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Sample records for bone growth mechanical

  1. Bone Growth, Mechanical Stimulus and IGF-1

    DTIC Science & Technology

    2006-10-01

    fragility, but, by enhancing peak bone mass – and retaining it through adulthood – may reduce the risk of osteoporosis and fractures later in life. This...recruits, and osteoporotic fractures in elderly women. Insulin-like growth factor-I (IGF-I), a major regulator of longitudinal bone growth, has...females with low bone density. Ultimately, this information could be of great benefit to enhance musculoskeletal development and decrease the risk

  2. Bone Growth, Mechanical Stimulus and IGF-I

    DTIC Science & Technology

    2007-10-01

    in the elderly. 15. SUBJECT TERMS Mechanical Intervention, Fractures, IGF-I, Teenagers , Low Bone Mass 16. SECURITY CLASSIFICATION OF: 17...for low bone mass is present early in life, the amount of bone gained during adolescence is a main contributor to peak bone mass in the young adult...reversing osteoporosis in the elderly, these data from children, adolescents and young adults indicate that enhancing bone health early in life represents a

  3. Factors affecting bone growth.

    PubMed

    Gkiatas, Ioannis; Lykissas, Marios; Kostas-Agnantis, Ioannis; Korompilias, Anastasios; Batistatou, Anna; Beris, Alexandros

    2015-02-01

    Bone growth and development are products of the complex interactions of genetic and environmental factors. Longitudinal bone growth depends on the growth plate. The growth plate has 5 different zones-each with a different functional role-and is the final target organ for longitudinal growth. Bone length is affected by several systemic, local, and mechanical factors. All these regulation systems control the final length of bones in a complicated way. Despite its significance to bone stability, bone growth in width has not been studied as extensively as longitudinal bone growth. Bone growth in width is also controlled by genetic factors, but mechanical loading regulates periosteal apposition. In this article, we review the most recent data regarding bone growth from the embryonic age and analyze the factors that control bone growth. An understanding of this complex system is important in identifying metabolic and developmental bone diseases and fracture risk.

  4. 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

  5. Bone Growth, Mechanical Stimulus and IGF-I

    DTIC Science & Technology

    2005-10-01

    genetic susceptibility for low bone mass is present very early in life. The aim of this project is to establish whether bone acquisition in teenagers who...twelve-month interventions on musculoskeletal development will be studied and the results will be compared to matched teenagers undergoing no...3, and IGF-I genotypes, and between bone acquisition induced by interventions and insulin-like growth factors, in teenagers ages 15 to 20 years old

  6. Cortical bone development under the growth plate is regulated by mechanical load transfer.

    PubMed

    Tanck, E; Hannink, G; Ruimerman, R; Buma, P; Burger, E H; Huiskes, R

    2006-01-01

    Longitudinal growth of long bones takes place at the growth plates. The growth plate produces new bone trabeculae, which are later resorbed or merged into the cortical shell. This process implies transition of trabecular metaphyseal sections into diaphyseal sections. We hypothesize that the development of cortical bone is governed by mechanical stimuli. We also hypothesize that trabecular and cortical bone share the same regulatory mechanisms for adaptation to mechanical loads. To test these hypotheses, we monitored the development of the tibial cortex in growing pigs, using micro-computer tomography and histology. We then tested the concept that regulatory mechanisms for trabecular bone adaptation can also explain cortical bone development using our mechanical stimulation theory, which could explain trabecular bone (re)modelling. The main results showed that, from the growth plate towards the diaphysis, the pores of the trabecular structure were gradually filled in with bone, which resulted in increased density and cortical bone. The computer model largely predicted this morphological development. We conclude that merging of metaphyseal trabeculae into cortex is likely to be governed by mechanical stimuli. Furthermore, cortex development of growing long bones can be explained as a form of trabecular bone adaptation, without the need for different regulatory mechanisms for cortical and trabecular bone.

  7. Mechanisms of nerve growth factor signaling in bone nociceptors and in an animal model of inflammatory bone pain.

    PubMed

    Nencini, Sara; Ringuet, Mitchell; Kim, Dong-Hyun; Chen, Yu-Jen; Greenhill, Claire; Ivanusic, Jason J

    2017-01-01

    Sequestration of nerve growth factor has been used successfully in the management of pain in animal models of bone disease and in human osteoarthritis. However, the mechanisms of nerve growth factor-induced bone pain and its role in modulating inflammatory bone pain remain to be determined. In this study, we show that nerve growth factor receptors (TrkA and p75) and some other nerve growth factor-signaling molecules (TRPV1 and Nav1.8, but not Nav1.9) are expressed in substantial proportions of rat bone nociceptors. We demonstrate that nerve growth factor injected directly into rat tibia rapidly activates and sensitizes bone nociceptors and produces acute behavioral responses with a similar time course. The nerve growth factor-induced changes in the activity and sensitivity of bone nociceptors we report are dependent on signaling through the TrkA receptor, but are not affected by mast cell stabilization. We failed to show evidence for longer term changes in expression of TrkA, TRPV1, Nav1.8 or Nav1.9 in the soma of bone nociceptors in a rat model of inflammatory bone pain. Thus, retrograde transport of NGF/TrkA and increased expression of some of the common nerve growth factor signaling molecules do not appear to be important for the maintenance of inflammatory bone pain. The findings are relevant to understand the basis of nerve growth factor sequestration and other therapies directed at nerve growth factor signaling, in managing pain in bone disease.

  8. [The skeletal regulating mechanisms and concepts in growth and development of cranial-facial bones and orthodontic treatment].

    PubMed

    Chen, Song; Chen, Yang-xi

    2009-10-01

    There are three kinds of mechanisms regulating the growth and development of skeletal tissue: Bone growth, bone modeling and bone remodeling. However, in the current orthodontics literature, there continues to be substantial confusion regarding the usage of the term "bone remodeling". This article reviews the historical causes for this semantics problem and explains the difference between bone modeling and remodeling, as well as the detailed skeletal regulating mechanisms in the growth and development of cranial-facial bones and orthodontic treatment. At last, this article suggests Chinese orthodontists use the terms "bone modeling" and "bone remodeling" more precisely to avoid scientific confusion and barriers to scientific exchange with other biomedical disciplines.

  9. [Mechanism of bone and cartilage growth during childhood and growth disorders].

    PubMed

    Ozono, Keiichi

    2008-05-01

    Longitudinal growth of bone depends on the proliferation and differentiation of chondrocytes located in growth plate. Recent advances in understanding the process of chondrocyte proliferation and differentiation reveal the local and systemic factors responsible for the process. SOX9, Ihh and FGFR3 are the former, growth hormone and thyroid hormone the latter. Achondroplasia, a representative entity of skeletal dysplