelial cells. Tumor cell proliferation, shown by proliferating cell nuclear antigen positivity, was decreased in all treatment groups. In addition, the integrity of the bone was maintained in mice treated with PKI 166 or PKI 166 plus Taxol, whereas massive bone destruction was seen in control and Taxol-treated mice. These results suggest that blockade of EGF-R signaling inhibits growth of RCC in the bone by its effect on tumor cells and tumor-associated endothelial cells.

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.

[Progress of Masquelet technique to repair bone defect].

PubMed

Yin, Qudong; Sun, Zhenzhong; Gu, Sanjun

2013-10-01

To summarize the progress of Masquelet technique to repair bone defect. The recent literature concerning the application of Masquelet technique to repair bone defect was extensively reviewed and summarized. Masquelet technique involves a two-step procedure. First, bone cement is used to fill the bone defect after a thorough debridement, and an induced membrane structure surrounding the spacer formed; then the bone cement is removed after 6-8 weeks, and rich cancellous bone is implanted into the induced membrane. Massive cortical bone defect is repaired by new bone forming and consolidation. Experiments show that the induced membrane has vascular system and is also rich in vascular endothelial growth factor, transforming growth factor beta1, bone morphogenetic protein 2, and bone progenitor cells, so it has osteoinductive property; satisfactory results have been achieved in clinical application of almost all parts of defects, various types of bone defect and massive defect up to 25 cm long. Compared with other repair methods, Masquelet technique has the advantages of reliable effect, easy to operate, few complications, low requirements for recipient site, and wide application. Masquelet technique is an effective method to repair bone defect and is suitable for various types of bone defect, especially for bone defects caused by infection and tumor resection.

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

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.

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.

Cryostored autologous skull bone for cranioplasty? A study on cranial bone flaps' viability and microbial contamination after deep-frozen storage at -80°C.

PubMed

Chan, David Yuen Chung; Mok, Yi Tan; Lam, Ping Kuen; Tong, Cindy See Wai; Ng, Stephanie Chi Ping; Sun, Tin Fung David; Poon, Wai Sang

2017-08-01

Craniectomy is a life-saving procedure. Subsequent cranioplasty with autologous skull bone has a bone resorption rate from 4% to 22.8% and an infection rate from 3.3% to 26%. There are concerns with their viability and the potential microbial contamination as they were explanted for a long period of time. Eighteen cranial bone flaps stored at Prince of Wales Hospital Skull Bone Bank during the period from June 2011 to March 2016 were identified. Ethics approval was obtained. Bone chips and deep bone swabs were collected for osteoblast culture and microbial culture. Skull Bone Bank was kept at -80°C under strict aseptic technique during the study period. The storage period ranged from 4months to 55months. For the osteoblast culture, all eighteen bone flaps had no viable osteoblast growth. For the bacterial culture, five had positive bacteria growth (27.8%). Three were Pasteurella multocida and two were Methicillin-resistant Staphylococcus aureus. The mean duration of storage of the infected bone flap was 32.9months (±15.1months) versus 19.9months (±17.9months) of those bone flaps with no bacterial growth (p=0.1716). The mean size of the infected versus non-infected bone flaps was 117.7cm 2 (±44.96cm 2 ) versus 76.8cm 2 (±50.24cm 2 ) respectively (p=0.1318). Although in this study statistical significance was not reached, it was postulated that infected bone flaps tended to be larger in size and had a longer duration of storage. In conclusion, cryostored skull bone flaps beyond four months showed no viable osteoblasts. Bacterial contamination rate of bone flaps was 27.8% in this study. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Life-History Traits of the Miocene Hipparion concudense (Spain) Inferred from Bone Histological Structure

PubMed Central

Martinez-Maza, Cayetana; Alberdi, Maria Teresa; Nieto-Diaz, Manuel; Prado, José Luis

2014-01-01

Histological analyses of fossil bones have provided clues on the growth patterns and life history traits of several extinct vertebrates that would be unavailable for classical morphological studies. We analyzed the bone histology of Hipparion to infer features of its life history traits and growth pattern. Microscope analysis of thin sections of a large sample of humeri, femora, tibiae and metapodials of Hipparion concudense from the upper Miocene site of Los Valles de Fuentidueña (Segovia, Spain) has shown that the number of growth marks is similar among the different limb bones, suggesting that equivalent skeletochronological inferences for this Hipparion population might be achieved by means of any of the elements studied. Considering their abundance, we conducted a skeletechronological study based on the large sample of third metapodials from Los Valles de Fuentidueña together with another large sample from the Upper Miocene locality of Concud (Teruel, Spain). The data obtained enabled us to distinguish four age groups in both samples and to determine that Hipparion concudense tended to reach skeletal maturity during its third year of life. Integration of bone microstructure and skeletochronological data allowed us to identify ontogenetic changes in bone structure and growth rate and to distinguish three histologic ontogenetic stages corresponding to immature, subadult and adult individuals. Data on secondary osteon density revealed an increase in bone remodeling throughout the ontogenetic stages and a lesser degree thereof in the Concud population, which indicates different biomechanical stresses in the two populations, likely due to environmental differences. Several individuals showed atypical growth patterns in the Concud sample, which may also reflect environmental differences between the two localities. Finally, classification of the specimens’ age within groups enabled us to characterize the age structure of both samples, which is typical of attritional assemblages. PMID:25098950

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.

Forest stand growth dynamics in Central Europe have accelerated since 1870

PubMed Central

Pretzsch, Hans; Biber, Peter; Schütze, Gerhard; Uhl, Enno; Rötzer, Thomas

2014-01-01

Forest ecosystems have been exposed to climate change for more than 100 years, whereas the consequences on forest growth remain elusive. Based on the oldest existing experimental forest plots in Central Europe, we show that, currently, the dominant tree species Norway spruce and European beech exhibit significantly faster tree growth (+32 to 77%), stand volume growth (+10 to 30%) and standing stock accumulation (+6 to 7%) than in 1960. Stands still follow similar general allometric rules, but proceed more rapidly through usual trajectories. As forest stands develop faster, tree numbers are currently 17–20% lower than in past same-aged stands. Self-thinning lines remain constant, while growth rates increase indicating the stock of resources have not changed, while growth velocity and turnover have altered. Statistical analyses of the experimental plots, and application of an ecophysiological model, suggest that mainly the rise in temperature and extended growing seasons contribute to increased growth acceleration, particularly on fertile sites. PMID:25216297

Organic Condensation and Particle Growth to CCN Sizes in the Summertime Marine Arctic Is Driven by Materials More Semivolatile Than at Continental Sites

NASA Astrophysics Data System (ADS)

Burkart, Julia; Hodshire, Anna L.; Mungall, Emma L.; Pierce, Jeffrey R.; Collins, Douglas B.; Ladino, Luis A.; Lee, Alex K. Y.; Irish, Victoria; Wentzell, Jeremy J. B.; Liggio, John; Papakyriakou, Tim; Murphy, Jennifer; Abbatt, Jonathan

2017-10-01

Ship-based aerosol measurements in the summertime Arctic indicate elevated concentrations of ultrafine particles with occasional growth to cloud condensation nuclei (CCN) sizes. Focusing on one episode with two continuously growing modes, growth occurs faster for a large, preexisting mode (dp ≈ 90 nm) than for a smaller nucleation mode (dp ≈ 20 nm). We use microphysical modeling to show that growth is largely via organic condensation. Unlike results for midlatitude forested regions, most of these condensing species behave as semivolatile organics, as lower volatility organics would lead to faster growth of the smaller mode. The magnitude of the CCN hygroscopicity parameter for the growing particles, 0.1, is also consistent with organic species constituting a large fraction of the particle composition. Mixing ratios of common aerosol growth precursors, such as isoprene and sulfur dioxide, are not elevated during the episode, indicating that an unidentified aerosol growth precursor is present in this high-latitude marine environment.

A computed microtomography method for understanding epiphyseal growth plate fusion

NASA Astrophysics Data System (ADS)

Staines, Katherine A.; Madi, Kamel; Javaheri, Behzad; Lee, Peter D.; Pitsillides, Andrew A.

2017-12-01

The epiphyseal growth plate is a developmental region responsible for linear bone growth, in which chondrocytes undertake a tightly regulated series of biological processes. Concomitant with the cessation of growth and sexual maturation, the human growth plate undergoes progressive narrowing, and ultimately disappears. Despite the crucial role of this growth plate fusion ‘bridging’ event, the precise mechanisms by which it is governed are complex and yet to be established. Progress is likely hindered by the current methods for growth plate visualisation; these are invasive and largely rely on histological procedures. Here we describe our non-invasive method utilising synchrotron x-ray computed microtomography for the examination of growth plate bridging, which ultimately leads to its closure coincident with termination of further longitudinal bone growth. We then apply this method to a dataset obtained from a benchtop microcomputed tomography scanner to highlight its potential for wide usage. Furthermore, we conduct finite element modelling at the micron-scale to reveal the effects of growth plate bridging on local tissue mechanics. Employment of these 3D analyses of growth plate bone bridging is likely to advance our understanding of the physiological mechanisms that control growth plate fusion.

Interstitial ultrasound ablation of tumors within or adjacent to bone: Contributions of preferential heating at the bone surface

NASA Astrophysics Data System (ADS)

Scott, Serena J.; Prakash, Punit; Salgaonkar, Vasant; Jones, Peter D.; Cam, Richard N.; Han, Misung; Rieke, Viola; Burdette, E. Clif; Diederich, Chris J.

2013-02-01

Preferential heating of bone due to high ultrasound attenuation may enhance thermal ablation performed with cathetercooled interstitial ultrasound applicators in or near bone. At the same time, thermally and acoustically insulating cortical bone may protect sensitive structures nearby. 3D acoustic and biothermal transient finite element models were developed to simulate temperature and thermal dose distributions during catheter-cooled interstitial ultrasound ablation near bone. Experiments in ex vivo tissues and tissue-mimicking phantoms were performed to validate the models and to quantify the temperature profiles and ablated volumes for various distances between the interstitial applicator and the bone surface. 3D patient-specific models selected to bracket the range of clinical usage were developed to investigate what types of tumors could be treated, applicator configurations, insertion paths, safety margins, and other parameters. Experiments show that preferential heating at the bone surface decreases treatment times compared to when bone is absent and that all tissue between an applicator and bone can be ablated when they are up to 2 cm apart. Simulations indicate that a 5-7 mm safety margin of normal bone is needed to protect (thermal dose < 6 CEM43°C and T < 45°C) sensitive structures behind ablated bone. In 3D patient-specific simulations, tumors 1.0-3.8 cm (L) and 1.3-3.0 cm (D) near or within bone were ablated (thermal dose > 240 CEM43°C) within 10 min without damaging the nearby spinal cord, lungs, esophagus, trachea, or major vasculature. Preferential absorption of ultrasound by bone may provide improved localization, faster treatment times, and larger treatment zones in tumors in and near bone compared to other heating modalities.

Role of Vascular Endothelial Growth Factor and Transforming Growth Factor-β2 in Rat Bone Tissue after Bone Fracture and Placement of Titanium Implants with Bioactive Bioresorbable Coatings.

PubMed

Kalinichenko, S G; Matveeva, N Yu; Kostiv, R E; Puz', A V

2017-03-01

The study established enhanced expression of vascular endothelial growth factor (VEGF) in the subpopulation of osteoblasts located in the regeneration region of femoral bone fracture near the titanium implants with bioactive calcium phosphate and hydroxyapatite coatings and suppressed activity of transforming growth factor-β2 (TGF-β2) in chondroblasts during the two weeks after surgery. In the delayed posttraumatic period, the distribution of TGF-β2 inversely related to its maximal activity. The data revealed the up-regulating effect of bioresorbable coatings on expression of VEGF and TGF-β2 and their implication in the control over various stages of reparative osteogenesis.

Immunohistochemical response in rats of beta-tricalcium phosphate (TCP) with or without BMP-2 in the production of collagen matrix critical defects.

PubMed

Luvizuto, Eloá Rodrigues; de Oliveira, Júlio César Silva; Gomes-Ferreira, Pedro Henrique Silva; Pereira, Cassiano Costa Silva; Faverani, Leonardo Perez; Antoniali, Cristina; Okamoto, Roberta

2017-04-01

This study aimed to assess the biological response of BMP-2 (bone morphogenetic protein-2) in supplementation with β-tricalcium phosphate (TCP) as a carrier in the bone healing of surgical defects in rats' calvaria. A critical-size defect (5mm in diameter) was filled with β-TCP alone or added with that plus 5mg of BMP-2 at 5, 15, and 30 postoperative days. Histomorphometric and immunohistochemical (osteocalcin, collagen type I, and metalloproteinase-9) analysis was performed to assess the features of bone healing. Histological behavior and collagen type I labeling showed increased formation of the collagen matrix, leading to a higher percentage of newly formed bone and biomaterial for tissue and more total mineralization of pure TCP when compared to the other groups. The supplementation with BMP-2 promoted faster TCP remodeling; however, there was no statistically significant difference for the bone formed in both groups (P>0.05). Collagen-matrix formation and new bone formation reached maximum levels when the defects were filled with pure TCP, even exceeding the levels from BMP-2 supplementation. Copyright © 2017 Elsevier GmbH. All rights reserved.

Animal Bone Supported SnO2 as Recyclable Photocatalyst for Degradation of Rhodamine B Dye.

PubMed

Wu, Yun; Wang, Hui; Cao, Mengdie; Zhang, Yichi; Cao, Feifei; Zheng, Xinsheng; Hu, Jinfei; Dong, Jiangshan; Xiao, Zhidong

2015-09-01

SnO2 nanoparticles supported on an animal bone which serves as inexpensive and environment-friendly natural products were developed by a facile hydrothermal approach. As a promising photocatalyst, the novel SnO2/porcine bone material exhibited high photocatalytic activity towards the degradation of rhodamine B (RhB) dye under UV-Vis irradiation. About 97.3% of RhB can be effectively decomposed by the catalysis with the SnO2/porcine bone in 90 min, while only 51.5% of RhB can be degraded by pure SnO2 nanoparticles. Moreover, the photocatalytic activity was incremental with the increase of cycle times in previous five cycles. It is mainly because the photocatalyst which has been used for several times possesses a stronger ability of light absorption and utilization compared to the fresh catalyst according to the results of the characterization and relative experiments. It is noteworthy that the animal bone support can improve the activity for the photocatalyst, which would provide further impetus to alternate synthesis strategies for photocatalysts and make the photocatalysis process faster, less expensive, and more environmentally friendly.

Selenite-Releasing Bone Mineral Nanoparticles Retard Bone Tumor Growth and Improve Healthy Tissue Functions In Vivo.

PubMed

Wang, Yanhua; Hao, Hang; Liu, Haoming; Wang, Yifan; Li, Yan; Yang, Gaojie; Ma, Jun; Mao, Chuanbin; Zhang, Shengmin

2015-08-26

Selenite-doped bone mineral nanoparticles can retard the growth of osteosarcoma in a nude mice model, through sustained release of selenite ions. The selenite ions released from the nanoparticles through a degradation-mediated fashion inhibit tumor metastasis. Blood routine analysis indicates that selenite ions can also improve the functions of liver, kidney, and heart. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Advancing osteochondral tissue engineering: bone morphogenetic protein, transforming growth factor, and fibroblast growth factor signaling drive ordered differentiation of periosteal cells resulting in stable cartilage and bone formation in vivo.

PubMed

Mendes, L F; Katagiri, H; Tam, W L; Chai, Y C; Geris, L; Roberts, S J; Luyten, F P

2018-02-21

Chondrogenic mesenchymal stem cells (MSCs) have not yet been used to address the clinical demands of large osteochondral joint surface defects. In this study, self-assembling tissue intermediates (TIs) derived from human periosteum-derived stem/progenitor cells (hPDCs) were generated and validated for stable cartilage formation in vivo using two different animal models. hPDCs were aggregated and cultured in the presence of a novel growth factor (GF) cocktail comprising of transforming growth factor (TGF)-β1, bone morphogenetic protein (BMP)2, growth differentiation factor (GDF)5, BMP6, and fibroblast growth factor (FGF)2. Quantitative polymerase chain reaction (PCR) and immunohistochemistry were used to study in vitro differentiation. Aggregates were then implanted ectopically in nude mice and orthotopically in critical-size osteochondral defects in nude rats and evaluated by microcomputed tomography (µCT) and immunohistochemistry. Gene expression analysis after 28 days of in vitro culture revealed the expression of early and late chondrogenic markers and a significant upregulation of NOGGIN as compared to human articular chondrocytes (hACs). Histological examination revealed a bilayered structure comprising of chondrocytes at different stages of maturity. Ectopically, TIs generated both bone and mineralized cartilage at 8 weeks after implantation. Osteochondral defects treated with TIs displayed glycosaminoglycan (GAG) production, type-II collagen, and lubricin expression. Immunostaining for human nuclei protein suggested that hPDCs contributed to both subchondral bone and articular cartilage repair. Our data indicate that in vitro derived osteochondral-like tissues can be generated from hPDCs, which are capable of producing bone and cartilage ectopically and behave orthotopically as osteochondral units.

Genetic evidence that thyroid hormone is indispensable for prepubertal insulin-like growth factor-I expression and bone acquisition in mice.

PubMed

Xing, Weirong; Govoni, Kristen E; Donahue, Leah Rae; Kesavan, Chandrasekhar; Wergedal, Jon; Long, Carlin; Bassett, J H Duncan; Gogakos, Apostolos; Wojcicka, Anna; Williams, Graham R; Mohan, Subburaman

2012-05-01

Understanding how bone growth is regulated by hormonal and mechanical factors during early growth periods is important for optimizing the attainment of peak bone mass to prevent or postpone the occurrence of fragility fractures later in life. Using genetic mouse models that are deficient in thyroid hormone (TH) (Tshr(-/-) and Duox2(-/-)), growth hormone (GH) (Ghrhr(lit/lit)), or both (Tshr(-/-); Ghrhr(lit/lit)), we demonstrate that there is an important period prior to puberty when the effects of GH are surprisingly small and TH plays a critical role in the regulation of skeletal growth. Daily administration of T3/T4 during days 5 to 14, the time when serum levels of T3 increase rapidly in mice, rescued the skeletal deficit in TH-deficient mice but not in mice lacking both TH and GH. However, treatment of double-mutant mice with both GH and T3/T4 rescued the bone density deficit. Increased body fat in the TH-deficient as well as TH/GH double-mutant mice was rescued by T3/T4 treatment during days 5 to 14. In vitro studies in osteoblasts revealed that T3 in the presence of TH receptor (TR) α1 bound to a TH response element in intron 1 of the IGF-I gene to stimulate transcription. In vivo studies using TRα and TRβ knockout mice revealed evidence for differential regulation of insulin-like growth factor (IGF)-I expression by the two receptors. Furthermore, blockade of IGF-I action partially inhibited the biological effects of TH, thus suggesting that both IGF-I-dependent and IGF-I-independent mechanisms contribute to TH effects on prepubertal bone acquisition. Copyright © 2012 American Society for Bone and Mineral Research.

Effects of Recombinant Human Lactoferrin on Osteoblast Growth and Bone Status in Piglets.

PubMed

Li, Qiuling; Zhao, Jie; Hu, Wenping; Wang, Jianwu; Yu, Tian; Dai, Yunping; Li, Ning

2018-04-03

Lactoferrin (LF), an ~80 kDa iron-binding glycoprotein, modulates many biological effects, including antimicrobial and immunomodulatory activities. Recently, it was shown that LF also regulates bone cell activity, suggesting its therapeutic effect on postmenopausal bone loss. However, a minimal amount is known regarding the effects of recombinant human LF (rhLF) supplementation on bone status in young healthy infants. We found osteoblast cell differentiation was significantly promoted in vitro. Furthermore, treatment of human osteoblast cells with rhLF rapidly induced phosphorylation of p44/p42 mitogen-activated protein kinase (p44/p42 MAPK, ERK1/2). In order to investigate the effects of rhLF on bone status in vivo, we used a piglet model, which is a useful model for human infants. Piglets were supplemented with rhLF milk for 30 days. Bone formation markers, Serum calcium concentration, bone mineral density (BMD), bone mineral content (BMC), tibia bone strength, and the overall metabolite profile analysis showed that rhLF was advantageous to the bone growth in piglets. These findings suggest that rhLF supplementation benefits neonate bone health by modulating bone formation.

Impact of prenatal hypoxia on fetal bone growth and osteoporosis in ovariectomized offspring rats.

PubMed

Yang, Yuxian; Fan, Xiaorong; Tao, Jianying; Xu, Ting; Zhang, Yingying; Zhang, Wenna; Li, Lingjun; Li, Xiang; Ding, Hongmei; Sun, Miao; Gao, Qinqin; Xu, Zhice

2018-03-07

Prenatal hypoxia causes intrauterine growth retardation. It is unclear whether/how hypoxia affects the bone in fetal and offspring life. This study showed that prenatal hypoxia retarded fetal skeletal growth in rats, inhibited extracellular matrix (ECM) synthesis and down-regulated of insulin-like growth factor 1 (IGF1) signaling in fetal growth plate chondrocytes in vivo and in vitro. In addition, ovariectomized (OVX) was used for study of postmenopausal osteoporosis. Compared with the control, OVX offspring in prenatal hypoxic group showed an enhanced osteoporosis in the femurs, associated with reduced proteoglycan and IGF1 signaling. The results indicated prenatal hypoxia not only delayed fetal skeletal growth, but also increased OVX-induced osteoporosis in the elder offspring probably through down-regulated IGF1 signaling and inhibition of ECM synthesis, providing important information of prenatal hypoxia on functional and molecular bone growth and metabolism in fetal and offspring. Copyright © 2018 Elsevier Inc. All rights reserved.

Carbon nanotubes functionalized with fibroblast growth factor accelerate proliferation of bone marrow-derived stromal cells and bone formation

NASA Astrophysics Data System (ADS)

Hirata, Eri; Ménard-Moyon, Cécilia; Venturelli, Enrica; Takita, Hiroko; Watari, Fumio; Bianco, Alberto; Yokoyama, Atsuro

2013-11-01

Multi-walled carbon nanotubes (MWCNTs) were functionalized with fibroblast growth factor (FGF) and the advantages of their use as scaffolds for bone augmentation were evaluated in vitro and in vivo. The activity of FGF was assessed by measuring the effect on the proliferation of rat bone marrow stromal cells (RBMSCs). The presence of FGF enhanced the proliferation of RBMSCs and the FGF covalently conjugated to the nanotubes (FGF-CNT) showed the same effect as FGF alone. In addition, FGF-CNT coated sponges were implanted between the parietal bone and the periosteum of rats and the formation of new bone was investigated. At day 14 after implantation, a larger amount of newly formed bone was clearly observed in most pores of FGF-CNT coated sponges. These findings indicated that MWCNTs accelerated new bone formation in response to FGF, as well as the integration of particles into new bone during its formation. Scaffolds coated with FGF-CNT could be considered as promising novel substituting materials for bone regeneration in future tissue engineering applications.

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.

Synergistic Effects of Vascular Endothelial Growth Factor on Bone Morphogenetic Proteins Induced Bone Formation In Vivo: Influencing Factors and Future Research Directions

PubMed Central

Li, Bo; Wang, Hai; Qiu, Guixing; Su, Xinlin

2016-01-01

Vascular endothelial growth factor (VEGF) and bone morphogenetic proteins (BMPs), as key mediators in angiogenesis and osteogenesis, are used in a combined delivery manner as a novel strategy in bone tissue engineering. VEGF has the potential to enhance BMPs induced bone formation. Both gene delivery and material-based delivery systems were incorporated in previous studies to investigate the synergistic effects of VEGF and BMPs. However, their results were controversial due to variation of methods incorporated in different studies. Factors influencing the synergistic effects of VEGF on BMPs induced bone formation were identified and analyzed in this review to reduce confusion on this issue. The potential mechanisms and directions of future studies were also proposed here. Further investigating mechanisms of the synergistic effects and optimizing these influencing factors will help to generate more effective bone regeneration. PMID:28070506

Decreased heterotopic osteogenesis in vitamin-D-deficient, but normocalcemic guinea pigs

NASA Technical Reports Server (NTRS)

Dziedzic-Goclawska, A.; Toverud, S. U.; Kaminski, A.; Boass, A.; Yamauchi, M.

1992-01-01

The effect of vitamin D deficiency unhampered by hypocalcemia on de novo bone formation was studied in guinea pigs. Heterotopic induction of osteogenesis was evaluated 4 weeks after intramuscular transplantation of allogenic urinary bladder transitional epithelium from vitamin-D-repleted (+D) donors into +D and -D recipients. In -D recipients the frequency of osteogenesis and the amount of induced bone were significantly diminished; induced bone was less mature, scantly cellular woven bone poorly repopulated with bone marrow. No effect of vitamin D deficiency on orthotopic bone growth and on mineralization of orthotopic and heterotopically induced bone was observed. It is proposed that in addition to inducing factors (BMPs, growth factors) which may be responsible for transformation of mesenchymal cells to osteoprogenitor cells, normal concentrations of 1,25-(OH)2D3 may be required for proliferation and further differentiation of these cells into osteoblasts and for expression of genes engaged in extracellular matrix formation and maturation.

Interaction of the endocrine system with inflammation: a function of energy and volume regulation

PubMed Central

2014-01-01

During acute systemic infectious disease, precisely regulated release of energy-rich substrates (glucose, free fatty acids, and amino acids) and auxiliary elements such as calcium/phosphorus from storage sites (fat tissue, muscle, liver, and bone) are highly important because these factors are needed by an energy-consuming immune system in a situation with little or no food/water intake (sickness behavior). This positively selected program for short-lived infectious diseases is similarly applied during chronic inflammatory diseases. This review presents the interaction of hormones and inflammation by focusing on energy storage/expenditure and volume regulation. Energy storage hormones are represented by insulin (glucose/lipid storage and growth-related processes), insulin-like growth factor-1 (IGF-1) (muscle and bone growth), androgens (muscle and bone growth), vitamin D (bone growth), and osteocalcin (bone growth, support of insulin, and testosterone). Energy expenditure hormones are represented by cortisol (breakdown of liver glycogen/adipose tissue triglycerides/muscle protein, and gluconeogenesis; water retention), noradrenaline/adrenaline (breakdown of liver glycogen/adipose tissue triglycerides, and gluconeogenesis; water retention), growth hormone (glucogenic, lipolytic; has also growth-related aspects; water retention), thyroid gland hormones (increase metabolic effects of adrenaline/noradrenaline), and angiotensin II (induce insulin resistance and retain water). In chronic inflammatory diseases, a preponderance of energy expenditure pathways is switched on, leading to typical hormonal changes such as insulin/IGF-1 resistance, hypoandrogenemia, hypovitaminosis D, mild hypercortisolemia, and increased activity of the sympathetic nervous system and the renin-angiotensin-aldosterone system. Though necessary during acute inflammation in the context of systemic infection or trauma, these long-standing changes contribute to increased mortality in chronic inflammatory diseases. PMID:24524669

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

Interaction of the endocrine system with inflammation: a function of energy and volume regulation.

PubMed

Straub, Rainer H

2014-02-13

During acute systemic infectious disease, precisely regulated release of energy-rich substrates (glucose, free fatty acids, and amino acids) and auxiliary elements such as calcium/phosphorus from storage sites (fat tissue, muscle, liver, and bone) are highly important because these factors are needed by an energy-consuming immune system in a situation with little or no food/water intake (sickness behavior). This positively selected program for short-lived infectious diseases is similarly applied during chronic inflammatory diseases. This review presents the interaction of hormones and inflammation by focusing on energy storage/expenditure and volume regulation. Energy storage hormones are represented by insulin (glucose/lipid storage and growth-related processes), insulin-like growth factor-1 (IGF-1) (muscle and bone growth), androgens (muscle and bone growth), vitamin D (bone growth), and osteocalcin (bone growth, support of insulin, and testosterone). Energy expenditure hormones are represented by cortisol (breakdown of liver glycogen/adipose tissue triglycerides/muscle protein, and gluconeogenesis; water retention), noradrenaline/adrenaline (breakdown of liver glycogen/adipose tissue triglycerides, and gluconeogenesis; water retention), growth hormone (glucogenic, lipolytic; has also growth-related aspects; water retention), thyroid gland hormones (increase metabolic effects of adrenaline/noradrenaline), and angiotensin II (induce insulin resistance and retain water). In chronic inflammatory diseases, a preponderance of energy expenditure pathways is switched on, leading to typical hormonal changes such as insulin/IGF-1 resistance, hypoandrogenemia, hypovitaminosis D, mild hypercortisolemia, and increased activity of the sympathetic nervous system and the renin-angiotensin-aldosterone system. Though necessary during acute inflammation in the context of systemic infection or trauma, these long-standing changes contribute to increased mortality in chronic inflammatory diseases.

Growth factors--BMPs, DBMs, and buffy coat products: are there any proven differences amongst them?

PubMed

Veillette, Christian J H; McKee, Michael D

2007-03-01

Advances in the understanding of bone repair and improved biotechnology have led to the introduction of new strategies for orthopedic surgeons to control and modulate bone healing using growth factors. However, many orthopedic surgeons are uncertain about the current levels of evidence supporting the use of materials that possess these properties and their therapeutic role in the management of skeletal problems such as fracture, long-bone nonunion, and spine fusion. In particular, the differences amongst osteoinductive factors synthesized by recombinant gene technology, or derived from demineralized bone matrix or platelet rich plasma requires clarification.

Isometric Scaling in Developing Long Bones Is Achieved by an Optimal Epiphyseal Growth Balance

PubMed Central

Stern, Tomer; Aviram, Rona; Rot, Chagai; Galili, Tal; Sharir, Amnon; Kalish Achrai, Noga; Keller, Yosi; Shahar, Ron; Zelzer, Elazar

2015-01-01

One of the major challenges that developing organs face is scaling, that is, the adjustment of physical proportions during the massive increase in size. Although organ scaling is fundamental for development and function, little is known about the mechanisms that regulate it. Bone superstructures are projections that typically serve for tendon and ligament insertion or articulation and, therefore, their position along the bone is crucial for musculoskeletal functionality. As bones are rigid structures that elongate only from their ends, it is unclear how superstructure positions are regulated during growth to end up in the right locations. Here, we document the process of longitudinal scaling in developing mouse long bones and uncover the mechanism that regulates it. To that end, we performed a computational analysis of hundreds of three-dimensional micro-CT images, using a newly developed method for recovering the morphogenetic sequence of developing bones. Strikingly, analysis revealed that the relative position of all superstructures along the bone is highly preserved during more than a 5-fold increase in length, indicating isometric scaling. It has been suggested that during development, bone superstructures are continuously reconstructed and relocated along the shaft, a process known as drift. Surprisingly, our results showed that most superstructures did not drift at all. Instead, we identified a novel mechanism for bone scaling, whereby each bone exhibits a specific and unique balance between proximal and distal growth rates, which accurately maintains the relative position of its superstructures. Moreover, we show mathematically that this mechanism minimizes the cumulative drift of all superstructures, thereby optimizing the scaling process. Our study reveals a general mechanism for the scaling of developing bones. More broadly, these findings suggest an evolutionary mechanism that facilitates variability in bone morphology by controlling the activity of individual epiphyseal plates. PMID:26241802

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

Skeletal Response of Male Mice to Anabolic Hormone Therapy in the Absence of the Igfals Gene

PubMed Central

Kennedy, Oran D.; Sun, Hui; Wu, YingJie; Courtland, Hayden-William; Williams, Garry A.; Cardoso, Luis; Basta-Pljakic, Jelena; Schaffler, Mitchell B.

2014-01-01

IGF-I is a critical regulator of skeletal acquisition, which acts in endocrine and autocrine/paracrine modes. In serum, IGF-I is carried by the IGF-binding proteins in binary complexes. Further stabilization of these complexes is achieved by binding to the acid labile subunit (ALS) in a ternary complex (of IGF-I-IGF-binding protein 3/5-ALS). Ablation of the Igfals gene in humans (ALS deficiency) and mice (ALS knockout [ALSKO]) leads to markedly decreased serum IGF-I levels, growth retardation, and impaired skeletal acquisition. To investigate whether hormonal replacement therapy would improve the skeletal phenotype in cases of Igfals gene ablation, we treated male ALSKO mice with GH, IGF-I, or a combination of both. Treatments were administered to animals between 4 and 16 weeks of age or from 8 to 16 weeks of age. Although all treatment groups showed an increase (20%) in serum IGF-I levels, there was no increase in body weight, weight gain, or bone length in either age group. Despite the blunted linear growth in response to hormone therapy, ALSKO mice treated with GH showed radial bone growth, which contributed to bone strength tested by 4-point bending. We found that ALSKO mice treated with GH showed increased total cross-sectional area, cortical bone area, and cortical thickness by microtomography. Dynamic histomorphometry showed that although GH and double treatment groups resulted in trends towards increased bone formation parameters, these did not reach significance. However, bone resorption parameters were significantly increased in all treatment groups. ALSKO mice treated between 4 and 16 weeks of age showed minor differences in bone traits compared with vehicle-treated mice. In conclusion, treatment with GH and IGF-I do not work synergistically to rescue the stunted growth found in mice lacking the Igfals gene. Although GH alone appears to increase bone parameters slightly, it does not affect body weight or linear growth. PMID:24424061

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.

Skeletal response of male mice to anabolic hormone therapy in the absence of the Igfals gene.

PubMed

Kennedy, Oran D; Sun, Hui; Wu, Yingjie; Courtland, Hayden-William; Williams, Garry A; Cardoso, Luis; Basta-Pljakic, Jelena; Schaffler, Mitchell B; Yakar, Shoshana

2014-03-01

IGF-I is a critical regulator of skeletal acquisition, which acts in endocrine and autocrine/paracrine modes. In serum, IGF-I is carried by the IGF-binding proteins in binary complexes. Further stabilization of these complexes is achieved by binding to the acid labile subunit (ALS) in a ternary complex (of IGF-I-IGF-binding protein 3/5-ALS). Ablation of the Igfals gene in humans (ALS deficiency) and mice (ALS knockout [ALSKO]) leads to markedly decreased serum IGF-I levels, growth retardation, and impaired skeletal acquisition. To investigate whether hormonal replacement therapy would improve the skeletal phenotype in cases of Igfals gene ablation, we treated male ALSKO mice with GH, IGF-I, or a combination of both. Treatments were administered to animals between 4 and 16 weeks of age or from 8 to 16 weeks of age. Although all treatment groups showed an increase (20%) in serum IGF-I levels, there was no increase in body weight, weight gain, or bone length in either age group. Despite the blunted linear growth in response to hormone therapy, ALSKO mice treated with GH showed radial bone growth, which contributed to bone strength tested by 4-point bending. We found that ALSKO mice treated with GH showed increased total cross-sectional area, cortical bone area, and cortical thickness by microtomography. Dynamic histomorphometry showed that although GH and double treatment groups resulted in trends towards increased bone formation parameters, these did not reach significance. However, bone resorption parameters were significantly increased in all treatment groups. ALSKO mice treated between 4 and 16 weeks of age showed minor differences in bone traits compared with vehicle-treated mice. In conclusion, treatment with GH and IGF-I do not work synergistically to rescue the stunted growth found in mice lacking the Igfals gene. Although GH alone appears to increase bone parameters slightly, it does not affect body weight or linear growth.

Biological Evaluation of Implant Drill Made from Zirconium Dioxide.

PubMed

Akiba, Yosuke; Eguchi, Kaori; Akiba, Nami; Uoshima, Katsumi

2017-04-01

Zirconia is a good candidate material in the dental field. In this study, we evaluated biological responses against a zirconia drill using a bone cavity healing model. Zirconia drills, stainless steel drills, and the drilled bone surface were observed by scanning electron microscopy (SEM), before and after cavity preparation. For the bone cavity healing model, the upper first and second molars of Wistar rats were extracted. After 4 weeks, cavities were prepared with zirconia drills on the left side. As a control, a stainless steel drill was used on the right side. At 3, 7, and 14 days after surgery, micro-CT images were taken. Samples were prepared for histological staining. SEM images revealed that zirconia drills maintained sharpness even after 30 drilling procedures. The bone surface was smoother with the zirconia drill. Micro-CT images showed faster and earlier bone healing in the zirconia drill cavity. On H-E staining, at 7 days, the zirconia drill defect had a smaller blank lacunae area. At 14 days, the zirconia drill defect was filled with newly formed bone. The zirconia drill induces less damage during cavity preparation and is advantageous for bone healing. (197 words). © 2016 The Authors Clinical Implant Dentistry and Related Research Published by Wiley Periodicals, Inc.

Transforming growth factor (TGF. beta. ) decreases the proliferation of human bone marrow fibroblasts by inhibiting the platelet-derived growth factor (PDGF) binding

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

Bryckaert, M.C.; Tobelem, G.; Lindroth, M.

1988-12-01

Human bone marrow fibroblasts were cultivated and characterized by immunofluorescent staining and electron microscopy. Their interactions with PDGF and TGF{beta} were studied. While a positive intracellular antifibronectin staining was observed, the cultured cells were not labeled with specific antibodies toward factor VIII von Willebrand factor (F VIII/vWF), desmin, and macrophage antigen. The binding of pure human PDGF to the cultured bone marrow fibroblasts was investigated. Addition of an excess of unlabeled PDGF decreased the binding to 75 and 80%, which means that the nonspecific binding represented 20-25% of total binding, whereas epidermal growth factor (EGF) had no effect. Two classesmore » of sites were detected by Scatchard analysis. The stimulation of DNA synthesis of PDGF was quantified by ({sup 3}H)thymidine incorporation. The results suggested that PDGF and TGF{beta} could modulate the growth of bone marrow fibroblasts.« less

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

Free bone graft reconstruction of irradiated facial tissue: Experimental effects of basic fibroblast growth factor stimulation

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

Eppley, B.L.; Connolly, D.T.; Winkelmann, T.

1991-07-01

A study was undertaken to evaluate the potential utility of basic fibroblast growth factor in the induction of angiogenesis and osseous healing in bone previously exposed to high doses of irradiation. Thirty New Zealand rabbits were evaluated by introducing basic fibroblast growth factor into irradiated mandibular resection sites either prior to or simultaneous with reconstruction by corticocancellous autografts harvested from the ilium. The fate of the free bone grafts was then evaluated at 90 days postoperatively by microangiographic, histologic, and fluorochrome bone-labeling techniques. Sequestration, necrosis, and failure to heal to recipient osseous margins was observed both clinically and histologically inmore » all nontreated irradiated graft sites as well as those receiving simultaneous angiogenic stimulation at the time of graft placement. No fluorescent activity was seen in these graft groups. In the recipient sites pretreated with basic fibroblast growth factor prior to placement of the graft, healing and reestablishment of mandibular contour occurred in nearly 50 percent of the animals. Active bone formation was evident at cortical margins adjacent to the recipient sites but was absent in the more central cancellous regions of the grafts.« less

[Long-term effects of 7-year growth hormone substitution on bone metabolism, bone density, and bone quality in growth hormone-deficient adults].

PubMed

Wilhelm, Birgit; Kann, Peter Herbert

2004-10-15

Subnormal bone mineral density (BMD) and increased fracture risk are described in patients with growth hormone deficiency (GHD). Growth hormone (GH) has been reported to have beneficial effects on bone in GHD. The aim of this study was to investigate the long-term effects of GH replacement therapy on bone metabolism, BMD, and bone quality in patients with GHD. 20 adult patients with GHD (eleven male, nine female, mean age 42.5 years) were included in the study and randomized to either GH or placebo in a dose of 0.25 U/kg body weight/week. After 6 months all patients received GH. After a 1-year double-blind, placebo-controlled study the patients were followed for another 72 months in an open study. The patients were compared to 20 age- und sex-matched healthy controls. Bone turnover was determined by ICTP (type I collagen carboxyterminal cross-linked telopeptide) as parameter of bone resorption and PICP (carboxyterminal propeptide of type I procollagen) as marker of bone formation. BMD was measured at the lumbar spine by dual-photon absorptiometry (DPA) and at the forearm by single-photon absorptiometry (SPA). Apparent phalangeal ultrasound transmission velocity (APU) was assessed as parameter of bone quality independent of BMD. At the beginning of the study BMD at both measuring sites was lower in patients with GHD than in healthy controls. During the 1st year of GH replacement therapy BMD decreased, followed by a continuous increase in BMD (about 12%) up to 60 months which remained unchanged thereafter, building up a plateau. After 72 months no significant difference between the patients and the healthy controls could be detected. Concerning parameters of bone turnover, first ICTP as marker of bone resorption showed a significant increase, later on the marker of bone formation increased as well. APU decreased during the first 6 months of treatment, but had returned to its baseline value after 24 months and remained unchanged throughout the rest of the study. BMD is subnormal in adults with GHD. GH replacement therapy stimulates bone turnover in patients with GHD and in the long term such stimulation results in an increased BMD. Thereby, GH shows a triphasic action on BMD: an initial decrease in BMD during the 1st year, followed by a continuous increase in BMD with buildup of a stable plateau after 60 months. The newly formed bone seems to have normal bone elasticity.

Seasonal bone growth and physiology in endotherms shed light on dinosaur physiology.

PubMed

Köhler, Meike; Marín-Moratalla, Nekane; Jordana, Xavier; Aanes, Ronny

2012-07-19

Cyclical growth leaves marks in bone tissue that are in the forefront of discussions about physiologies of extinct vertebrates. Ectotherms show pronounced annual cycles of growth arrest that correlate with a decrease in body temperature and metabolic rate; endotherms are assumed to grow continuously until they attain maturity because of their constant high body temperature and sustained metabolic rate. This apparent dichotomy has driven the argument that zonal bone denotes ectotherm-like physiologies, thus fuelling the controversy on dinosaur thermophysiology and the evolution of endothermy in birds and mammal-like reptiles. Here we show, from a comprehensive global study of wild ruminants from tropical to polar environments, that cyclical growth is a universal trait of homoeothermic endotherms. Growth is arrested during the unfavourable season concurrently with decreases in body temperature, metabolic rate and bone-growth-mediating plasma insulin-like growth factor-1 levels, forming part of a plesiomorphic thermometabolic strategy for energy conservation. Conversely, bouts of intense tissue growth coincide with peak metabolic rates and correlated hormonal changes at the beginning of the favourable season, indicating an increased efficiency in acquiring and using seasonal resources. Our study supplies the strongest evidence so far that homeothermic endotherms arrest growth seasonally, which precludes the use of lines of arrested growth as an argument in support of ectothermy. However, high growth rates are a distinctive trait of mammals, suggesting the capacity for endogenous heat generation. The ruminant annual cycle provides an extant model on which to base inferences regarding the thermophysiology of dinosaurs and other extinct taxa.

Human growth hormone may be detrimental when used to accelerate recovery from acute tendon-bone interface injuries.

PubMed

Baumgarten, Keith M; Oliver, Harvey A; Foley, Jack; Chen, Ding-Geng; Autenried, Peter; Duan, Shanzhong; Heiser, Patrick

2013-05-01

There have been few scientific studies that have examined usage of human growth hormone to accelerate recovery from injury. The hypothesis of this study was that human growth hormone would accelerate tendon-to-bone healing compared with control animals treated with placebo in a rat model of acute rotator cuff injury repair. Seventy-two rats underwent repair of acute rotator cuff injuries and were randomized into the following postoperative dosing regimens: placebo, and human growth hormone at 0.1, 1, 2, 5, and 10 mg/kg/day, administered subcutaneously once per day for fourteen days (Protocol 1). An additional twenty-four rats were randomized to receive either (1) placebo or (2) human growth hormone at 5 mg/kg, administered subcutaneously twice per day for seven days preoperatively and twenty-eight days postoperatively (Protocol 2). All rats were killed twenty-eight days postoperatively. Mechanical testing was performed. Ultimate stress, ultimate force, stiffness, energy to failure, and ultimate distension were determined. For Protocol 1, analysis of variance testing showed no significant difference between the groups with regard to ultimate stress, ultimate force, stiffness, energy to failure, or ultimate distension. In Protocol 2, ultimate force to failure was significantly worse in the human growth hormone group compared with the placebo group (21.1 ± 5.85 versus 26.3 ± 5.47 N; p = 0.035). Failure was more likely to occur through the bone than the tendon-bone interface in the human growth hormone group compared with the placebo group (p = 0.001). No significant difference was found for ultimate stress, ultimate force, stiffness, energy to failure, or ultimate distension between the groups in Protocol 2. In this rat model of acute tendon-bone injury repair, daily subcutaneous postoperative human growth hormone treatment for fourteen days failed to demonstrate a significant difference in any biomechanical parameter compared with placebo. Furthermore, subcutaneous administration of 5 mg/kg of human growth hormone twice daily from seven days preoperatively until twenty-eight days postoperatively demonstrated lower loads to ultimate failure and a higher risk of bone fracture failure compared with placebo.

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.

Osterix/Sp7 limits cranial bone initiation sites and is required for formation of sutures

PubMed Central

Kague, Erika; Roy, Paula; Asselin, Garrett; Hu, Gui; Stanley, Alexandra; Albertson, Craig; Simonet, Jacqueline; Fisher, Shannon

2017-01-01

During growth, individual skull bones overlap at sutures, where osteoblast differentiation and bone deposition occur. Mutations causing skull malformations have revealed some required genes, but many aspects of suture regulation remain poorly understood. We describe a zebrafish mutation in osterix/sp7, which causes a generalized delay in osteoblast maturation. While most of the skeleton is patterned normally, mutants have specific defects in the anterior skull and upper jaw, and the top of the skull comprises a random mosaic of bones derived from individual initiation sites. Osteoblasts at the edges of the bones are highly proliferative and fail to differentiate, consistent with global changes in gene expression. We propose that signals from the bone itself are required for orderly recruitment of precursor cells and growth along the edges. The delay in bone maturation caused by loss of Sp7 leads to unregulated bone formation, revealing a new mechanism for patterning the skull and sutures. PMID:26992365

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.

[Local injection of exogenous nerve growth factor improves early bone maturation of implants].

PubMed

Yao, Yang; Du, Yu; Gu, Xia; Guang, Meng-Kai; Huang, Bo; Gong, Ping

2018-04-01

To investigate the effects of nerve growth factor (NGF) in the osteogenic action of implants and the maturation and reconstruction changes in bone tissues in the early stage of osseointegration. The mouse implant model was established by placing titanium in the femoral head of the mouse and locally injecting NGF in the implant zone. On 1, 2 and 4 weeks after operation, stain samples were collected from animals using hematoxylin-eosin (HE) staining and Masson staining. The effect of NGF on the bone maturation was compared at different time points of early stage osseointegration. The results of HE and Masson staining indicated that the local injection of external NGF can up-regulate bone mass, amount of bone trabecula, and bone maturity in the mouse model. The mature bone rate in treatment group of 1 week and 4 weeks after operation were significantly higher than those in the control group (P<0.05). NGF can shorten the period of bone maturation.

Computed tomography-based finite element analysis to assess fracture risk and osteoporosis treatment

PubMed Central

Imai, Kazuhiro

2015-01-01

Finite element analysis (FEA) is a computer technique of structural stress analysis and developed in engineering mechanics. FEA has developed to investigate structural behavior of human bones over the past 40 years. When the faster computers have acquired, better FEA, using 3-dimensional computed tomography (CT) has been developed. This CT-based finite element analysis (CT/FEA) has provided clinicians with useful data. In this review, the mechanism of CT/FEA, validation studies of CT/FEA to evaluate accuracy and reliability in human bones, and clinical application studies to assess fracture risk and effects of osteoporosis medication are overviewed. PMID:26309819

MicroCT Analysis of Micro-Nano Titanium Implant Surface on the Osseointegration.

PubMed

Ban, Jaesam; Kang, Seongsoo; Kim, Jihyun; Lee, Kwangmin; Hyunpil, Lim; Vang, Mongsook; Yang, Hongso; Oh, Gyejeong; Kim, Hyunseung; Hwang, Gabwoon; Jung, Yongho; Lee, Kyungku; Park, Sangwon; Yunl, Kwidug

2015-01-01

This study was to investigate the effects of micro-nano titanium implant surface on the osseointegration. A total of 36 screw-shaped implants were used. The implant surfaces were classified into 3 groups (n = 12): machined surface (M group), nanosurface which is nanotube formation on the machined surface (MA group) and nano-micro surface which is nanotube formation on the RBM surface (RA group). Anodic oxidation was performed at a 20 V for 10 min with 1 M H3PO4 and 1.5 wt% HF solutions. The implants were installed on the humerus on 6 beagles. After 4 and 12 weeks, the morphometric analysis with micro CT (skyscan 1172, SKYSCAN, Antwerpen, Belgium) was done. The data were statistically analyzed with two-way ANOVA. Bone mineral density and bone volume were significantly increased depending on time. RA group showed the highest bone mineral density and bone volume at 4 weeks and 12 weeks significantly. It indicated that nano-micro titanium implant surface showed faster and more mature osseointegration.

Rotary powered device for bone marrow aspiration and biopsy yields excellent specimens quickly and efficiently.

PubMed

Swords, Ronan T; Kelly, Kevin R; Cohen, Stephen C; Miller, Larry J; Philbeck, Thomas E; Hacker, Sander O; Spadaccini, Cathy J; Giles, Francis J; Brenner, Andrew J

2010-06-01

Recently, a new FDA-cleared battery powered bone marrow biopsy system was developed to allow operators access to the bone marrow space quickly and efficiently. A pre-clinical evaluation of the device (OnControl, Vidacare Corporation, San Antonio, TX, USA) on anesthetized pigs was conducted, in addition to a clinical evaluation in hematology clinic patients requiring a bone marrow biopsy. Twenty-six samples were collected from the swine model. No cellular artifact or thermal damage was reported in any of the samples obtained. For the clinical evaluation of the device, 16 patients were recruited. Mean time from needle contact with skin to needle removal was 38.5 +/- 13.94 seconds. No complications were reported. In this study, the manual and powered samples were equivalent in specimen quality. In the patients evaluated, the device was safe, easy to use and the mean procedural time was significantly faster than previously reported with a manual technique.

Tribological Properties of Ti-Based Alloys in a Simulated Bone-Implant Interface with Ringer's Solution at Fretting Contacts

PubMed Central

Ramos-Saenz, C.R.; Sundaram, P.A.; Diffoot-Carlo, N.

2010-01-01

The wear properties of oxidized and non-oxidized gamma-TiAl (a potential biomaterial) as well as Ti-6Al-4V and CP-Ti disks were studied and characterized by means of standard wear tests using a custom made bone pin arrangement. The Ti-base disks were oxidized in air at 500°C and 800°C for one hour. The tribological properties of the oxides formed over the disks were studied using a linear reciprocating wear testing machine under both dry and simulated biological conditions using Ringer's solution. Loss of metal oxide and coefficient of friction values were determined from the wear testing. From the results, abrasion and adhesion were the primary wear mechanisms in each of the three alloy-bone pairs. Specifically, the oxide formed on gamma-TiAl possessed the highest COF and wear resistance of the three materials which were studied. Also, as expected, bone wears down faster than the Ti-base metal oxide. PMID:20826360

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.

Bioceramic bone graft substitute for treatment of unicameral bone cysts.

PubMed

Fillingham, Y A; Cvetanovich, G L; Haughom, B D; Erickson, B J; Gitelis, S

2016-08-01

To review the outcome of 12 patients who underwent debridement and injection of bioceramic for unicameral bone cyst (UBC). The resorption rate of the bioceramic was estimated by both traditional and novel methods. Records of 10 males and 2 females aged 6 to 34 years who underwent debridement and injection of bioceramic for UBC and were followed up for a mean of 41 (range, 26-57) months were reviewed. Functional outcome was assessed using the selfcompleted Musculoskeletal Tumor Society (MSTS) questionnaire. Radiological outcome was assessed using both original and modified Neer Outcome Rating System. The resorption rate of the bioceramic was estimated using both traditional and novel (ImageJ) methods. The mean MSTS score was 29.7 (range, 28-30) indicating excellent functional outcome. Of the 12 patients, 9 achieved complete healing and 3 had a residual cyst of 1%, 11%, and 52%. The last was considered a local recurrence, and the patient underwent repeat percutaneous injection of the bioceramic 1.5 years later and remained disease-free 4 years later. The mean resorption rate was 29% faster when estimated using the traditional rather than the ImageJ method (0.47 vs. 0.33 cm3/day, p=0.02). In the patient with recurrence, the resorption rate was faster than the average (0.68 vs. 0.33 cm3/day). A single percutaneous injection of the bioceramic for UBC achieved good functional and radiological outcome while avoiding donor-site morbidity.

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

Estrogen prevents bone loss through transforming growth factor β signaling in T cells

PubMed Central

Gao, Yuhao; Qian, Wei-Ping; Dark, Kimberly; Toraldo, Gianluca; Lin, Angela S. P.; Guldberg, Robert E.; Flavell, Richard A.; Weitzmann, M. Neale; Pacifici, Roberto

2004-01-01

Estrogen (E) deficiency leads to an expansion of the pool of tumor necrosis factor (TNF)-producing T cells through an IFN-γ-dependent pathway that results in increased levels of the osteoclastogenic cytokine TNF in the bone marrow. Disregulated IFN-γ production is instrumental for the bone loss induced by ovariectomy (ovx), but the responsible mechanism is unknown. We now show that mice with T cell-specific blockade of type β transforming growth factor (TGFβ) signaling are completely insensitive to the bone-sparing effect of E. This phenotype results from a failure of E to repress IFN-γ production, which, in turn, leads to increased T cell activation and T cell TNF production. Furthermore, ovx blunts TGFβ levels in the bone marrow, and overexpression of TGFβ in vivo prevents ovx-induced bone loss. These findings demonstrate that E prevents bone loss through a TGFβ-dependent mechanism, and that TGFβ signaling in T cells preserves bone homeostasis by blunting T cell activation. Thus, stimulation of TGFβ production in the bone marrow is a critical “upstream” mechanism by which E prevents bone loss, and enhancement of TGFβ levels in vivo may constitute a previously undescribed therapeutic approach for preventing bone loss. PMID:15531637

How tough is Brittle Bone? Investigating Osteogenesis Imperfecta in Mouse Bone††

PubMed Central

Carriero, A.; Zimmermann, E. A.; Paluszny, A.; Tang, S. Y.; Bale, H.; Busse, B.; Alliston, T.; Kazakia, G.

2015-01-01

The multiscale hierarchical structure of bone is naturally optimized to resist fractures. In osteogenesis imperfecta, or brittle bone disease, genetic mutations affect the quality and/or quantity of collagen, dramatically increasing bone fracture risk. Here we reveal how the collagen defect results in bone fragility in a mouse model of osteogenesis imperfecta (oim), which has homotrimeric α1(I) collagen. At the molecular level we attribute the loss in toughness to a decrease in the stabilizing enzymatic crosslinks and an increase in non-enzymatic crosslinks, which may break prematurely inhibiting plasticity. At the tissue level, high vascular canal density reduces the stable crack growth, and extensive woven bone limits the crack-deflection toughening during crack growth. This demonstrates how modifications at the bone molecular level have ramifications at larger length scales affecting the overall mechanical integrity of the bone; thus, treatment strategies have to address multiscale properties in order to regain bone toughness. In this regard, findings from the heterozygous oim bone, where defective as well as normal collagen are present, suggest that increasing the quantity of healthy collagen in these bones helps to recover toughness at the multiple length scales. PMID:24420672

In vitro effects of 0 to 120 Grays of irradiation on bone viability and release of growth factors.

PubMed

Sawada, Kosaku; Fujioka-Kobayashi, Masako; Kobayashi, Eizaburo; Brömme, Jens O; Schaller, Benoit; Miron, Richard J

2016-07-04

High dose radiation therapy is commonly used in maxillofacial surgeries to treat a number of head and neck tumors. Despite its widespread use, little information is available regarding the effects of irradiation on bone cell viability and release of growth factors following dose-dependent irradiation. Bone samples were collected from porcine mandibular cortical bone and irradiated at doses of 0, 7.5, 15, 30, 60 and 120 Grays. Thereafter, cell viability was quantified, and the release of growth factors including TGFβ1, BMP2, VEGF, IL1β and RANKL were investigated over time. It was observed that at only 7.5Gy of irradiation, over 85 % of cells were non-vital and by 60 Gy, all cells underwent apoptosis. Furthermore, over a 7-fold decrease in VEGF and a 2-fold decrease in TGFβ1 were observed following irradiation at all tested doses. Little change was observed for BMP2 and IL1β whereas RANKL was significantly increased for all irradiated samples. These results demonstrate the pronounced effects of irradiation on bone-cell vitality and subsequent release of growth factors. Interestingly, the largest observed change in gene expression was the 7-fold decrease in VEGF protein following irradiation. Future research aimed at improving our understanding of bone following irradiation is necessary to further improve future clinical treatments.

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.

Genetics Home Reference: Buschke-Ollendorff syndrome

MedlinePlus

... example, a small percentage of affected individuals have melorheostosis , which is characterized by excess bone growth on ... bones in a pattern resembling dripping candle wax. Melorheostosis usually affects the bones in one arm or ...

Bone regeneration in experimental animals using calcium phosphate cement combined with platelet growth factors and human growth hormone.

PubMed

Emilov-Velev, K; Clemente-de-Arriba, C; Alobera-García, M Á; Moreno-Sansalvador, E M; Campo-Loarte, J

2015-01-01

Many substances (growth factors and hormones) have osteoinduction properties and when added to some osteoconduction biomaterial they accelerate bone neoformation properties. The materials included 15 New Zealand rabbits, calcium phosphate cement (Calcibon(®)), human growth hormone (GH), and plasma rich in platelets (PRP). Each animal was operated on in both proximal tibias and a critical size bone defect of 6mm of diameter was made. The animals were separated into the following study groups: Control (regeneration only by Calcibon®), PRP (regeneration by Calcibon® and PRP), GH (regeneration by Calcibon® and GH). All the animals were sacrificed at 28 days. An evaluation was made of the appearance of the proximal extreme of rabbit tibiae in all the animals, and to check the filling of the critical size defect. A histological assessment was made of the tissue response, the presence of new bone formation, and the appearance of the biomaterial. Morphometry was performed using the MIP 45 image analyser. ANOVA statistical analysis was performed using the Statgraphics software application. The macroscopic appearance of the critical defect was better in the PRP and the GH group than in the control group. Histologically greater new bone formation was found in the PRP and GH groups. No statistically significant differences were detected in the morphometric study between bone formation observed in the PRP group and the control group. Significant differences in increased bone formation were found in the GH group (p=0.03) compared to the other two groups. GH facilitates bone regeneration in critical defects filled with calcium phosphate cement in the time period studied in New Zealand rabbits. Copyright © 2014 SECOT. Published by Elsevier Espana. All rights reserved.

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

Actual and Simulated Weightlessness Inhibit Osteogenesis in Long Bone Metaphysis by Different Mechanisms

NASA Technical Reports Server (NTRS)

Roberts, W. E.

1985-01-01

Weightlessness and simulated weightlessness inhibit the rate of periosteal bone formation in long bones. Formation of preosteoblasts is suppressed in periodontal ligament (PDL) of maxillary molars, which suggests a generalized block in osteoblast histogenesis. Growth in length of long bones is decreased by simulated weightlessness, but there are no reliable data on the influence of actual weightlessness on metaphyseal growth. The nuclear size assay for assessing relative numbers of osteoblast precursor cells was utilized in the primary spongiosa of growing long bones subjected to actual and simulated weightlessness. It is found that: (1) Actual weightlessness decreases total number of osteogenic cells and inhibits differentiation of osteoblast precursor cells, (2) Simulated weightlessness suppresses only osteoblast differentation; and (3) The nuclear morphometric assay is an effective means of assessing osteogenic activity in the growing metaphysis or long bones.

A variant microcephalic osteodysplastic slender-bone disorder with growth hormone deficiency and a pigmentary retinopathy.

PubMed

Maclean, K; Ambler, G; Flaherty, M; Kozlowski, K; Adès, L C

2002-10-01

We present the case of a 3-year-old boy with post-natal growth failure, microcephaly, developmental delay, facial dysmorphism, an evolving pigmentary retinopathy, pituitary hypoplasia, micropenis, and growth hormone (GH) deficiency. He has a microcephalic osteodysplastic slender-bone disorder with disharmonic delayed osseous maturation, most closely resembling patients with microcephalic osteodysplastic primordial dwarfism type II (MOPD II). Intrauterine growth retardation, a universal finding in the MOPD II, was absent in our patient.

Bone regeneration with active angiogenesis by basic fibroblast growth factor gene transfected mesenchymal stem cells seeded on porous beta-TCP ceramic scaffolds.

PubMed

Guo, Xiaodong; Zheng, Qixin; Kulbatski, Iris; Yuan, Quan; Yang, Shuhua; Shao, Zengwu; Wang, Hong; Xiao, Baojun; Pan, Zhengqi; Tang, Shuo

2006-09-01

Large segmental bone defect repair remains a clinical and scientific challenge with increasing interest focused on combining gene transfer with tissue engineering techniques. Basic fibroblast growth factor (bFGF) is one of the most prominent osteogenic growth factors that has the potential to accelerate bone healing by promoting the proliferation and differentiation of mesenchymal stem cells (MSCs) and the regeneration of capillary vasculature. However, the short biological half-lives of growth factors may impose severe restraints on their clinical usefulness. Gene-based delivery systems provide a better way of achieving a sustained high concentration of growth factors locally in the defect and delivering a more biologically active product than that achieved by exogenous application of recombinant proteins. The objective of this experimental study was to investigate whether the bFGF gene modified MSCs could enhance the repair of large segmental bone defects. The pcDNA3-bFGF gene transfected MSCs were seeded on biodegradable porous beta tricalcium phosphate (beta-TCP) ceramics and allografted into the 15 mm critical-sized segmental bone defects in the radius of 18 New Zealand White rabbits. The pcDNA3 vector gene transfected MSCs were taken as the control. The follow-up times were 2, 4, 6, 8, 10 and 12 weeks. Scanning electron microscopic, roentgenographic, histologic and immunohistological studies were used to assess angiogenesis and bone regeneration. In vitro, the proliferation and differentiation of bFGF gene transfected MSCs were more active than that of the control groups. In vivo, significantly more new bone formation accompanied by abundant active capillary regeneration was observed in pores of the ceramics loaded with bFGF gene transfected MSCs, compared with control groups. Transfer of gene encoding bFGF to MSCs increases their osteogenic properties by enhancing capillary regeneration, thus providing a rich blood supply for new bone formation. This new bFGF gene enhanced tissue engineering strategy could be of potential benefit to accelerate bone healing, especially in defects caused by atrophic nonunion and avascular necrosis of the femoral head.

Differential growth factor control of bone formation through osteoprogenitor differentiation.

PubMed

Chaudhary, L R; Hofmeister, A M; Hruska, K A

2004-03-01

The osteogenic factors bone morphogenetic protein (BMP-7), platelet-derived growth factor (PDGF)-BB, and fibroblast growth factor (FGF-2) regulate the recruitment of osteoprogenitor cells and their proliferation and differentiation into mature osteoblasts. However, their mechanisms of action on osteoprogenitor cell growth, differentiation, and bone mineralization remain unclear. Here, we tested the hypothesis that these osteogenic agents were capable of regulating osteoblast differentiation and bone formation in vitro. Normal human bone marrow stromal (HBMS) cells were treated with BMP-7 (40 ng ml(-1)), PDGF-BB (20 ng ml(-1)), FGF-2 (20 ng ml(-1)), or FGF-2 plus BMP-7 for 28 days in a serum-containing medium with 10 mM beta-glycerophosphate and 50 microg ml(-1) ascorbic acid. BMP-7 stimulated a morphological change to cuboidal-shaped cells, increased alkaline phosphatase (ALKP) activity, bone sialoprotein (BSP) gene expression, and alizarin red S positive nodule formation. Hydroxyapatite (HA) crystal deposition in the nodules was demonstrated by Fourier transform infrared (FTIR) spectroscopy only in BMP-7- and dexamethasone (DEX)-treated cells. DEX-treated cells appeared elongated and fibroblast-like compared to BMP-7-treated cells. FGF-2 did not stimulate ALKP, and cell morphology was dystrophic. PDGF-BB had little or no effect on ALKP activity and biomineralization. Alizarin Red S staining of cells and calcium assay indicated that BMP-7, DEX, and FGF-2 enhanced calcium mineral deposition, but FTIR spectroscopic analysis demonstrated no formation of HA similar to human bone in control, PDGF-BB-, and FGF-2-treated samples. Thus, FGF-2 stimulated amorphous octacalcium phosphate mineral deposition that failed to mature into HA. Interestingly, FGF-2 abrogated BMP-7-induced ALKP activity and HA formation. Results demonstrate that BMP-7 was competent as a sole factor in the differentiation of human bone marrow stromal cells to bone-forming osteoblasts confirmed by FTIR examination of mineralized matrix. Other growth factors, PDGF, and FGF-2 were incompetent as sole factors, and FGF-2 inhibited BMP-7-stimulated osteoblast differentiation.

Second hand tobacco smoke adversely affects the bone of immature rats.

PubMed

Rosa, Rodrigo César; Pereira, Sângela Cunha; Cardoso, Fabrizio Antônio Gomide; Caetano, Abadio Gonçalves; Santiago, Hildemberg Agostinho Rocha de; Volpon, José Batista

2017-12-01

To evaluate the influence of secondhand cigarette smoke exposure on longitudinal growth of the tibia of growing rats and some parameters of bone quality. Forty female rats were randomly divided into four groups: control: rats were sham exposed; 30 days: rats were exposed to tobacco smoke for 30 days; 45 days: rats were exposed to tobacco smoke for 45 days; and 60 days: rats were exposed to tobacco smoke for 60 days. Blood samples were collected to evaluate the levels of cotinine and alkaline phosphatase. Both tibias were dissected and weighed; the lengths were measured, and the bones were then stored in a freezer for analysis of bone mineral content and mechanical resistance (maximal load and stiffness). Exposure of rats to tobacco smoke significantly compromised bone health, suggesting that the harmful effects may be time dependent. Harmful effects on bone growth were detected and were more pronounced at 60-day follow-ups with a 41.8% reduction in alkaline phosphatase levels (p<0.01) and a decrease of 11.25% in tibia length (p<0.001). Furthermore, a 41.5% decrease in bone mineral density was observed (p<0.001), leading to a 42.8% reduction in maximum strength (p<0.001) and a 56.7% reduction in stiffness (p<0.001). Second hand cigarette smoke exposure in rats affected bones that were weaker, deforming them and making them osteopenic. Additionally, the long bone was shorter, suggesting interference with growth. Such events seem to be related to time of exposure.

Pre-osteoblastic MC3T3-E1 promote breast cancer cell growth in bone in a murine xenograft model

USDA-ARS?s Scientific Manuscript database

The bones are the most common sites of breast cancer metastasis. Upon arrival within the bone microenvironment, breast cancer cells coordinate the activities of stromal cells, resulting in an increase in osteoclast activity and bone matrix degradation. In late stages of bone metastasis, breast cance...

Apoptosis-induced CXCL5 accelerates inflammation and growth of prostate tumor metastases in bone.

PubMed

Roca, Hernan; Jones, Jacqueline D; Purica, Marta C; Weidner, Savannah; Koh, Amy J; Kuo, Robert; Wilkinson, John E; Wang, Yugang; Daignault-Newton, Stephanie; Pienta, Kenneth J; Morgan, Todd M; Keller, Evan T; Nör, Jacques E; Shea, Lonnie D; McCauley, Laurie K

2018-01-02

During tumor progression, immune system phagocytes continually clear apoptotic cancer cells in a process known as efferocytosis. However, the impact of efferocytosis in metastatic tumor growth is unknown. In this study, we observed that macrophage-driven efferocytosis of prostate cancer cells in vitro induced the expression of proinflammatory cytokines such as CXCL5 by activating Stat3 and NF-κB(p65) signaling. Administration of a dimerizer ligand (AP20187) triggered apoptosis in 2 in vivo syngeneic models of bone tumor growth in which apoptosis-inducible prostate cancer cells were either coimplanted with vertebral bodies, or inoculated in the tibiae of immunocompetent mice. Induction of 2 pulses of apoptosis correlated with increased infiltration of inflammatory cells and accelerated tumor growth in the bone. Apoptosis-induced tumors displayed elevated expression of the proinflammatory cytokine CXCL5. Likewise, CXCL5-deficient mice had reduced tumor progression. Peripheral blood monocytes isolated from patients with bone metastasis of prostate cancer were more efferocytic compared with normal controls, and CXCL5 serum levels were higher in metastatic prostate cancer patients relative to patients with localized prostate cancer or controls. Altogether, these findings suggest that the myeloid phagocytic clearance of apoptotic cancer cells accelerates CXCL5-mediated inflammation and tumor growth in bone, pointing to CXCL5 as a potential target for cancer therapeutics.

Bromocriptine modulates the expression of PTHrP receptor, Indian hedgehog, and Runx2 proteins in the growth plate of lactating rats.

PubMed

Wongdee, Kannikar; Thonapan, Natchayaporn; Saengamnart, Wasana; Krishnamra, Nateetip; Charoenphandhu, Narattaphol

2013-09-01

In lactating rats, the endochondral bone growth is markedly enhanced, leading to the lengthening of long bone. This lactation-induced bone elongation could be abolished by a dopaminergic D2 receptor agonist bromocriptine, but how bromocriptine altered the expression of major chondroregulatory proteins in the growth plate cartilage was elusive. Here, we performed a quantitative immunohistochemical analysis to determine the expression of various peptides and transcription factors known to control the growth plate chondrocyte proliferation and differentiation [i.e., parathyroid hormone-related protein (PTHrP), PTHrP receptor, Indian hedgehog (Ihh), and runt-related transcription factor 2 (Runx2)], in bromocriptine-treated lactating rats. The results showed that bromocriptine markedly increased Ihh expression in hypertrophic chondrocytes during early and mid-lactation, while the expression of PTHrP receptor, but not its ligand PTHrP, was upregulated in the proliferative and hypertrophic zones during mid and late lactation. In contrast, the expression of Runx2, an important transcription factor for chondrocyte differentiation, was suppressed in the hypertrophic chondrocytes of bromocriptine-treated rats. In conclusion, bromocriptine increased Ihh and PTHrP receptor expressions and decreased Runx2 expression, which might, in turn, enhance chondrocyte proliferation and delay chondrocyte hypertrophy, thereby slowing down endochondral bone growth. This finding could explain how bromocriptine compromised the lactation-induced bone elongation.

Compact biomedical pulsed signal generator for bone tissue stimulation

DOEpatents

Kronberg, J.W.

1993-06-08

An apparatus for stimulating bone tissue for stimulating bone growth or treating osteoporosis by applying directly to the skin of the patient an alternating current electrical signal comprising wave forms known to simulate the piezoelectric constituents in bone. The apparatus may, by moving a switch, stimulate bone growth or treat osteoporosis, as desired. Based on low-power CMOS technology and enclosed in a moisture-resistant case shaped to fit comfortably, two astable multivibrators produce the desired waveforms. The amplitude, pulse width and pulse frequency, and the subpulse width and subpulse frequency of the waveforms are adjustable. The apparatus, preferably powered by a standard 9-volt battery, includes signal amplitude sensors and warning signals indicate an output is being produced and the battery needs to be replaced.

Delivery of small molecules for bone regenerative engineering: preclinical studies and potential clinical applications

PubMed Central

Laurencin, Cato T.; Ashe, Keshia M.; Henry, Nicole; Kan, Ho Man; Lo, Kevin W-H.

2014-01-01

Stimulation of bone regeneration using growth factors is a promising approach for musculoskeletal regenerative engineering. Common limitations with protein growth factors are high manufacturing costs, protein instability, contamination issues, and unwanted immunogenic responses of the host. New strategies for bone regeneration that obviate these problems can have a significant impact on the treatment of skeletal injury and diseases. Over the past decade, a large number of small molecules with the potential of regenerating skeletal tissue have been reported in the literature. Here, we review this literature, paying specific attention to the prospects for small molecule-based bone-regenerative engineering. We also review the preclinical study of small molecules associated with bone regeneration. PMID:24508820

Compact biomedical pulsed signal generator for bone tissue stimulation

DOEpatents

Kronberg, James W.

1993-01-01

An apparatus for stimulating bone tissue for stimulating bone growth or treating osteoporosis by applying directly to the skin of the patient an alternating current electrical signal comprising wave forms known to simulate the piezoelectric constituents in bone. The apparatus may, by moving a switch, stimulate bone growth or treat osteoporosis, as desired. Based on low-power CMOS technology and enclosed in a moisture-resistant case shaped to fit comfortably, two astable multivibrators produce the desired waveforms. The amplitude, pulse width and pulse frequency, and the subpulse width and subpulse frequency of the waveforms are adjustable. The apparatus, preferably powered by a standard 9-volt battery, includes signal amplitude sensors and warning signals indicate an output is being produced and the battery needs to be replaced.

Associations between adiposity, hormones, and gains in height, whole-body height-adjusted bone size, and size-adjusted bone mineral content in 8- to 11-year-old children.

PubMed

Dalskov, S; Ritz, C; Larnkjær, A; Damsgaard, C T; Petersen, R A; Sørensen, L B; Ong, K K; Astrup, A; Michaelsen, K F; Mølgaard, C

2016-04-01

We examined fat-independent associations of hormones with height and whole-body bone size and mineral content in 633 school children. IGF-1 and osteocalcin predict growth in height, while fat, osteocalcin, and in girls also, IGF-1 predict growth in bone size. Leptin and ghrelin are inversely associated with bone size in girls. Obesity causes larger bone size and bone mass, but the role of hormones in this up-regulation of bone in obesity is not well elucidated. We examined longitudinal associations between baseline body fat mass (FM), and fat-independent fasting levels of ghrelin, adiponectin, leptin, insulin, insulin-like growth factor-I (IGF-1), osteocalcin, and intact parathyroid hormone, and subsequent changes in height and in whole-body height-adjusted bone area "BAheight" and size-adjusted bone mineral content "BMCsize" in 8- to 11-year-olds. Analyses were carried out separately for boys (n = 325) and girls (n = 308) including data from baseline, 3 and 6 months from OPUS School Meal Study. In both sexes: gain in BAheight was positively associated with baseline FM (≥2.05 cm(2)/kg, both p ≤ 0.003). Furthermore, gain in height was positively associated with baseline IGF-1 (≥0.02 cm/ng/ml, p = 0.001) and osteocalcin (≥0.13 cm/ng/ml, p ≤ 0.009); and gain in BAheight was positively associated with baseline osteocalcin (≥0.35 cm(2)/ng/ml, p ≤ 0.019). In girls only, gain in BAheight was also positively associated with baseline IGF-1 (0.06 cm(2)/ng/ml, p = 0.017) and inversely associated with both baseline ghrelin (-0.01 cm(2)/pg/ml, p = 0.001) and leptin (-1.21 cm(2)/μg/ml, p = 0.005). In boys, gain in BMCsize was positively associated with osteocalcin (0.18 g/ng/ml, p = 0.030). This large longitudinal study suggests that in 8- to 11-year-old children, IGF-1 and osteocalcin predict growth in height, while FM, osteocalcin, and in girls also, IGF-1 predict growth in BAheight. Fat-independent inverse associations of leptin and ghrelin with BAheight in girls' are contrary to proposed growth-stimulating effects of leptin. Osteocalcin in boys predicts gain in BMCsize.

Histomorphometric Parameters of the Growth Plate and Trabecular Bone in Wild-Type and Trefoil Factor Family 3 (Tff3)-Deficient Mice Analyzed by Free and Open-Source Image Processing Software.

PubMed

Bijelić, Nikola; Belovari, Tatjana; Stolnik, Dunja; Lovrić, Ivana; Baus Lončar, Mirela

2017-08-01

Trefoil factor family 3 (Tff3) peptide is present during intrauterine endochondral ossification in mice, and its deficiency affects cancellous bone quality in secondary ossification centers of mouse tibiae. The aim of this study was to quantitatively analyze parameters describing the growth plate and primary ossification centers in tibiae of 1-month-old wild-type and Tff3 knock-out mice (n=5 per genotype) by using free and open-source software. Digital photographs of the growth plates and trabecular bone were processed by open-source computer programs GIMP and FIJI. Histomorphometric parameters were calculated using measurements made with FIJI. Tff3 knock-out mice had significantly smaller trabecular number and significantly larger trabecular separation. Trabecular bone volume, trabecular bone surface, and trabecular thickness showed no significant difference between the two groups. Although such histomorphological differences were found in the cancellous bone structure, no significant differences were found in the epiphyseal plate histomorphology. Tff3 peptide probably has an effect on the formation and quality of the cancellous bone in the primary ossification centers, but not through disrupting the epiphyseal plate morphology. This work emphasizes the benefits of using free and open-source programs for morphological studies in life sciences.

Life history of Rhamphorhynchus inferred from bone histology and the diversity of pterosaurian growth strategies.

PubMed

Prondvai, Edina; Stein, Koen; Osi, Attila; Sander, Martin P

2012-01-01

Rhamphorhynchus from the Solnhofen Limestones is the most prevalent long tailed pterosaur with a debated life history. Whereas morphological studies suggested a slow crocodile-like growth strategy and superprecocial volant hatchlings, the only histological study hitherto conducted on Rhamphorhynchus concluded a relatively high growth rate for the genus. These controversial conclusions can be tested by a bone histological survey of an ontogenetic series of Rhamphorhynchus. Our results suggest that Bennett's second size category does not reflect real ontogenetic stage. Significant body size differences of histologically as well as morphologically adult specimens suggest developmental plasticity. Contrasting the 'superprecocial hatchling' hypothesis, the dominance of fibrolamellar bone in early juveniles implies that hatchlings sustained high growth rate, however only up to the attainment of 30-50% and 7-20% of adult wingspan and body mass, respectively. The early fast growth phase was followed by a prolonged, slow-growth phase indicated by parallel-fibred bone deposition and lines of arrested growth in the cortex, a transition which has also been observed in Pterodaustro. An external fundamental system is absent in all investigated specimens, but due to the restricted sample size, neither determinate nor indeterminate growth could be confirmed in Rhamphorhynchus. The initial rapid growth phase early in Rhamphorhynchus ontogeny supports the non-volant nature of its hatchlings, and refutes the widely accepted 'superprecocial hatchling' hypothesis. We suggest the onset of powered flight, and not of reproduction as the cause of the transition from the fast growth phase to a prolonged slower growth phase. Rapidly growing early juveniles may have been attended by their parents, or could have been independent precocial, but non-volant arboreal creatures until attaining a certain somatic maturity to get airborne. This study adds to the understanding on the diversity of pterosaurian growth strategies.

Release of growth factors and the effect of age, sex, and severity of injury after long bone fracture. A preliminary report.

PubMed

Pountos, Ippokratis; Georgouli, Theodora; Henshaw, Karen; Bird, Howard; Giannoudis, Peter V

2013-02-01

The systemic response after fracture is regulated by a complex mechanism involving numerous growth factors. In this study, we analyzed the kinetics of key growth factors following lower-limb long bone fracture. Human serum was isolated from 15 patients suffering from lower-limb long bone fracture (tibia/femur) requiring surgical fixation. The levels of platelet-derived growth factor (PDGF-BB), vascular edothelial growth factor (VEGF), insulin growth factor-I (IGF-I), and transforming growth factor β1 (TGF-β1) were assayed by colorimetric ELISA at different time points during the first week after fracture. 10 healthy volunteers made up the control group of the study. Serum levels of the growth factors measured were compared to age, sex, and injury severity score. We found that there was a decline in the levels of PDGF-BB, IGF-I and TGF-β1 during the first 3 days after fracture. However, VEGF levels remained unchanged. The levels of all the growth factors studied then increased, with the highest concentrations noted at day 7 after surgery. No correlation was found between circulating levels of growth factors and age, injury severity score (ISS), blood loss, or fluid administration. There are systemic mitogenic and osteogenic signals after fracture. Important growth factors are released into the peripheral circulation, but early after surgery it appears that serum levels of key growth factors fall. By 7 days postoperatively, the levels had increased considerably. Our findings should be considered in cases where autologous serum is used for ex vivo expansion of mesenchymal stem cells. There should be further evaluation of the use of these molecules as biomarkers of bone union.

Low-frequency pulsed electromagnetic field pretreated bone marrow-derived mesenchymal stem cells promote the regeneration of crush-injured rat mental nerve.

PubMed

Seo, NaRi; Lee, Sung-Ho; Ju, Kyung Won; Woo, JaeMan; Kim, BongJu; Kim, SoungMin; Jahng, Jeong Won; Lee, Jong-Ho

2018-01-01

Bone marrow-derived mesenchymal stem cells (BMSCs) have been shown to promote the regeneration of injured peripheral nerves. Pulsed electromagnetic field (PEMF) reportedly promotes the proliferation and neuronal differentiation of BMSCs. Low-frequency PEMF can induce the neuronal differentiation of BMSCs in the absence of nerve growth factors. This study was designed to investigate the effects of low-frequency PEMF pretreatment on the proliferation and function of BMSCs and the effects of low-frequency PEMF pre-treated BMSCs on the regeneration of injured peripheral nerve using in vitro and in vivo experiments. In in vitro experiments, quantitative DNA analysis was performed to determine the proliferation of BMSCs, and reverse transcription-polymerase chain reaction was performed to detect S100 (Schwann cell marker), glial fibrillary acidic protein (astrocyte marker), and brain-derived neurotrophic factor and nerve growth factor (neurotrophic factors) mRNA expression. In the in vivo experiments, rat models of crush-injured mental nerve established using clamp method were randomly injected with low-frequency PEMF pretreated BMSCs, unpretreated BMSCs or PBS at the injury site (1 × 10 6 cells). DiI-labeled BMSCs injected at the injury site were counted under the fluorescence microscope to determine cell survival. One or two weeks after cell injection, functional recovery of the injured nerve was assessed using the sensory test with von Frey filaments. Two weeks after cell injection, axonal regeneration was evaluated using histomorphometric analysis and retrograde labeling of trigeminal ganglion neurons. In vitro experiment results revealed that low-frequency PEMF pretreated BMSCs proliferated faster and had greater mRNA expression of growth factors than unpretreated BMSCs. In vivo experiment results revealed that compared with injection of unpretreated BMSCs, injection of low-frequency PEMF pretreated BMSCs led to higher myelinated axon count and axon density and more DiI-labeled neurons in the trigeminal ganglia, contributing to rapider functional recovery of injured mental nerve. These findings suggest that low-frequency PEMF pretreatment is a promising approach to enhance the efficacy of cell therapy for peripheral nerve injury repair.

Prophylactic pamidronate partially protects from glucocorticoid-induced bone loss in the mdx mouse model of Duchenne muscular dystrophy.

PubMed

Yoon, Sung-Hee; Chen, Jinghan; Grynpas, Marc D; Mitchell, Jane

2016-09-01

Glucocorticoids are extensively used to treat patients with Duchenne muscular dystrophy because of their ability to delay muscle damage, prolong ambulation and extend life. However, use of glucocorticoids significantly increases bone loss, fragility and fractures. To determine if antiresorptive bisphosphonates could prevent the effects of glucocorticoids on bone quality, we used dystrophic mdx mice treated with the glucocorticoid prednisone during 8weeks of rapid bone growth from 5 to 13weeks of age and treated some mice with the bisphosphonate pamidronate during the first two weeks of prednisone administration. Prednisone reduced long bone growth, decreased cortical bone thickness and area and decreased the strength of the femurs. Pamidronate treatment protected mice from cortical bone loss but did not increase bone strength. The combination of prednisone and pamidronate inhibited remodeling of metaphyseal trabecular bone with large numbers of trabeculae containing remnants of calcified cartilage. Prednisone improved muscle strength in the mdx mice and decreased serum creatine kinase with evidence of improved muscle histology and these effects were maintained in mice treated with pamidronate. Copyright © 2016. Published by Elsevier Inc.

Bone repair in mandibular body osteotomy after using 2.0 miniplate system – histological and histometric analysis in dogs

PubMed Central

Sverzut, Cássio Edvard; Lucas, Marina Amaral; Sverzut, Alexander Tadeu; Trivellato, Alexandre Elias; Beloti, Marcio Mateus; Rosa, Adalberto Luiz; de Oliveira, Paulo Tambasco

2008-01-01

The objective of this study was to evaluate the bone repair along a mandibular body osteotomy after using a 2.0 miniplate system. Nine adult mongrel dogs were subjected to unilateral continuous defect through an osteotomy between the mandibular 3rd and 4th premolars. Two four-hole miniplates were placed in accordance with the Arbeitgeimeinschaft für Osteosynthesefragen Manual. Miniplates adapted to the alveolar processes were fixed monocortically with 6.0-mm-length titanium alloy self-tapping screws, whereas miniplates placed near the mandible bases were fixed bicortically. At 2, 6 and 12 weeks, three dogs were sacrificed per period, and the osteotomy sites were removed, divided into three thirds (Tension Third, TT; Intermediary Third, IT; Compression Third, CT) and prepared for conventional and polarized light microscopy. At 6 weeks, while the CT repaired faster and showed bone union by woven bone formation, the TT and IT exhibited a ligament-like fibrous connective tissue inserted in, and connecting, newly formed woven bone overlying the parent lamellar bone edges. At 12 weeks, bone repair took place at all thirds. Histometrically, proportions of newly formed bone did not alter at TT, IT and CT, whereas significantly enhanced bone formation was observed for the 12-week group, irrespective of the third. The results demonstrated that although the method used to stabilize the mandibular osteotomy allowed bone repair to occur, differences in the dynamics of bone healing may take place along the osteotomy site, depending on the action of tension and compression forces generated by masticatory muscles. PMID:18336526

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.

Nerve growth factor and associated nerve sprouting contribute to local mechanical hyperalgesia in a rat model of bone injury.

PubMed

Yasui, M; Shiraishi, Y; Ozaki, N; Hayashi, K; Hori, K; Ichiyanagi, M; Sugiura, Y

2012-08-01

To clarify the mechanism of tenderness after bone injury, we investigated changes in the withdrawal threshold to mechanical stimuli, nerve distribution and nerve growth factor (NGF)-expression in a rat model of bone injury without immobilization for bone injury healing. Rats were divided into three groups as follows: (1) rats incised in the skin and periosteum, followed by drilling a hole in the tibia [bone lesion group (BLG)]; (2) those incised in the skin and periosteum without bone drilling [periosteum lesion group (PLG)]; and (3) those incised in the skin [skin lesion group (SLG)]. Mechanical hyperalgesia continued for 28 days at a lesion in the BLG, 21 days in PLG and 5 days in SLG after treatments, respectively. Endochondral ossification was observed on days 5-28 in BLG and on days 5-21 in PLG. Nerve growth appeared in deep connective tissue (DCT) at day 28 in BLG. Nerve fibres increased in both cutaneous tissue and DCT at day 7 in PLG, but they were not found at day 28. Mechanical hyperalgesia accompanied with endochondral ossification and nerve fibres increasing at the lesion in both BLG and PLG. NGF was expressed in bone-regenerating cells during the bone injury healing. Anti-NGF and trk inhibitor K252a inhibited hyperalgesia in the different time course. This study shows that localized tenderness coincides with the bone healing and involves NGF expression and nerve sprouting after bone injury. The findings present underlying mechanisms and provide pathophysiological relevance of local tenderness to determination of bone fracture and its healing. © 2011 European Federation of International Association for the Study of Pain Chapters.

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

Programmed administration of parathyroid hormone increases bone formation and reduces bone loss in hindlimb-unloaded ovariectomized rats

NASA Technical Reports Server (NTRS)

Turner, R. T.; Evans, G. L.; Cavolina, J. M.; Halloran, B.; Morey-Holton, E.

1998-01-01

Gonadal insufficiency and reduced mechanical usage are two important risk factors for osteoporosis. The beneficial effects of PTH therapy to reverse the estrogen deficiency-induced bone loss in the laboratory rat are well known, but the influence of mechanical usage in this response has not been established. In this study, the effects of programed administration of PTH on cancellous bone volume and turnover at the proximal tibial metaphysis were determined in hindlimb-unloaded, ovariectomized (OVX), 3-month-old Sprague-Dawley rats. PTH was administered to weight-bearing and hindlimb-unloaded OVX rats with osmotic pumps programed to deliver 20 microg human PTH (approximately 80 microg/kg x day) during a daily 1-h infusion for 7 days. Compared with sham-operated rats, OVX increased longitudinal and radial bone growth, increased indexes of cancellous bone turnover, and resulted in net resorption of cancellous bone. Hindlimb unloading of OVX rats decreased longitudinal and radial bone growth, decreased osteoblast number, increased osteoclast number, and resulted in a further decrease in cancellous bone volume compared with those in weight-bearing OVX rats. Programed administration of PTH had no effect on either radial or longitudinal bone growth in weight-bearing and hindlimb-unloaded OVX rats. PTH treatment had dramatic effects on selected cancellous bone measurements; PTH maintained cancellous bone volume in OVX weight-bearing rats and greatly reduced cancellous bone loss in OVX hindlimb-unloaded rats. In the latter animals, PTH treatment prevented the hindlimb unloading-induced reduction in trabecular thickness, but the hormone was ineffective in preventing either the increase in osteoclast number or the loss of trabecular plates. Importantly, PTH treatment increased the retention of a baseline flurochrome label, osteoblast number, and bone formation in the proximal tibial metaphysis regardless of the level of mechanical usage. These findings demonstrate that programed administration of PTH is effective in increasing osteoblast number and bone formation and has beneficial effects on bone volume in the absence of weight-bearing and gonadal hormones. We conclude that the actions of PTH on cancellous bone are independent of the level of mechanical usage.

The Ontogenetic Osteohistology of Tenontosaurus tilletti

PubMed Central

Werning, Sarah

2012-01-01

Tenontosaurus tilletti is an ornithopod dinosaur known from the Early Cretaceous (Aptian-Albian) Cloverly and Antlers formations of the Western United States. It is represented by a large number of specimens spanning a number of ontogenetic stages, and these specimens have been collected across a wide geographic range (from central Montana to southern Oklahoma). Here I describe the long bone histology of T. tilletti and discuss histological variation at the individual, ontogenetic and geographic levels. The ontogenetic pattern of bone histology in T. tilletti is similar to that of other dinosaurs, reflecting extremely rapid growth early in life, and sustained rapid growth through sub-adult ontogeny. But unlike other iguanodontians, this dinosaur shows an extended multi-year period of slow growth as skeletal maturity approached. Evidence of termination of growth (e.g., an external fundamental system) is observed in only the largest individuals, although other histological signals in only slightly smaller specimens suggest a substantial slowing of growth later in life. Histological differences in the amount of remodeling and the number of lines of arrested growth varied among elements within individuals, but bone histology was conservative across sampled individuals of the species, despite known paleoenvironmental differences between the Antlers and Cloverly formations. The bone histology of T. tilletti indicates a much slower growth trajectory than observed for other iguanodontians (e.g., hadrosaurids), suggesting that those taxa reached much larger sizes than Tenontosaurus in a shorter time. PMID:22470454

Histomorphometric Study of New Bone Formation Comparing Defect Healing with Three Bone Grafting Materials: The Effect of Osteoporosis on Graft Consolidation.

PubMed

Zhang, Qiao; Jing, Dai; Zhang, Yufeng; Miron, Richard J

Bone grafting materials are frequently utilized in oral surgery and periodontology to fill bone defects and augment lost or missing bone. The purpose of this study was to compare new bone formation in bone defects created in both normal and osteoporotic animals loaded with three types of bone grafts from different origins. Forty-eight female Wistar rats were equally divided into control normal and ovariectomized animals. Bilateral 2.5-mm femur defects were created and filled with an equal weight of (1) natural bone mineral (NBM, BioOss) of bovine origin, (2) demineralized freeze-dried bone allograft (DFDBA, LifeNet), or (3) biphasic calcium phosphate (BCP, Vivoss). Following 3 and 6 weeks of healing, hematoxylin and eosin and TRAP staining was performed to determine new bone formation, material degradation, and osteoclast activity. All bone substitutes demonstrated osteoconductive potential at 3 and 6 weeks with higher osteoclast numbers observed in all ovariectomized animals. NBM displayed continual new bone formation with little to no sign of particle degradation, even in osteoporotic animals. DFDBA particles showed similar levels of new bone formation but rapid particle degradation rates with lower levels of mineralized tissue. BCP bone grafts demonstrated significantly higher new bone formation when compared with both NBM and DFDBA particles; however, the material was associated with higher osteoclast activity and particle degradation. Interestingly, in osteoporotic animals, BCP displayed synergistically and markedly more rapid rates of particle degradation. Recent modifications to synthetically fabricated materials were shown to be equally or more osteopromotive than NBM and DFDBA. However, the current BCP utilized demonstrated much faster resorption properties in osteoporotic animals associated with a decrease in total bone volume when compared with the slowly/nonresorbing NBM. The results from this study point to the clinical relevance of minimizing fast-resorbing bone grafting materials in osteoporotic phenotypes due to the higher osteoclastic activity and greater material resorption.

Ensemble Solute Transport in 2-D Operator-Stable Random Fields

NASA Astrophysics Data System (ADS)

Monnig, N. D.; Benson, D. A.

2006-12-01

The heterogeneous velocity field that exists at many scales in an aquifer will typically cause a dissolved solute plume to grow at a rate faster than Fick's Law predicts. Some statistical model must be adopted to account for the aquifer structure that engenders the velocity heterogeneity. A fractional Brownian motion (fBm) model has been shown to create the long-range correlation that can produce continually faster-than-Fickian plume growth. Previous fBm models have assumed isotropic scaling (defined here by a scalar Hurst coefficient). Motivated by field measurements of aquifer hydraulic conductivity, recent techniques were developed to construct random fields with anisotropic scaling with a self-similarity parameter that is defined by a matrix. The growth of ensemble plumes is analyzed for transport through 2-D "operator- stable" fBm hydraulic conductivity (K) fields. Both the longitudinal and transverse Hurst coefficients are important to both plume growth rates and the timing and duration of breakthrough. Smaller Hurst coefficients in the transverse direction lead to more "continuity" or stratification in the direction of transport. The result is continually faster-than-Fickian growth rates, highly non-Gaussian ensemble plumes, and a longer tail early in the breakthrough curve. Contrary to some analytic stochastic theories for monofractal K fields, the plume growth rate never exceeds Mercado's [1967] purely stratified aquifer growth rate of plume apparent dispersivity proportional to mean distance. Apparent super-Mercado growth must be the result of other factors, such as larger plumes corresponding to either a larger initial plume size or greater variance of the ln(K) field.

Better Bones Buddies: An Osteoporosis Prevention Program

ERIC Educational Resources Information Center

Schrader, Susan L.; Blue, Rebecca; Horner, Arlene

2005-01-01

Although osteoporosis typically surfaces in later life, peak bone mass attained before age 20 is a key factor in its prevention. However, most American children's diets lack sufficient calcium during the critical growth periods of preadolescence and adolescence to achieve peak bone mass. "Better Bones (BB) Buddies" is an educational…

Hormonal and Local Regulation of Bone Formation.

ERIC Educational Resources Information Center

Canalis, Ernesto

1985-01-01

Reviews effects of hormones, systemic factors, and local regulators on bone formation. Identifies and explains the impact on bone growth of several hormones as well as the components of systemic and local systems. Concentrates on bone collagen and DNA synthesis. (Physicians may earn continuing education credit by completing an appended test). (ML)

Comparison of the osteogenic potential of bone dust and iliac bone chip.

PubMed

Ye, Shuai; Seo, Kyu-Bum; Park, Byung-Hyun; Song, Kyung-Jin; Kim, Jung-Ryul; Jang, Kyu-Yun; Chae, Young Ju; Lee, Kwang-Bok

2013-11-01

There is no comparative study of the in vitro and in vivo osteogenic potential of iliac bone chips (autogenous iliac cancellous bone chips) compared with bone dusts generated during the decortication process with a high-speed burr in spine fracture or fusion surgery. To compare the osteogenic potential of three sizes of bone dusts with iliac bone chips and to determine whether bone dusts can be used as a bone graft substitute. In vitro and in vivo study. Bone chips were harvested from the posterior superior iliac spine and bone dusts from the vertebrae of 15 patients who underwent spinal fracture surgery. Bone dust was divided into three groups: small (3 mm), middle (4 mm), and large (5 mm) according to the size of the burr tip. A comparison was made using a cell proliferation assay, alkaline phosphatase (ALP) activity, the degree of mineralization in an in vitro model, and radiographic and histologic studies (the change of absorbable area and tissue density) after implantation of the various materials into back muscles of nude mice. Although all three bone dust groups were less active with regard to cell proliferation, ALP activity, and the degree of mineralization, than were bone chips, they still exhibited osteogenic potential. Furthermore, there was no significant difference among the three bone dust groups. The three bone dust groups did show greater absorbable area and change of the tissue density than did the iliac bone chip group. Again, there was no significant difference among the three bone dust groups in this regard. Histologically, specimens from the bone dust groups had a higher osteoclast cell number than specimens from the iliac bone chip group. The osteogenic potential of bone dusts is lower than that of iliac bone chips, and the absorption speed of bone dusts in vivo is faster than that of iliac bone chips. The increased resorption speed appeared to result from an increase in osteoclast cell number. Therefore, caution needs to be used when surgeons employ bone dust as a bone graft substitute. Copyright © 2013 Elsevier Inc. All rights reserved.

The Nell-1 Growth Factor Stimulates Bone Formation by Purified Human Perivascular Cells

PubMed Central

Zhang, Xinli; Péault, Bruno; Chen, Weiwei; Li, Weiming; Corselli, Mirko; James, Aaron W.; Lee, Min; Siu, Ronald K.; Shen, Pang; Zheng, Zhong; Shen, Jia; Kwak, Jinny; Zara, Janette N.; Chen, Feng; Zhang, Hong; Yin, Zack; Wu, Ben; Ting, Kang

2011-01-01

The search for novel sources of stem cells other than bone marrow mesenchymal stem cells (MSCs) for bone regeneration and repair has been a critical endeavor. We previously established an effective protocol to homogeneously purify human pericytes from multiple fetal and adult tissues, including adipose, bone marrow, skeletal muscle, and pancreas, and identified pericytes as a primitive origin of human MSCs. In the present study, we further characterized the osteogenic potential of purified human pericytes combined with a novel osteoinductive growth factor, Nell-1. Purified pericytes grown on either standard culture ware or human cancellous bone chip (hCBC) scaffolds exhibited robust osteogenic differentiation in vitro. Using a nude mouse muscle pouch model, pericytes formed significant new bone in vivo as compared to scaffold alone (hCBC). Moreover, Nell-1 significantly increased pericyte osteogenic differentiation, both in vitro and in vivo. Interestingly, Nell-1 significantly induced pericyte proliferation and was observed to have pro-angiogenic effects, both in vitro and in vivo. These studies suggest that pericytes are a potential new cell source for future efforts in skeletal regenerative medicine, and that Nell-1 is a candidate growth factor able to induce pericyte osteogenic differentiation. PMID:21615216

Extracellular vesicles released from mesenchymal stromal cells stimulate bone growth in osteogenesis imperfecta.

PubMed

Otsuru, Satoru; Desbourdes, Laura; Guess, Adam J; Hofmann, Ted J; Relation, Theresa; Kaito, Takashi; Dominici, Massimo; Iwamoto, Masahiro; Horwitz, Edwin M

2018-01-01

Systemic infusion of mesenchymal stromal cells (MSCs) has been shown to induce acute acceleration of growth velocity in children with osteogenesis imperfecta (OI) despite minimal engraftment of infused MSCs in bones. Using an animal model of OI we have previously shown that MSC infusion stimulates chondrocyte proliferation in the growth plate and that this enhanced proliferation is also observed with infusion of MSC conditioned medium in lieu of MSCs, suggesting that bone growth is due to trophic effects of MSCs. Here we sought to identify the trophic factor secreted by MSCs that mediates this therapeutic activity. To examine whether extracellular vesicles (EVs) released from MSCs have therapeutic activity, EVs were isolated from MSC conditioned medium by ultracentrifugation. To further characterize the trophic factor, RNA or microRNA (miRNA) within EVs was depleted by either ribonuclease (RNase) treatment or suppressing miRNA biogenesis in MSCs. The functional activity of these modified EVs was evaluated using an in vitro chondrocyte proliferation assay. Finally, bone growth was evaluated in an animal model of OI treated with EVs. We found that infusion of MSC-derived EVs stimulated chondrocyte proliferation in the growth plate, resulting in improved bone growth in a mouse model of OI. However, infusion of neither RNase-treated EVs nor miRNA-depleted EVs enhanced chondrocyte proliferation. MSCs exert therapeutic effects in OI by secreting EVs containing miRNA, and EV therapy has the potential to become a novel cell-free therapy for OI that will overcome some of the current limitations in MSC therapy. Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Quantification of various growth factors in different demineralized bone matrix preparations.

PubMed

Wildemann, B; Kadow-Romacker, A; Haas, N P; Schmidmaier, G

2007-05-01

Besides autografts, allografts, and synthetic materials, demineralized bone matrix (DBM) is used for bone defect filling and treatment of non-unions. Different DBM formulations are introduced in clinic since years. However, little is known about the presents and quantities of growth factors in DBM. Aim of the present study was the quantification of eight growth factors important for bone healing in three different "off the shelf" DBM formulations, which are already in human use: DBX putty, Grafton DBM putty, and AlloMatrix putty. All three DBM formulations are produced from human donor tissue but they differ in the substitutes added. From each of the three products 10 different lots were analyzed. Protein was extracted from the samples with Guanidine HCL/EDTA method and human ELISA kits were used for growth factor quantification. Differences between the three different products were seen in total protein contend and the absolute growth factor values but also a large variability between the different lots was found. The order of the growth factors, however, is almost comparable between the materials. In the three investigated materials FGF basic and BMP-4 were not detectable in any analyzed sample. BMP-2 revealed the highest concentration extractable from the samples with approximately 3.6 microg/g tissue without a significant difference between the three DBM formulations. In DBX putty significantly more TGF-beta1 and FGFa were measurable compared to the two other DBMs. IGF-I revealed the significantly highest value in the AlloMatrix and PDGF in Grafton. No differences were accessed for VEGF. Due to the differences in the growth factor concentration between the individual samples, independently from the product formulation, further analyzes are required to optimize the clinical outcome of the used demineralized bone matrix. Copyright 2006 Wiley Periodicals, Inc.

Triazolopyrimidine (trapidil), a platelet-derived growth factor antagonist, inhibits parathyroid bone disease in an animal model for chronic hyperparathyroidism

NASA Technical Reports Server (NTRS)

Lotinun, Sutada; Sibonga, Jean D.; Turner, Russell T.

2003-01-01

Parathyroid bone disease in humans is caused by chronic hyperparathyroidism (HPT). Continuous infusion of PTH into rats results in histological changes similar to parathyroid bone disease, including increased bone formation, focal bone resorption, and severe peritrabecular fibrosis, whereas pulsatile PTH increases bone formation without skeletal abnormalities. Using a cDNA microarray with over 5000 genes, we identified an association between increased platelet-derived growth factor-A (PDGF-A) signaling and PTH-induced bone disease in rats. Verification of PDGF-A overexpression was accomplished with a ribonuclease protection assay. Using immunohistochemistry, PDGF-A peptide was localized to mast cells in PTH-treated rats. We also report a novel strategy for prevention of parathyroid bone disease using triazolopyrimidine (trapidil). Trapidil, an inhibitor of PDGF signaling, did not have any effect on indexes of bone turnover in normal rats. However, dramatic reductions in marrow fibrosis and bone resorption, but not bone formation, were observed in PTH-treated rats given trapidil. Also, trapidil antagonized the PTH-induced increases in mRNA levels for PDGF-A. These results suggest that PDGF signaling is important for the detrimental skeletal effects of HPT, and drugs that target the cytokine or its receptor might be useful in reducing or preventing parathyroid bone disease.

Healing of donor site in bone-tendon-bone ACL reconstruction accelerated with plasma rich in growth factors: a randomized clinical trial.

PubMed

Seijas, Roberto; Rius, Marta; Ares, Oscar; García-Balletbó, Montserrat; Serra, Iván; Cugat, Ramón

2015-04-01

To determine whether the use of plasma rich in growth factors accelerates healing of the donor site in bone-tendon-bone anterior cruciate ligament (ACL) reconstruction (patellar graft). The use of the patellar graft presents post-operative problems such as anterior knee pain, which limits its use and leads to preference being taken for alternative grafts. A double-blind, randomized, clinical trial was performed comparing two groups of patients who underwent ACL reconstruction using patellar tendon graft and comparing the use of plasma rich in growth factors at the donor site after graft harvest in terms of local regeneration by ultrasound assessment. The plasma rich in growth factors group shows earlier donor site regeneration in comparison with the control group (2 months earlier), with significant differences in the first 4 months of the follow-up. The application of plasma rich in growth factors shows accelerated tissue regeneration processes with respect to the control group. This fact, together with the previously published with similar conclusions, can create a knowledge basis in order to set out new recovery guidelines following ACL reconstruction. Therapeutic study, Level I.

Ectopic osteogenesis and angiogenesis regulated by porous architecture of hydroxyapatite scaffolds with similar interconnecting structure in vivo

PubMed Central

Li, Jinyu; Zhi, Wei; Xu, Taotao; Shi, Feng; Duan, Ke; Wang, Jianxin; Mu, Yandong; Weng, Jie

2016-01-01

The macro-pore sizes of porous scaffold play a key role for regulating ectopic osteogenesis and angiogenesis but many researches ignored the influence of interconnection between macro-pores with different sizes. In order to accurately reveal the relationship between ectopic osteogenesis and macro-pore sizes in dorsal muscle and abdominal cavities of dogs, hydroxyapatite (HA) scaffolds with three different macro-pore sizes of 500–650, 750–900 and 1100–1250 µm were prepared via sugar spheres-leaching process, which also had similar interconnecting structure determined by keeping the d/s ratio of interconnecting window diameter to macro-pore size constant. The permeability test showed that the seepage flow of fluid through the porous scaffolds increased with the increase of macro-pore sizes. The cell growth in three scaffolds was not affected by the macro-pore sizes. The in vivo ectopic implantation results indicated that the macro-pore sizes of HA scaffolds with the similar interconnecting structure have impact not only the speed of osteogenesis and angiogenesis but also the space distribution of newly formed bone. The scaffold with macro-pore sizes of 750–900 µm exhibited much faster angiogenesis and osteogenesis, and much more uniformly distribution of new bone than those with other macro-pore sizes. This work illustrates the importance of a suitable macro-pore sizes in HA scaffolds with the similar interconnecting structure which provides the environment for ectopic osteogenesis and angiogenesis. PMID:27699059

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

Effect of COX-2 (PGE2) and IL-6 on Prostate Cancer Bone Metastases

DTIC Science & Technology

2008-02-02

to stimulate both bone targeting and bone reaction (4). Several factors, such as basic fibroblast growth factor (4), osteocalcin, bone sialoprotein (8...Proc Natl Acad Sci U S A 1990;87:75–9. 8. Huang WC, Xie Z, Konaka H, Sodek J, Zhau HE, Chung LWK. Human osteocalcin and bone sialoprotein medi- ating

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.

The effects of prostaglandin E2 in growing rats - Increased metaphyseal hard tissue and cortico-endosteal bone formation

NASA Technical Reports Server (NTRS)

Jee, W. S. S.; Ueno, K.; Deng, Y. P.; Woodbury, D. M.

1985-01-01

The role of in vivo prostaglandin E2 (PGE2) in bone formation is investigated. Twenty-five male Sprague-Dawley rats weighing between 223-267 g were injected subcutaneously with 0.3, 1.0, 3.0, and 6.0 mg of PGE2-kg daily for 21 days. The processing of the tibiae for observation is described. Radiographs and histomorphometric analyses are also utilized to study bone formation. Body weight, weights of soft tissues and bones morphometry are evaluated. It is observed that PGE2 depressed longitudinal bone growth, increased growth cartilage thickness, decreased degenerative cartilage cell size and cartilage cell production, and significantly increased proximal tibial metaphyseal hard tissue mass. The data reveal that periosteal bone formation is slowed down at higher doses of PGE2 and endosteal bone formation is slightly depressed less than 10 days post injection; however, here is a late increase (10 days after post injection) in endosteal bone formation and in the formation of trabecular bone in the marrow cavity of the tibial shaft. It is noted that the effects of PGE2 on bone formation are similar to the responses of weaning rats to PGE2.

Role of Prostaglandin Pathway and Alendronate-Based Carriers to Enhance Statin-induced Bone

PubMed Central

Lee, Yeonju; Liu, Xinming; Nawshad, Ali; Marx, David B.; Wang, Dong; Reinhardt, Richard A.

2011-01-01

Objective This study investigated the role of the prostaglandin (PG) pathway in locally-applied, simvastatin-induced oral bone growth. The possibility of enhancing long-term bone augmentation with an alendronate-based carrier was initiated. Methods Mandibles of 44 mature female rats were treated bilaterally with the following combinations: 2 mg simvastatin in ethanol (SIM-EtOH), EtOH, 2 mg simvastatin acid complexed with alendronate-beta-cyclodextrin conjugate (SIM/ALN-CD), ALN-CD, or ALN. Bone wash technology (injection of PBS and recollection by suction) was used to sample injection sites at baseline (day 0), and 3, 7, 14 and 21 days post-treatment. After 21-24 or 48 days, histomorphometric analysis was done. The amount of PGE2 in bone wash fluid was measured by ELISA, normalized by total protein, and compared between high and low bone growth groups (ANOVA) and correlated with subsequent bone histology at 21 days (Spearman). SIM-stimulated PGE2 synthase and EP4 receptor mRNA in murine osteoblast and fibroblast cell lines were evaluated with real-time PCR. Results Single injections of 2 mg SIM-EtOH induced significantly more new bone than control side after 21 days. PGE2/protein ratios peaked at day 7 and were correlated with the subsequent 21-day new bone width. The correlations at day 14 between PGE2 and new bone width changed to a negative relationship in the test group. SIM-stimulated osteoblasts expressed increased mRNA levels of PGE receptor EP4, while SIM activated PGE synthesis in fibroblasts. SIM/ALN-CD tended to preserve bone long-term. Conclusion Findings suggest that PGE pathway activation and higher levels of PGE2 during the first week following SIM-induced bone growth are desirable, and alendronate-beta-cyclodextrin conjugates not only act as tissue-specific carriers, but preserve new bone. PMID:21438610

Quantification of osteoblastic activity in epiphyseal growth plates by quantitative bone SPECT/CT.

PubMed

Yamane, Tomohiko; Kuji, Ichiei; Seto, Akira; Matsunari, Ichiro

2018-06-01

Quantifying the function of the epiphyseal plate is worthwhile for the management of children with growth disorders. The aim of this retrospective study was to quantify the osteoblastic activity at the epiphyseal plate using the quantitative bone SPECT/CT. We enrolled patients under the age of 20 years who received Tc-99m hydroxymethylene diphosphonate bone scintigraphy acquired by a quantitative SPECT/CT scanner. The images were reconstructed by ordered subset conjugate-gradient minimizer, and the uptake on the distal margin of the femur was quantified by peak standardized uptake value (SUVpeak). A public database of standard body height was used to calculate growth velocities (cm/year). Fifteen patients (6.9-19.7 years, 9 female, 6 male) were enrolled and a total of 25 legs were analyzed. SUVpeak in the epiphyseal plate was 18.9 ± 2.4 (average ± standard deviation) in the subjects under 15 years and decreased gradually by aging. The SUVpeak correlated significantly with the age- and sex-matched growth velocity obtained from the database (R 2  = 0.83, p < 0.0001). The SUV measured by quantitative bone SPECT/CT was increased at the epiphyseal plates of children under the age of 15 years in comparison with the older group, corresponding to higher osteoblastic activity. Moreover, this study suggested a correlation between growth velocity and the SUV. Although this is a small retrospective pilot study, the objective and quantitative values measured by the quantitative bone SPECT/CT has the potential to improve the management of children with growth disorder.

The growth hormone secretagogue ipamorelin counteracts glucocorticoid-induced decrease in bone formation of adult rats.

PubMed

Andersen, N B; Malmlöf, K; Johansen, P B; Andreassen, T T; Ørtoft, G; Oxlund, H

2001-10-01

The ability of the growth hormone secretagogue (GHS) Ipamorelin to counteract the catabolic effects of glucocorticoid (GC) on skeletal muscles and bone was investigated in vivo in an adult rat model. Groups of 8-month-old female rats were injected subcutaneously for 3 months with GC (methylprednisolone) 9 mg/kg/day or GHS (Ipamorelin) 100 microg/kg three times daily, or both GC and GHS in combination. The maximum tetanic tension of the calf muscles was determined in vivo in a materials testing machine. The maximum tetanic tension was increased significantly, and the periosteal bone formation rate increased four-fold in animals injected with GC and GHS in combination, compared with the group injected with GC alone. In conclusion, the decrease in muscle strength and bone formation found in GC-injected rats was counteracted by simultaneous administration of the growth hormone secretagogue. Copyright 2001 Harcourt Publishers Ltd.

Skeletal unloading induces selective resistance to the anabolic actions of growth hormone on bone

NASA Technical Reports Server (NTRS)

Halloran, B. P.; Bikle, D. D.; Harris, J.; Autry, C. P.; Currier, P. A.; Tanner, S.; Patterson-Buckendahl, P.; Morey-Holton, E.

1995-01-01

Loss of skeletal weight bearing or physical unloading of bone in the growing animal inhibits bone formation and induces a bone mineral deficit. To determine whether the inhibition of bone formation induced by skeletal unloading in the growing animal is a consequence of diminished sensitivity to growth hormone (GH) we studied the effects of skeletal unloading in young hypophysectomized rats treated with GH (0, 50, 500 micrograms/100 g body weight/day). Skeletal unloading reduced serum osteocalcin, impaired uptake of 3H-proline into bone, decreased proximal tibial mass, and diminished periosteal bone formation at the tibiofibular junction. When compared with animals receiving excipient alone, GH administration increased bone mass in all animals. The responses in serum osteocalcin, uptake of 3H-proline and 45Ca into the proximal tibia, and proximal tibial mass in non-weight bearing animals were equal to those in weight bearing animals. The responses in trabecular bone volume in the proximal tibia and bone formation at the tibiofibular junction to GH, however, were reduced significantly by skeletal unloading. Bone unloading prevented completely the increase in metaphyseal trabecular bone normally induced by GH and severely dampened the stimulatory effect (158% vs. 313%, p < 0.002) of GH on periosteal bone formation. These results suggest that while GH can stimulate the overall accumulation of bone mineral in both weight bearing and non-weight bearing animals, skeletal unloading selectively impairs the response of trabecular bone and periosteal bone formation to the anabolic actions of GH.

Measurement of Bone Growth in Osteopetrosis

PubMed Central

Sanger, V. L.; Frederickson, T. N.; Morrill, C. C.

1964-01-01

Day-old chicks were injected with 0.2 ml. of a suspension of lymphomatosis virus which was known to cause osteopetrosis in a high percentage of susceptible birds. A comparable number of uninoculated chicks were kept for controls. Alizarin red S was administered for the purpose of marking the bones in order to measure the rate of growth of normal bone and the osteopetrotic bone. The dye was given at 27, 41 and 55 days of age. In this experiment it was found that a layer of normal bone was formed on the surface of the tibia at a rate of 0.25 mm. per week but in the largest osteopetrotic lesion that was found in any chicken spongy bone was formed at a rate greater than 1 mm. per week. Alizarin red S was irritating to tissue and was toxic when given intravenously. ImagesFig. 1.Fig. 2. PMID:17649533

Endocrine Consequences of Anorexia Nervosa

PubMed Central

Misra, Madhusmita; Klibanski, Anne

2014-01-01

Summary Anorexia nervosa (AN) is prevalent in adolescents and young adults, and endocrine changes include hypothalamic amenorrhea, a nutritionally acquired growth hormone resistance with low insulin like growth factor-1 (IGF-1), relative hypercortisolemia, decreases in leptin, insulin, amylin and incretins, and increases in ghrelin, PYY and adiponectin. These changes in turn have deleterious effects on bone, and may affect neurocognition, anxiety, depression and eating disorder psychopathology. Low bone density is particularly concerning; clinical fractures occur and changes in both bone microarchitecture and strength estimates have been reported. Recovery causes improvement of many, but not all, hormonal changes, and deficits in bone accrual may persist despite recovery. Physiologic, primarily transdermal, estrogen replacement increases bone density in adolescents, although catch-up is incomplete. In adults, oral estrogen co-administered with rhIGF-1 in one study, and bisphosphonates in another increased bone density, though not to normal. More studies are necessary to determine the optimal therapeutic approach in AN. PMID:24731664

Lower-limb growth: how predictable are predictions?

PubMed

Kelly, Paula M; Diméglio, Alain

2008-12-01

The purpose of this review is to clarify the different methods of predictions for growth of the lower limb and to propose a simplified method to calculate the final limb deficit and the correct timing of epiphysiodesis. Lower-limb growth is characterized by four different periods: antenatal growth (exponential); birth to 5 years (rapid growth); 5 years to puberty (stable growth); and puberty, which is the final growth spurt characterized by a rapid acceleration phase lasting 1 year followed by a more gradual deceleration phase lasting 1.5 years. The younger the child, the less precise is the prediction. Repeating measurements can increase the accuracy of predictions and those calculated at the beginning of puberty are the most accurate. The challenge is to reduce the margin of uncertainty. Confrontation of the different parameters-bone age, Tanner signs, annual growth velocity of the standing height, sub-ischial length and sitting height-is the most accurate method. Charts and diagrams are only models and templates. There are many mathematical equations in the literature; we must be able to step back from these rigid calculations because they are a false guarantee. The dynamic of growth needs a flexible approach. There are, however, some rules of thumb that may be helpful for different clinical scenarios. For congenital malformations, at birth the limb length discrepancy must be multiplied by 5 to give the final limb length discrepancy. Multiple by 3 at 1 year of age; by 2 at 3 years in girls and 4 years in boys; by 1.5 at 7 years in girls and boys, by 1.2 at 9 years in girls and 11 years in boys and by 1.1 at the onset of puberty (11 years bone age for girls and 13 years bone age for boys). For the timing of epiphysiodesis, several simple principles must be observed to reduce the margin of error; strict and repeated measurements, rigorous analysis of the data obtained, perfect evaluation of bone age with elbow plus hand radiographs and confirmation with Tanner signs. The decision should always be taken at the beginning of puberty. A simple rule is that, at the beginning of puberty, there is an average of 5 cm growth remaining at the knee. There are four common different scenarios: (1) A 5-cm discrepancy-epiphysiodesis of both femur and tibia at the beginning of puberty (11 years bone age girls and 13 years in boys). (2) A 4-cm discrepancy-epiphysiodesis of femur and tibia 6 months after the onset of puberty (11 years 6 months bone age girls, 13 years 6 months bone age boys, tri-radiate cartilage open). (3) A 3-cm discrepancy-epiphysiodesis of femur only at the start of puberty, (skeletal age of 11 years in girls and 13 years in boys). (4) A 2-cm discrepancy-epiphysiodesis of femur only, 1 year after the start of puberty (12 years bone age girls and 14 years in boys).

Nuclear chromatin-concentrated osteoblasts in renal bone diseases.

PubMed

Kazama, Junichiro James; Yamamoto, Suguru; Narita, Ichiei; Kurihara, Satoshi

2011-06-01

The morphological appearance of an osteoblast largely alters with its differentiation and maturation, along with the change of cell function. We quantitatively observed the osteoblast morphology and compared it with bone metabolism. Biopsied iliac bone samples obtained from 77 dialysis patients (14 mild change, 37 osteitis fibrosa, 2 osteomalacia, 8 mixed, and 16 adynamic bone) were included in the study. Osteoblast appearances were classified into three groups: (i) type II and III osteoblasts, namely, active osteoblasts characterized by cuboidal or columnar shapes with or without a nuclear clear zone; (ii) type IV osteoblasts, lining osteoblasts characterized by extremely thin cytoplasm; and (iii) type V osteoblasts, apoptotic osteoblasts characterized by nuclear chromatin concentration. The results were quantitatively expressed as the length of bone surface covered by each type of osteoblasts. The type II and III osteoblasts were predominant in osteitis fibrosa, mixed, and mild change. The type IV osteoblasts were overwhelmingly predominant in adynamic bone. The type V osteoblasts appeared most frequently in osteitis fibrosa, followed by mixed and mild change. Both absolute and relative lengths of bone surface covered by the type V osteoblasts were significantly higher in the high-turnover bone group (osteitis fibrosa and mixed) than the low-turnover bone group (adynamic bone and osteomalacia). The type V osteoblasts were slightly correlated with serum intact parathyroid hormone levels. In conclusion, a high bone-turnover condition seems to be associated with the promotion of osteoblastic apoptosis in dialysis patients. This finding may explain the fact that osteopenia develops faster in CKD patients with high turnover of bone. © 2011 The Authors. Therapeutic Apheresis and Dialysis © 2011 International Society for Apheresis.

Salicylic Acid-Based Polymers for Guided Bone Regeneration Using Bone Morphogenetic Protein-2

PubMed Central

Subramanian, Sangeeta; Mitchell, Ashley; Yu, Weiling; Snyder, Sabrina; Uhrich, Kathryn

2015-01-01

Bone morphogenetic protein-2 (BMP-2) is used clinically to promote spinal fusion, treat complex tibia fractures, and to promote bone formation in craniomaxillofacial surgery. Excessive bone formation at sites where BMP-2 has been applied is an established complication and one that could be corrected by guided tissue regeneration methods. In this study, anti-inflammatory polymers containing salicylic acid [salicylic acid-based poly(anhydride-ester), SAPAE] were electrospun with polycaprolactone (PCL) to create thin flexible matrices for use as guided bone regeneration membranes. SAPAE polymers hydrolyze to release salicylic acid, which is a nonsteroidal anti-inflammatory drug. PCL was used to enhance the mechanical integrity of the matrices. Two different SAPAE-containing membranes were produced and compared: fast-degrading (FD-SAPAE) and slow-degrading (SD-SAPAE) membranes that release salicylic acid at a faster and slower rate, respectively. Rat femur defects were treated with BMP-2 and wrapped with FD-SAPAE, SD-SAPAE, or PCL membrane or were left unwrapped. The effects of different membranes on bone formation within and outside of the femur defects were measured by histomorphometry and microcomputed tomography. Bone formation within the defect was not affected by membrane wrapping at BMP-2 doses of 12 μg or more. In contrast, the FD-SAPAE membrane significantly reduced bone formation outside the defect compared with all other treatments. The rapid release of salicylic acid from the FD-SAPAE membrane suggests that localized salicylic acid treatment during the first few days of BMP-2 treatment can limit ectopic bone formation. The data support development of SAPAE polymer membranes for guided bone regeneration applications as well as barriers to excessive bone formation. PMID:25813520

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

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

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.

PhD7Faster: predicting clones propagating faster from the Ph.D.-7 phage display peptide library.

PubMed

Ru, Beibei; 't Hoen, Peter A C; Nie, Fulei; Lin, Hao; Guo, Feng-Biao; Huang, Jian

2014-02-01

Phage display can rapidly discover peptides binding to any given target; thus, it has been widely used in basic and applied research. Each round of panning consists of two basic processes: Selection and amplification. However, recent studies have showed that the amplification step would decrease the diversity of phage display libraries due to different propagation capacity of phage clones. This may induce phages with growth advantage rather than specific affinity to appear in the final experimental results. The peptides displayed by such phages are termed as propagation-related target-unrelated peptides (PrTUPs). They would mislead further analysis and research if not removed. In this paper, we describe PhD7Faster, an ensemble predictor based on support vector machine (SVM) for predicting clones with growth advantage from the Ph.D.-7 phage display peptide library. By using reduced dipeptide composition (ReDPC) as features, an accuracy (Acc) of 79.67% and a Matthews correlation coefficient (MCC) of 0.595 were achieved in 5-fold cross-validation. In addition, the SVM-based model was demonstrated to perform better than several representative machine learning algorithms. We anticipate that PhD7Faster can assist biologists to exclude potential PrTUPs and accelerate the finding of specific binders from the popular Ph.D.-7 library. The web server of PhD7Faster can be freely accessed at http://immunet.cn/sarotup/cgi-bin/PhD7Faster.pl.

Repression of Multiple Myeloma Growth and Preservation of Bone with Combined Radiotherapy and Anti-angiogenic Agent

PubMed Central

Jia, Dan; Koonce, Nathan A.; Halakatti, Roopa; Li, Xin; Yaccoby, Shmuel; Swain, Frances L.; Suva, Larry J.; Hennings, Leah; Berridge, Marc S.; Apana, Scott M.; Mayo, Kevin; Corry, Peter M.; Griffin, Robert J.

2011-01-01

The effects of ionizing radiation, with or without the antiangiogenic agent anginex (Ax), on multiple myeloma growth were tested in a SCID-rab mouse model. Mice carrying human multiple myeloma cell-containing pre-implanted bone grafts were treated weekly with various regimens for 8 weeks. Rapid multiple myeloma growth, assessed by bioluminescence intensity (IVIS), human lambda Ig light chain level in serum (ELISA), and the volume of bone grafts (caliper), was observed in untreated mice. Tumor burden in mice receiving combined therapy was reduced to 59% (by caliper), 43% (by ELISA), and 2% (by IVIS) of baseline values after 8 weeks of treatment. Ax or radiation alone slowed but did not stop tumor growth. Four weeks after the withdrawal of the treatments, tumor burden remained minimal in mice given Ax + radiation but increased noticeably in the other three groups. Multiple myeloma suppression by Ax + radiation was accompanied by a marked decrease in the number and activity of osteoclasts in bone grafts assessed by histology. Bone graft integrity was preserved by Ax + radiation but was lost in the other three groups, as assessed by microCT imaging and radiography. These results suggest that radiotherapy, when primed by anti-angiogenic agents, may be a potent therapy for focal multiple myeloma. PMID:20518660

National Health Spending: Faster Growth In 2015 As Coverage Expands And Utilization Increases.

PubMed

Martin, Anne B; Hartman, Micah; Washington, Benjamin; Catlin, Aaron

2017-01-01

Total nominal US health care spending increased 5.8 percent and reached $3.2 trillion in 2015. On a per person basis, spending on health care increased 5.0 percent, reaching $9,990. The share of gross domestic product devoted to health care spending was 17.8 percent in 2015, up from 17.4 percent in 2014. Coverage expansions that began in 2014 as a result of the Affordable Care Act continued to affect health spending growth in 2015. In that year, the faster growth in total health care spending was primarily due to accelerated growth in spending for private health insurance (growth of 7.2 percent), hospital care (5.6 percent), and physician and clinical services (6.3 percent). Continued strong growth in Medicaid (9.7 percent) and retail prescription drug spending (9.0 percent), albeit at a slower rate than in 2014, contributed to overall health care spending growth in 2015. Project HOPE—The People-to-People Health Foundation, Inc.

Business, Households, and Governments: Health Spending, 1991

PubMed Central

Cowan, Cathy A.; McDonnell, Patricia A.

1993-01-01

Governments have been thrust to the forefront of health care reform efforts as growth in government health care costs was faster than growth in all other sponsor sectors in 1991. In the business sector, real health care costs per worker have risen 65 times faster than real wages and salaries per worker during the past 26 years. Households continue to devote 5 percent of income after taxes to health care, the same percentage for the last 8 years. This article presents data supporting these findings, and an analysis of health care spending by each sponsor sector. PMID:10130577

A numerical simulation of the effect of using porous superelastic Nitinol and stiff Titanium fixation hardware on the bone remodeling

NASA Astrophysics Data System (ADS)

Raad, Bahram; Shayesteh Moghaddam, Narges; Elahinia, Mohammad

2016-04-01

The aim of this article is to investigate the effect of two different fixation hardware materials on bone remodeling after a mandibular reconstruction surgery and to restore the mandible's function, healthy appearance, mastication, swallowing, breathing, and speech. The hypothesis is that using fixation hardware with stiffness close to that of the surrounding bone will result in a more successful healing process in the mandible bone. The finite element model includes the material properties and forces of the cancellous bone, cortical bone, ligaments, muscles, and teeth. The reconstruction surgery is modeled by including the fixation hardware and the grafted bone. In the sectioned mandible, to best mimic the geometry of the mandible, two single barrel grafts are placed at the top of each other to form a double barrel graft set. Two different materials were used as the mandibular fixation parts, stiff Ti-6Al-4V, and porous superelastic Nickel-Titanium (NiTi) alloys. A comparison of these two alloys demonstrates that using porous NiTi alloy as the fixation part results in a faster healing pace. Furthermore, the density distribution in the mandibular bone after the healing process is more similar to the normal mandible density distribution. The simulations results indicate that the porous superelastic NiTi fixation hardware transfers and distributes the existing forces on the mandible bone more favorably. The probability of stress shielding and/or stress concentration decrease. This type of fixation hardware, therefore, is more appropriate for mandible bone reconstruction surgery. These predictions are in agreement with the clinical observations.

The effects of bone on proton NMR relaxation times of surrounding liquids

NASA Technical Reports Server (NTRS)

Davis, C. A.; Genant, H. K.; Dunham, J. S.

1986-01-01

Preliminary attempts by our group at UCSF to assess fat content of vertebral marrow in the lumbar spine using relaxation time information demonstrated that the presence of trabecular bone affects relaxation times. The objective of this work was a thorough study of the effects of bone on NMR relaxation characteristics of surrounding liquids. Trabecular bone from autopsy specimens was ground up and sifted into a series of powders with graded densities ranging from 0.3 gm/cc to 0.8 gm/cc. Each powder was placed first in n-saline and then in cottonseed oil. With spectroscopy, spin-lattice relaxation times (T1) and effective spin-spin relaxation times (T2*) were measured for each liquid in each bone powder. As bone density and surface to volume ratio increased, T1 decreased faster for saline than for oil. T2* decreased significantly for both water and oil as the surface to volume ratio increased. It was concluded that effects of water on T1 could be explained by a surface interaction at the bone/liquid interface, which restricted rotational and translational motion of nearby molecules. The T1s of oil were not affected since oil molecules are nonpolar, do not participate in significant intermolecular hydrogen bonding, and therefore would not be expected to interact strongly with the bone surface. Effects on T2* could be explained by local magnetic field inhomogeneities created by discontinuous magnetic susceptibility near the bone surface. These preliminary results suggest that water in contact with trabecular bone in vivo will exhibit shortened relaxation times.

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.

Maternal stress does not exacerbate long-term bone deficits in female rats born growth restricted, with differential effects on offspring bone health.

PubMed

Anevska, Kristina; Cheong, Jean N; Wark, John D; Wlodek, Mary E; Romano, Tania

2018-02-01

Females born growth restricted have poor adult bone health. Stress exposure during pregnancy increases risk of pregnancy complications. We determined whether maternal stress exposure in growth-restricted females exacerbates long-term maternal and offspring bone phenotypes. On gestational day 18, bilateral uterine vessel ligation (restricted) or sham (control) surgery was performed on Wistar-Kyoto rats. At 4 mo, control and restricted females were mated and allocated to unstressed or stressed pregnancies. Stressed pregnancies had physiological measurements performed; unstressed females were not handled. After birth, mothers were aged to 13 mo. Second-generation (F2) offspring generated four experimental groups: control unstressed, restricted unstressed, control stressed and restricted stressed. F2 offspring were studied at postnatal day 35 (PN35), 6, 12, and 16 mo. Peripheral quantitative computed tomography was performed on maternal and F2 offspring femurs. Restricted females, irrespective of stress during pregnancy, had decreased endosteal circumference, bending strength, and increased osteocalcin concentrations after pregnancy at 13 mo. F2 offspring of stressed mothers were born lighter. F2 male offspring from stressed pregnancies had decreased trabecular content at 6 mo and decreased endosteal circumference at 16 mo. F2 female offspring from growth-restricted mothers had reduced cortical thickness at PN35 and reduced endosteal circumference at 6 mo. At 12 mo, females from unstressed restricted and stressed control mothers had decreased trabecular content. Low birth weight females had long-term bone changes, highlighting programming effects on bone health. Stress during pregnancy did not exacerbate these programmed effects. Male and female offspring responded differently to maternal growth restriction and stress, indicating gender-specific programming effects.

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

Second hand tobacco smoke adversely affects the bone of immature rats

PubMed Central

Rosa, Rodrigo César; Pereira, Sângela Cunha; Cardoso, Fabrizio Antônio Gomide; Caetano, Abadio Gonçalves; de Santiago, Hildemberg Agostinho Rocha; Volpon, José Batista

2017-01-01

OBJECTIVES: To evaluate the influence of secondhand cigarette smoke exposure on longitudinal growth of the tibia of growing rats and some parameters of bone quality. METHODS: Forty female rats were randomly divided into four groups: control: rats were sham exposed; 30 days: rats were exposed to tobacco smoke for 30 days; 45 days: rats were exposed to tobacco smoke for 45 days; and 60 days: rats were exposed to tobacco smoke for 60 days. Blood samples were collected to evaluate the levels of cotinine and alkaline phosphatase. Both tibias were dissected and weighed; the lengths were measured, and the bones were then stored in a freezer for analysis of bone mineral content and mechanical resistance (maximal load and stiffness). RESULTS: Exposure of rats to tobacco smoke significantly compromised bone health, suggesting that the harmful effects may be time dependent. Harmful effects on bone growth were detected and were more pronounced at 60-day follow-ups with a 41.8% reduction in alkaline phosphatase levels (p<0.01) and a decrease of 11.25% in tibia length (p<0.001). Furthermore, a 41.5% decrease in bone mineral density was observed (p<0.001), leading to a 42.8% reduction in maximum strength (p<0.001) and a 56.7% reduction in stiffness (p<0.001). CONCLUSION: Second hand cigarette smoke exposure in rats affected bones that were weaker, deforming them and making them osteopenic. Additionally, the long bone was shorter, suggesting interference with growth. Such events seem to be related to time of exposure. PMID:29319726

Administration of growth hormone in selectively protein-deprived rats decreases BMD and bone strength.

PubMed

Ammann, Patrick; Brennan, Tara C; Mekraldi, Samia; Aubert, Michel L; Rizzoli, René

2010-06-01

Isocaloric protein undernutrition is associated with decreased bone mass and decreased bone strength, together with lower IGF-I levels. It remains unclear whether administration of growth hormone (GH) corrects these alterations in bone metabolism. Six-month-old female rats were fed isocaloric diets containing either 2.5% or 15% casein for 2 weeks. Bovine growth hormone (bGH, 0.5 or 2.5mg/kg of body weight) or vehicle was then administered as subcutaneous injections, twice daily, to rats on either diet for 4 weeks. At the proximal tibia, analysis of bone mineral density (BMD), maximal load and histomorphometry were performed. In addition, urinary deoxypyridinoline, plasma osteocalcin and IGF-I concentrations were measured. Weight was monitored weekly. bGH caused a dose-dependent increase in plasma IGF-I regardless of the dietary protein content. However, bGH dose-dependently decreased BMD and bone strength in rats fed the low-protein diet. There was no significant effect of bGH on BMD in rats fed the normal protein diet within this short-term treatment period, however bone formation as detected by histomorphometry was improved in this group but not the low-protein group. Osteoclast surface was increased in the low-protein bGH-treated animals only. Changes in bone turnover markers were detectable under both normal and low-protein diets. These results emphasize the major importance of dietary protein intake in the bone response to short-term GH administration, and highlight the need for further investigation into the effects of GH treatment in patients with reduced protein intake. Copyright 2010 Elsevier Inc. All rights reserved.

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

Delayed osteon formation in long-bone diaphysis of an 11-year-old giant cow with dermal dysplasia.

PubMed

Mori, R; Kodaka, T; Naito, Y

1999-02-01

The transverse sections of radius diaphysis in an 11-year-old giant Holstein cow with dermal dysplasia of a collagen disorder-related skin fragility (Cow 1), probably based on increasing turnover of the dermal collagen as reported previously, were morphologically and physico-chemically investigated. Cow 1 had about one and a half times as much as the body weight of normal Holstein cows, aged 5 to 6.5 years with stabilized growth. The bone samples were compared with those of a 12-year-old Holstein cow as controls (Cow 2). It has been reported that the long-bone diaphysis of young calves and some herbivorous dinosaurs are occupied with laminar bone showing a concentric appositional formation, and that such a laminar bone is characteristically seen during the growing period of some farm animals and large dogs that show very rapid growth rates. Cow 1 had a smaller number of osteons than Cow 2 in the outer-half layer of the diaphysis, and showed an intermediate type between Cow 2 and a 1-year-old Holstein ox in the entire layers, although their bone volumes were similar among them. There were no significant differences in Ca and P concentrations and the Vickers microhardness values between the bone matrix of Cow 1 and Cow 2. The bone-collagen fibrils of Cow 1 showed uneven diameters and a disordered arrangement. Thus, there may be some relation in collagen formation between the bone matrix of Cow 1 and the dermis. From the remaining volume of laminar bone, Cow 1, aged 11 years, had probably shown growth until quite recently, so that we consider that Cow 1 became a giant animal, in the same way as some herbivorous dinosaurs.

Derangement of calcium metabolism in diabetes mellitus: negative outcome from the synergy between impaired bone turnover and intestinal calcium absorption.

PubMed

Wongdee, Kannikar; Krishnamra, Nateetip; Charoenphandhu, Narattaphol

2017-01-01

Both types 1 and 2 diabetes mellitus (T1DM and T2DM) are associated with profound deterioration of calcium and bone metabolism, partly from impaired intestinal calcium absorption, leading to a reduction in calcium uptake into the body. T1DM is associated with low bone mineral density (BMD) and osteoporosis, whereas the skeletal changes in T2DM are variable, ranging from normal to increased and to decreased BMD. However, both types of DM eventually compromise bone quality through production of advanced glycation end products and misalignment of collagen fibrils (so-called matrix failure), thereby culminating in a reduction of bone strength. The underlying cellular mechanisms (cellular failure) are related to suppression of osteoblast-induced bone formation and bone calcium accretion, as well as to enhancement of osteoclast-induced bone resorption. Several other T2DM-related pathophysiological changes, e.g., osteoblast insulin resistance, impaired productions of osteogenic growth factors (particularly insulin-like growth factor 1 and bone morphogenetic proteins), overproduction of pro-inflammatory cytokines, hyperglycemia, and dyslipidemia, also aggravate diabetic osteopathy. In the kidney, DM and the resultant hyperglycemia lead to calciuresis and hypercalciuria in both humans and rodents. Furthermore, DM causes deranged functions of endocrine factors related to mineral metabolism, e.g., parathyroid hormone, 1,25-dihydroxyvitamin D 3 , and fibroblast growth factor-23. Despite the wealth of information regarding impaired bone remodeling in DM, the long-lasting effects of DM on calcium metabolism in young growing individuals, pregnant women, and neonates born to women with gestational DM have received scant attention, and their underlying mechanisms are almost unknown and worth exploring.

Low-carbohydrate, high-fat diets have sex-specific effects on bone health in rats.

PubMed

Zengin, Ayse; Kropp, Benedikt; Chevalier, Yan; Junnila, Riia; Sustarsic, Elahu; Herbach, Nadja; Fanelli, Flaminia; Mezzullo, Marco; Milz, Stefan; Bidlingmaier, Martin; Bielohuby, Maximilian

2016-10-01

Studies in humans suggest that consumption of low-carbohydrate, high-fat diets (LC-HF) could be detrimental for growth and bone health. In young male rats, LC-HF diets negatively affect bone health by impairing the growth hormone/insulin-like growth factor axis (GH/IGF axis), while the effects in female rats remain unknown. Therefore, we investigated whether sex-specific effects of LC-HF diets on bone health exist. Twelve-week-old male and female Wistar rats were isoenergetically pair-fed either a control diet (CD), "Atkins-style" protein-matched diet (LC-HF-1), or ketogenic low-protein diet (LC-HF-2) for 4 weeks. In females, microcomputed tomography and histomorphometry analyses were performed on the distal femur. Sex hormones were analysed with liquid chromatography-tandem mass spectrometry, and endocrine parameters including GH and IGF-I were measured by immunoassay. Trabecular bone volume, serum IGF-I and the bone formation marker P1NP were lower in male rats fed both LC-HF diets versus CD. LC-HF diets did not impair bone health in female rats, with no change in trabecular or cortical bone volume nor in serum markers of bone turnover between CD versus both LC-HF diet groups. Pituitary GH secretion was lower in female rats fed LC-HF diet, with no difference in circulating IGF-I. Circulating sex hormone concentrations remained unchanged in male and female rats fed LC-HF diets. A 4-week consumption of LC-HF diets has sex-specific effects on bone health-with no effects in adult female rats yet negative effects in adult male rats. This response seems to be driven by a sex-specific effect of LC-HF diets on the GH/IGF system.

Palaeobiological implications of the bone histology of Pterodaustro guinazui.

PubMed

Chinsamy, Anusuya; Codorniú, Laura; Chiappe, Luis

2009-09-01

This study provides a comprehensive investigation of the bone microstructure of multiple bones of the Early Cretaceous filter-feeder, Pterodaustro guinazui, from the Largacito Formation of Central Argentina. We provide information regarding the bone histology of multiple elements from single skeletons, as well as a variety of bones from different individuals. In addition, we analysed changes in bone microstructure through ontogeny in growth series of several long bones of the taxon. Our investigation of skeletal and ontogenetic variation in Pterodaustro gives insights into the developmental growth dynamics of this unusual ctenochasmatid pterodactyloid from early ontogeny through to adulthood and also provides information pertaining to histological variability within and between bones of individuals. This study also documents the presence of what appears to be medullary bone tissue within the medullary cavity of a large femur of Pterodaustro. This suggests that, like birds, reproductively active female pterosaurs may have deposited a special bone tissue (medullary bone) to cope with the demand of calcium during eggshelling. Our study supports the hypothesis that small Jurassic pterodactyloids took several years to reach adult body size. More specifically, we provide data that suggests that Pterodaustro attained sexual maturity at about 2 years of age, and continued to grow for a further 3-4 years doubling in size before attaining skeletal maturity. (c) 2009 Wiley-Liss, Inc.

Recombinant human basic fibroblast growth factor (bFGF) stimulates periodontal regeneration in class II furcation defects created in beagle dogs.

PubMed

Murakami, S; Takayama, S; Kitamura, M; Shimabukuro, Y; Yanagi, K; Ikezawa, K; Saho, T; Nozaki, T; Okada, H

2003-02-01

Several growth factors (or cytokines) have been recently investigated for their use as potential therapeutics for periodontal tissue regeneration. The objective of this study was to evaluate periodontal tissue regeneration, including new bone and cementum formation, following topical application of recombinant basic fibroblast growth factor (bFGF, FGF-2) to furcation class II defects. Twelve furcation class II bone defects were surgically created in six beagle dogs, then recombinant bFGF (30 micro g/site) + gelatinous carrier was topically applied to the bony defects. Six weeks after application, periodontal regeneration was analyzed. In all sites where bFGF was applied, periodontal ligament formation with new cementum deposits and new bone formation was observed histomorphometrically, in amounts greater than in the control sites. Basic FGF-applied sites exhibited significant regeneration as represented by the new bone formation rate (NBR) (83.6 +/- 14.3%), new trabecular bone formation rate (NTBR) (44.1 +/- 9.5%), and new cementum formation rate (NCR) (97.0 +/- 7.5%). In contrast, in the carrier-only sites, the NBR, NTBR, and NCR were 35.4 +/- 8.9%, 16.6 +/- 6.2%, and 37.2 +/- 15.1%, respectively. Moreover, no instances of epithelial down growth, ankylosis, or root resorption were observed in the bFGF-applied sites examined. The present results indicate that topical application of bFGF can enhance considerable periodontal regeneration in artificially created furcation class II bone defects of beagle dogs.

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.

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.

Osteoblastic molecular scaffold Gab1 is required for maintaining bone homeostasis.

PubMed

Weng, Tujun; Mao, Fengfeng; Wang, Youliang; Sun, Qiang; Li, Ruixin; Yang, Guan; Zhang, Xizheng; Luo, Jincai; Feng, Gen-Sheng; Yang, Xiao

2010-03-01

The Grb2-associated binder 1 (Gab1), which serves as a scaffolding adaptor protein, plays a crucial role in transmitting key signals that control cell growth, differentiation and function from multiple receptors. However, its biological role in osteoblast activity and postnatal bone metabolism remains unclear. To elucidate the in vivo function of Gab1 in postnatal bone remodeling, we generated osteoblast-specific Gab1 knockout mice. Disruption of Gab1 expression in osteoblasts led to decreased trabecular bone mass with a reduced bone formation rate and a decreased bone resorption. Bones from Gab1 mutants also exhibited inferior mechanical properties. Moreover, primary osteoblasts from Gab1 mutant mice demonstrated markedly suppressed osteoblast mineralization, increased susceptibility to apoptosis and decreased expression of receptor activator of NF-kappaB ligand (RANKL). Activation of serine-threonine Akt kinase and extracellular signal-regulated kinase in response to insulin and insulin-like growth factor 1 was attenuated in Gab1 mutant osteoblasts. Our results show that Gab1-mediated signals in osteoblasts are crucial for normal postnatal bone homeostasis.

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.

Migration of cemented femoral components after THR. Roentgen stereophotogrammetric analysis.

PubMed

Kiss, J; Murray, D W; Turner-Smith, A R; Bithell, J; Bulstrode, C J

1996-09-01

We studied the migration of 58 cemented Hinek femoral components for total hip replacement, using roentgen stereophotogrammetric analysis over four years. The implants migrated faster during the first year than subsequently, and the pattern of migration in the second period was very different. During the first year they subsided, tilted into varus and internally rotated. After this there was slow distal migration with no change in orientation. None of the prostheses has yet failed. The early migration is probably caused by resorption of bone damaged by surgical trauma or the heat generated by the polymerisation of bone cement. Later migration may be due to creep in the bone cement or the surrounding fibrous membrane. The prosthesis which we studied allows the preservation of some of the femoral neck, and comparison with published migration studies of the Charnley stem suggests that this decreases rotation and may help to prevent loosening.

Brushite coatings on titanium for orthopedic implants: Studies on deposition and transformation

NASA Astrophysics Data System (ADS)

Kumar, Mukesh

Hydroxyapatite (HA, Ca5(PO4)3OH) coating on the metallic substrate is expected to assist bone growth and implant integration. However, HA is quite stable in physiological solution and the use of other more reactive calcium phosphate ceramics (CPC) could induce faster bone growth by providing calcium and phosphate ions to the interacting physiological solution. This study utilized a non-line of sight electrodeposition process to achieve brushite (CaHPO4.2H2O) coatings. The uses of potassium or sodium chloride as a conducting electrolyte in the depositing bath enhanced deposition rates and altered the morphology of the coatings. Analysis suggested a strained deposit with sight specific substitution of cations from the conducting electrolyte. Such a deposit (modified brushite) was determined to have CaHPO 4.2H2O and CaY2(1-x)HPO4•2H 2O (x ˜0.95) with Y as Na0 or K. Whereas normal brushite was obtained from unsupported baths. The deposited mass of brushite increased with charge consumed and bonding to the substrate decreased with increasing deposition time. Though inconclusive. in-situ studies on electrodeposition did not rule out the possibility of ionic species responsible for the deposit. Transformations of both forms of brushite were investigated in calcium free Hank's type simulated body fluid. Modified brushite showed periodic appearance of freshly precipitated, but poorly crystalline HA, without the benefit of monetite (CaHPO4) as an intermediate. However, normal brushite transformation showed nonstoichiometric HA with monetite as an intermediate. Normal brushite demonstrated a slower transformation to HA when compared to the transformation kinetics of modified brushite. It is shown that lattice strain due to localized ion incorporation could be used to after the properties of brushite coatings to adjust the kinetics of transformation and indirectly the amount of calcium and phosphate ions released into the surrounding.

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.

Piezosurgery for osteotomies in orbital surgery: Our experience and review of the literature

PubMed Central

Iacoangeli, Maurizio; Neri, Piergiorgio; Balercia, Paolo; Lupi, Ettore; Di Rienzo, Alessandro; Nocchi, Niccolò; Alvaro, Lorenzo; Scerrati, Massimo

2012-01-01

INTRODUCTION Piezoelectric bone surgery, simply known as Piezosurgery®, is a new promising technique for bone cutting based on ultrasonic microvibrations that allows to perform precise and thin osteotomies with soft tissue sparing. PRESENTATION OF CASE A 45-years-old woman presenting with progressive left ocular pain, diplopia on the lateral left gaze, and visible exophthalmos was admitted to our department. CT scan and MRI images documented a left supero-lateral orbital lesion. A left lateral orbitotomy using the piezoelectric scalpel was performed. The tumour (lacrimal gland lymphoma) was completely removed with no injuries to the orbital structures and with a perfect realignment of the bone stumps. DISCUSSION High powered pneumatic osteotome are commonly used to perform craniotomies. Large bone cutting groove and high temperatures developing at the contact site could produce an uneasy bone healing. The use of a piezoelectric scalpel allows to realize precise and thin osteotomies, facilitating craniotomy's borders ossification and avoiding injuries to non-osseous structures. CONCLUSION Widely used in Oral and Maxillofacial Surgery, Piezosurgery® can also be useful in neurosurgical approaches in order to obtain a faster bone flap re-ossification, a better aesthetic result, and a lower risks of dural layer and soft tissue damage. PMID:23276764

Constitutional Delay Influences the Auxological Response to Growth Hormone Treatment in Children with Short Stature and Growth Hormone Sufficiency

PubMed Central

Gunn, Katherine C.; Cutfield, Wayne S.; Hofman, Paul L.; Jefferies, Craig A.; Albert, Benjamin B.; Gunn, Alistair J.

2014-01-01

In a retrospective, population based cohort study, we examined whether constitutional delay was associated with the growth response to growth hormone (GH) in children with short stature and normal GH responses. 70 patients were treated with 21 GH iu/m2/week from 1975 to 2013 throughout New Zealand. Demographic and auxological data were prospectively collected and standard deviation scores (SDS) were calculated for height (HtSDS), yearly growth velocity (GV-SDS), body mass index (BMI-SDS) and predicted adult height (PAH-SDS) at time of the last available bone age. In the first year, GH was associated with marked increase in HtSDS (+0.46 (0.19, 0.76), p < 0.001) and GV-SDS (from −1.9 (−3.6, −0.7) to +2.7 (0.45, 4.2), p < 0.001). The increase in HtSDS but not in GV-SDS was greatest with younger patients and greater bone age delay, with no effect of sex, BMI-SDS or baseline HtSDS. PAH-SDS increased with treatment (+0.94 (0.18, 1.5)); increased PAH-SDS was associated with less bone age delay and greater initial increase in HtSDS. This study shows that greater bone age delay was associated with greater initial improvement in height but less improvement in predicted adult heights, suggesting that children with very delayed bone ages may show accelerated maturation during GH treatment. PMID:25317732

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).

Constitutional delay influences the auxological response to growth hormone treatment in children with short stature and growth hormone sufficiency.

PubMed

Gunn, Katherine C; Cutfield, Wayne S; Hofman, Paul L; Jefferies, Craig A; Albert, Benjamin B; Gunn, Alistair J

2014-08-14

In a retrospective, population based cohort study, we examined whether constitutional delay was associated with the growth response to growth hormone (GH) in children with short stature and normal GH responses. 70 patients were treated with 21 GH iu/m2/week from 1975 to 2013 throughout New Zealand. Demographic and auxological data were prospectively collected and standard deviation scores (SDS) were calculated for height (HtSDS), yearly growth velocity (GV-SDS), body mass index (BMI-SDS) and predicted adult height (PAH-SDS) at time of the last available bone age. In the first year, GH was associated with marked increase in HtSDS (+0.46 (0.19, 0.76), p < 0.001) and GV-SDS (from -1.9 (-3.6, -0.7) to +2.7 (0.45, 4.2), p < 0.001). The increase in HtSDS but not in GV-SDS was greatest with younger patients and greater bone age delay, with no effect of sex, BMI-SDS or baseline HtSDS. PAH-SDS increased with treatment (+0.94 (0.18, 1.5)); increased PAH-SDS was associated with less bone age delay and greater initial increase in HtSDS. This study shows that greater bone age delay was associated with greater initial improvement in height but less improvement in predicted adult heights, suggesting that children with very delayed bone ages may show accelerated maturation during GH treatment.

Growth hormone treatment of growth failure secondary to total body irradiation and bone marrow transplantation.

PubMed Central

Papadimitriou, A; Urena, M; Hamill, G; Stanhope, R; Leiper, A D

1991-01-01

Growth hormone was given to 13 children (nine boys, four girls) with acute leukaemia who had undergone treatment with cyclophosphamide and total body irradiation before bone marrow transplantation. Mean age at total body irradiation and bone marrow transplantation was 9.0 years (range 3.7-15.8). Endocrinological investigation was carried out at a mean of 2.0 years (range 0.4-4.0) after bone marrow transplantation. Peak serum growth hormone responses to hypoglycaemia were less than 10.0 micrograms/l (less than 20.0 mU/l) in 10, 10.5 micrograms/l (21.0 mU/l) in one, greater than 16.0 micrograms/l (greater than 32.0 mU/l) in two patients. Mean age of the patients at the start of growth hormone treatment was 12.2 years (range 5.8-18.2). The mean time between total body irradiation and bone marrow transplantation and the start of growth hormone treatment was 3.2 years (range, 1.1-5.0). Height velocity SD score (SD) increased from a mean pretreatment value of -1.27 (0.65) to + 0.22 (0.81) in the first year, +0.16 (1.11) in the second year, and +0.42 (0.71) in the third year of treatment. Height SD score (SD) changed only slightly from -1.52 (0.42) to -1.50 (0.47) in the first year, to -1.50 (0.46) in the second year, and -1.74 (0.92) in the third year. Measurement of segmental proportions showed no significant increase in subischial leg length from -0.87 (0.67) to -0.63 (0.65) in the first year, to -0.58 (0.70) in the second year, and -0.80 (1.14) in the third year of treatment. Our data indicate that children who have undergone total body irradiation and bone marrow transplantation respond to treatment with growth hormone in either of two dose regimens, with an increase in height velocity that is adequate to restore a normal growth rate but not to 'catch up', and that total body irradiation impairs not only spinal but also leg growth, possibly by a direct effect of irradiation on the epiphyses and soft tissues. PMID:2053788

Red deer bone and antler collagen are not isotopically equivalent in carbon and nitrogen.

PubMed

Stevens, Rhiannon E; O'Connell, Tamsin C

2016-09-15

Bone and antler collagen δ(13) C and δ(15) N values are often assumed to be equivalent when measured in palaeodietary, palaeoclimate and palaeocological studies. Although compositionally similar, bone grows slowly and is remodelled whereas antler growth is rapid and remodelling does not occur. These different patterns of growth could result in isotopic difference within antler and between the two tissue types. Here we test whether red deer (Cervus elaphus) bone and antler δ(13) C and δ(15) N values are equivalent, and whether intra-antler isotopic values are uniform. Bone and antler were isotopically analysed from six stags that lived in a temperate maritime climate on the Isle of Rum, Scotland. Multiple antlers from different years were sampled per individual, together with a single bone sample per individual. Up to 12 samples were taken along the length of each antler (total of 25 antlers, 259 samples) so that a chronological record of the isotopic composition during antler growth could be obtained. Collagen was extracted and its δ(13) C and δ(15) N values were measured by continuous-flow isotope ratio mass spectrometry. Intra-antler collagen isotope signatures vary, and show that not all antlers from an individual or a growth year are equivalent in carbon and nitrogen isotopic ratios. δ(15) N values typically increase with distance along antler length, but no overall trend is observed in δ(13) C values. An isotopic offset is visible between bone and antler, with bone δ(13) C and δ(15) N values being higher in most cases. Bone and antler collagen δ(13) C and δ(15) N values are not isotopically equivalent and are therefore not directly comparable in palaeodietary, palaeoclimate and palaeocological studies. Bone and antler collagen isotopic differences probably relate to differential metabolic processes during the formation of the two tissues. Intra- and inter-antler isotopic variations probably reflect the isotopic composition of an individual's diet rather than physiological parameters, and may have the potential to provide high-resolution individual-specific information in modern and ancient cervid populations. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

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.

Biomimetic fabrication of a three-level hierarchical calcium phosphate/collagen/hydroxyapatite scaffold for bone tissue engineering.

PubMed

Zhou, Changchun; Ye, Xingjiang; Fan, Yujiang; Ma, Liang; Tan, Yanfei; Qing, Fangzu; Zhang, Xingdong

2014-09-01

A three-level hierarchical calcium phosphate/collagen/hydroxyapatite (CaP/Col/HAp) scaffold for bone tissue engineering was developed using biomimetic synthesis. Porous CaP ceramics were first prepared as substrate materials to mimic the porous bone structure. A second-level Col network was then composited into porous CaP ceramics by vacuum infusion. Finally, a third-level HAp layer was achieved by biomimetic mineralization. The three-level hierarchical biomimetic scaffold was characterized using scanning electron microscopy, energy-dispersive x-ray spectra, x-ray diffraction and Fourier transform infrared spectroscopy, and the mechanical properties of the scaffold were evaluated using dynamic mechanical analysis. The results show that this scaffold exhibits a similar structure and composition to natural bone tissues. Furthermore, this three-level hierarchical biomimetic scaffold showed enhanced mechanical strength compared with pure porous CaP scaffolds. The biocompatibility and osteoinductivity of the biomimetic scaffolds were evaluated using in vitro and in vivo tests. Cell culture results indicated the good biocompatibility of this biomimetic scaffold. Faster and increased bone formation was observed in these scaffolds following a six-month implantation in the dorsal muscles of rabbits, indicating that this biomimetic scaffold exhibits better osteoinductivity than common CaP scaffolds.

Science and Technology Review December 2006

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

Radousky, H B

2006-10-30

This month's issue has the following articles: (1) Livermore's Biosecurity Research Directly Benefits Public Health--Commentary by Raymond J. Juzaitis; (2) Diagnosing Flu Fast--Livermore's FluIDx device can diagnose flu and four other respiratory viruses in just two hours; (3) An Action Plan to Reopen a Contaminated Airport--New planning tools and faster sample analysis methods will hasten restoration of a major airport to full use following a bioterrorist attack; (4) Early Detection of Bone Disease--A Livermore technique detects small changes in skeletal calcium balance that may signal bone disease; and (5) Taking a Gander with Gamma Rays--Gamma rays may be the nextmore » source for looking deep inside the atom.« less

The use of power tools in the insertion of cortical bone screws.

PubMed

Elliott, D

1992-01-01

Cortical bone screws are commonly used in fracture surgery, most patterns are non-self-tapping and require a thread to be pre-cut. This is traditionally performed using hand tools rather than their powered counterparts. Reasons given usually imply that power tools are more dangerous and cut a less precise thread, but there is no evidence to support this supposition. A series of experiments has been performed which show that the thread pattern cut with either method is identical and that over-penetration with the powered tap is easy to control. The conclusion reached is that both methods produce consistently reliable results but use of power tools is much faster.

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.

Bone fracture healing in mechanobiological modeling: A review of principles and methods.

PubMed

Ghiasi, Mohammad S; Chen, Jason; Vaziri, Ashkan; Rodriguez, Edward K; Nazarian, Ara

2017-06-01

Bone fracture is a very common body injury. The healing process is physiologically complex, involving both biological and mechanical aspects. Following a fracture, cell migration, cell/tissue differentiation, tissue synthesis, and cytokine and growth factor release occur, regulated by the mechanical environment. Over the past decade, bone healing simulation and modeling has been employed to understand its details and mechanisms, to investigate specific clinical questions, and to design healing strategies. The goal of this effort is to review the history and the most recent work in bone healing simulations with an emphasis on both biological and mechanical properties. Therefore, we provide a brief review of the biology of bone fracture repair, followed by an outline of the key growth factors and mechanical factors influencing it. We then compare different methodologies of bone healing simulation, including conceptual modeling (qualitative modeling of bone healing to understand the general mechanisms), biological modeling (considering only the biological factors and processes), and mechanobiological modeling (considering both biological aspects and mechanical environment). Finally we evaluate different components and clinical applications of bone healing simulation such as mechanical stimuli, phases of bone healing, and angiogenesis.

Circulating osteocrin stimulates bone growth by limiting C-type natriuretic peptide clearance.

PubMed

Kanai, Yugo; Yasoda, Akihiro; Mori, Keita P; Watanabe-Takano, Haruko; Nagai-Okatani, Chiaki; Yamashita, Yui; Hirota, Keisho; Ueda, Yohei; Yamauchi, Ichiro; Kondo, Eri; Yamanaka, Shigeki; Sakane, Yoriko; Nakao, Kazumasa; Fujii, Toshihito; Yokoi, Hideki; Minamino, Naoto; Mukoyama, Masashi; Mochizuki, Naoki; Inagaki, Nobuya

2017-11-01

Although peptides are safe and useful as therapeutics, they are often easily degraded or metabolized. Dampening the clearance system for peptide ligands is a promising strategy for increasing the efficacy of peptide therapies. Natriuretic peptide receptor B (NPR-B) and its naturally occurring ligand, C-type natriuretic peptide (CNP), are potent stimulators of endochondral bone growth, and activating the CNP/NPR-B system is expected to be a powerful strategy for treating impaired skeletal growth. CNP is cleared by natriuretic peptide clearance receptor (NPR-C); therefore, we investigated the effect of reducing the rate of CNP clearance on skeletal growth by limiting the interaction between CNP and NPR-C. Specifically, we generated transgenic mice with increased circulating levels of osteocrin (OSTN) protein, a natural NPR-C ligand without natriuretic activity, and observed a dose-dependent skeletal overgrowth phenotype in these animals. Skeletal overgrowth in OSTN-transgenic mice was diminished in either CNP- or NPR-C-depleted backgrounds, confirming that CNP and NPR-C are indispensable for the bone growth-stimulating effect of OSTN. Interestingly, double-transgenic mice of CNP and OSTN had even higher levels of circulating CNP and additional increases in bone length, as compared with mice with elevated CNP alone. Together, these results support OSTN administration as an adjuvant agent for CNP therapy and provide a potential therapeutic approach for diseases with impaired skeletal growth.

Histomorphometric study of tibia of rats exposed aboard American Spacelab Life Sciences 2 Shuttle Mission

NASA Technical Reports Server (NTRS)

Durnova, G.; Kaplansky, A.; Morey-Holton, E.

1996-01-01

Tibial bones of rats flown onboard the SLS-2 shuttle mission were studied. Trabecular bone parameters were investigated, including growth plate height, trabecular bone volume, thickness and number, and trabecular separation in the primary and secondary spongiosa. Several histomorphometric changes were noted, allowing researchers to conclude that exposure to microgravity resulted in osteopenia of spongy bone of tibial metaphysis. The roles of bone formation and bone resorption are discussed.

Healing bone lesion defects using injectable CaSO4 /CaPO4 -TCP bone graft substitute compared to cancellous allograft bone chips in a canine model.

PubMed

Hall, Deborah J; Turner, Thomas M; Urban, Robert M

2018-04-16

CaSO 4 /CaPO 4 -TCP bone graft substitute has been shown to be effective for treatment of bone lesion defects, but its mechanical, histological, and radiographic characteristics have not been studied in direct comparison with a conventional treatment such as cancellous allograft bone. Thirteen canines had a critical-size axial defect created bilaterally into the proximal humerus. CaSO 4 /CaPO 4 -TCP bone graft substitute (PRO-DENSE™, Wright Medical Technology) was injected into the defect in one humerus, and an equal volume of freeze-dried cancellous allograft bone chips was placed in the contralateral defect. The area fraction of new bone, residual graft, and fibrous tissue and the compressive strength and elastic modulus of bone within the defects were determined after 6, 13, or 26 weeks and correlated with radiographic changes. The data were analyzed using Friedman and Mann-Whitney tests. There was more bone in defects treated with the CaSO 4 /CaPO 4 -TCP bone graft substitute compared to defects treated with cancellous bone allograft at all three time points, and the difference at 13 weeks was significant (p = 0.025). The new bone was significantly stronger and stiffer in defects treated with the CaSO 4 /CaPO 4 -TCP bone graft substitute compared to defects treated with cancellous bone allograft at 13 (p = 0.046) and 26 weeks (p = 0.025). At 26 weeks, all defects treated with CaSO 4 /CaPO 4 -TCP bone graft substitute demonstrated complete healing with new bone, whereas healing was incomplete in all defects treated with cancellous allograft chips. The CaSO 4 /CaPO 4 -TCP bone graft substitute could provide faster and significantly stronger healing of bone lesions compared to the conventional treatment using freeze-dried cancellous allograft bone. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2018. © 2018 Wiley Periodicals, Inc.

Ultrafast Formation of ZnO Nanorods via Seed-Mediated Microwave Assisted Hydrolysis Process

NASA Astrophysics Data System (ADS)

Tan, S. T.; Umar, A. A.; Yahaya, M.; Yap, C. C.; Salleh, M. M.

2013-04-01

One dimensional (1D) zinc oxide, ZnO nanostructures have shown promising results for usage in photodiode and optoelectronic device due to their high surface area. Faster and conventional method for synthesis ZnO nanorods has become an attention for researcher today. In this paper, ZnO nanorods have been successfully synthesized via two-step process, namely alcothermal seeding and seed-mediated microwave hydrolysis process. In typical process, the ZnO nanoseeds were grown in the growth solution that contained equimolar (0.04 M) of zinc nitrate hexahydrate, Zn (NO3).6H2O and hexamethylenetetramine, HMT. The growth process was carried inside the inverted microwave within 5- 20 s. The effect of growth parameters (i.e. concentration, microwave power, time reaction) upon the modification of ZnO morphology was studied. ZnO nanostructures were characterized by Field emission scanning electron microscope (FESEM) and X-ray diffraction (XRD). The densities of nanorods were evaluated by the Image J analysis. It was found that the morphology (e.g. shape and size) of nanostructures has changed drastically with the increment of growth solution concentration. The density of ZnO nanorods was proven to increase with the increasing of reaction time and microwave power. We hypothesize that the microwave power might enhance the rate of nucleation and promote the faster nanostructure growth as compared with the normal heating condition due to the superheating phenomenon. This method might promote a new and faster alternative way in nanostructure growth which can be applied in currently existing application.

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.

Delivery of small molecules for bone regenerative engineering: preclinical studies and potential clinical applications.

PubMed

Laurencin, Cato T; Ashe, Keshia M; Henry, Nicole; Kan, Ho Man; Lo, Kevin W-H

2014-06-01

Stimulation of bone regeneration using growth factors is a promising approach for musculoskeletal regenerative engineering. However, common limitations with protein growth factors, such as high manufacturing costs, protein instability, contamination issues, and unwanted immunogenic responses of the host reduce potential clinical applications. New strategies for bone regeneration that involve inexpensive and stable small molecules can obviate these problems and have a significant impact on the treatment of skeletal injury and diseases. Over the past decade, a large number of small molecules with the potential of regenerating skeletal tissue have been reported in the literature. Here, we review this literature, paying specific attention to the prospects for small molecule-based bone-regenerative engineering. We also review the preclinical study of small molecules associated with bone regeneration. Copyright © 2014 Elsevier Ltd. All rights reserved.

Molecular Genetic Studies of Bone Mechanical Strain and of Pedigrees With Very High Bone Density

DTIC Science & Technology

2008-11-01

J Cell Biol 1993, 62(2):352-361. 19. Petersen W, Rafii M: Immunolocalization of the angiogenetic factor pleiotrophin (PTN) in the growth plate of mice...361. 13. Petersen W, Rafii M: Immunolocalization of the angiogenetic factor pleiotrophin (PTN) in the growth plate of mice. Arch Orthop Trauma Surg

Method for protecting bone marrow against chemotherapeutic drugs and radiation therapy using transforming growth factor beta 1

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

Keller, J.R.; Ruscetti, F.W.; Wiltrout, R.

1989-06-29

Presented is a method for protecting hematopoietic stem cells from the myelotoxicity of chemotherapeutic drugs or radiation therapy, which comprises administering to a subject a therapeutically effective amount of transforming growth factor beta 1 for protecting bone marrow from the myelotoxicity of chemotherapeutic drugs or radiation therapy.

The Role of GH/IGF-I Axis in Muscle Homeostasis During Weightlessness

NASA Technical Reports Server (NTRS)

Schwartz, Robert J.

1997-01-01

Exposure to reduced gravity during space travel profoundly alters the loads placed on bone and muscle. Astronauts suffer significant losses of muscle and bone strength during weightlessness. Exercise as a countermeasure is only partially effective in remedying severe muscle atrophy and bone demineralization. Similar wasting of muscles and bones affects people on Earth during prolonged bed rest or immobilization due to injury. In the absence of weight bearing activity, atrophy occurs primarily in the muscles that act in low power, routine movements and in maintaining posture. Hormonal disfunction could contribute in part to the loss of muscle and bone during spaceflight. Reduced levels of human Growth Hormone (hGH) were found in astronauts during space flight, as well as reduced GH secretory activity was observed from the anterior pituitary in 7-day space flight rats. Growth hormone has been shown to be required for maintenance of muscle mass and bone mineralization, in part by mediating the biosynthesis IGF-I, a small polypeptide growth factor. IGF biosynthesis and secretion plays an important role in potentiating muscle cell differentiation and has been shown to drive the expression of myogenin, a myogenic specific basic helix-loop-helix factor. IGF-I has also been shown to have an important role in potentiating muscle regeneration, repair and adult muscle hypertrophy.

Infrared spectroscopy reveals both qualitative and quantitative differences in equine subchondral bone during maturation

NASA Astrophysics Data System (ADS)

Kobrina, Yevgeniya; Isaksson, Hanna; Sinisaari, Miikka; Rieppo, Lassi; Brama, Pieter A.; van Weeren, René; Helminen, Heikki J.; Jurvelin, Jukka S.; Saarakkala, Simo

2010-11-01

The collagen phase in bone is known to undergo major changes during growth and maturation. The objective of this study is to clarify whether Fourier transform infrared (FTIR) microspectroscopy, coupled with cluster analysis, can detect quantitative and qualitative changes in the collagen matrix of subchondral bone in horses during maturation and growth. Equine subchondral bone samples (n = 29) from the proximal joint surface of the first phalanx are prepared from two sites subjected to different loading conditions. Three age groups are studied: newborn (0 days old), immature (5 to 11 months old), and adult (6 to 10 years old) horses. Spatial collagen content and collagen cross-link ratio are quantified from the spectra. Additionally, normalized second derivative spectra of samples are clustered using the k-means clustering algorithm. In quantitative analysis, collagen content in the subchondral bone increases rapidly between the newborn and immature horses. The collagen cross-link ratio increases significantly with age. In qualitative analysis, clustering is able to separate newborn and adult samples into two different groups. The immature samples display some nonhomogeneity. In conclusion, this is the first study showing that FTIR spectral imaging combined with clustering techniques can detect quantitative and qualitative changes in the collagen matrix of subchondral bone during growth and maturation.

Strategies for delivering bone morphogenetic protein for bone healing.

PubMed

Begam, Howa; Nandi, Samit Kumar; Kundu, Biswanath; Chanda, Abhijit

2017-01-01

Bone morphogenetic proteins (BMPs) are the most significant growth factors that belong to the Transforming Growth Factor Beta (TGF-β) super-family. Though more than twenty members of this family have been identified so far in humans, Food and Drug Administration (FDA) approved two growth factors: BMP-2 and BMP-7 for treatments of spinal fusion and long-bone fractures with collagen carriers. Currently BMPs are clinically used in spinal fusion, oral and maxillofacial surgery and also in the repair of long bone defects. The efficiency of BMPs depends a lot on the selection of suitable carriers. At present, different types of carrier materials are used: natural and synthetic polymers, calcium phosphate and ceramic-polymer composite materials. Number of research articles has been published on the minute intricacies of the loading process and release kinetics of BMPs. Despite the significant evidence of its potential for bone healing demonstrated in animal models, future clinical investigations are needed to define dose, scaffold and route of administration. The efficacy and application of BMPs in various levels with a proper carrier and dose is yet to be established. The present article collates various aspects of success and limitation and identifies the prospects and challenges associated with the use of BMPs in orthopaedic surgery. Copyright © 2016 Elsevier B.V. All rights reserved.

Kidney tubular-cell secretion of osteoblast growth factor is increased by kaempferol: a scientific basis for "the kidney controlling the bone" theory of Chinese medicine.

PubMed

Long, Mian; Li, Shun-xiang; Xiao, Jiang-feng; Wang, Jian; Lozanoff, Scott; Zhang, Zhi-guang; Luft, Benjamin J; Johnson, Francis

2014-09-01

To study, at the cytological level, the basic concept of Chinese medicine that "the Kidney (Shen) controls the bone". Kaempferol was isolated form Rhizoma Drynariae (Gu Sui Bu, GSB) and at several concentrations was incubated with opossum kidney (OK) cells, osteoblasts (MC3T3 E1) and human fibroblasts (HF) at cell concentrations of 2×10(4)/mL. Opossum kidney cell-conditioned culture media with kaempferol at 70 nmol/L (70kaeOKM) and without kaempferol (0OKM) were used to stimulate MC3T3 E1 and HF proliferation. The bone morphological protein receptors I and II (BMPR I and II) in OK cells were identified by immune-fluorescence staining and Western blot analysis. Kaempferol was found to increase OK cell growth (P<0.05), but alone did not promote MC3T3 E1 or HF cell proliferation. However, although OKM by itself increased MC3T3 E1 growth by 198% (P<0.01), the 70kaeOKM further increased the growth of these cells by an additional 127% (P<0.01). It indicates that the kidney cell generates a previously unknown osteoblast growth factor (OGF) and kaempferol increases kidney cell secretion of OGF. Neither of these media had any significant effect on HF growth. Kaempferol also was found to increase the level of the BMPR II in OK cells. This lends strong support to the original idea that the Kidney has a significant influence over bone-formation, as suggested by some long-standing Chinese medical beliefs, kaempferol may also serve to stimulate kidney repair and indirectly stimulate bone formation.

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

Global deletion of tetraspanin CD82 attenuates bone growth and enhances bone marrow adipogenesis.

PubMed

Bergsma, Alexis; Ganguly, Sourik S; Dick, Daniel; Williams, Bart O; Miranti, Cindy K

2018-05-18

CD82 is a widely expressed member of the tetraspanin family of transmembrane proteins known to control cell signaling, adhesion, and migration. Tetraspanin CD82 is induced over 9-fold during osteoclast differentiation in vitro; however, its role in bone homeostasis is unknown. A globally deleted CD82 mouse model was used to assess the bone phenotype. Based on microCT and 4-point bending tests, CD82-deficient bones are smaller in diameter and weaker, but display no changes in bone density. Histomorphometry shows a decrease in size, erosion perimeter, and number of osteoclasts in situ, with a corresponding increase in trabecular surface area, specifically in male mice. Male-specific alterations are observed in trabecular structure by microCT and in vitro differentiated osteoclasts are morphologically abnormal. Histomorphometry did not reveal a significant reduction in osteoblast number; however, dynamic labeling reveals a significant decrease in bone growth. Consistent with defects in OB function, OB differentiation and mineralization are defective in vitro, whereas adipogenesis is enhanced. There is a corresponding increase in bone marrow adipocytes in situ. Thus, combined defects in both osteoclasts and osteoblasts can account for the observed bone phenotypes, and suggests a role for CD82 in both bone mesenchyme and myeloid cells. Copyright © 2018 Elsevier Inc. All rights reserved.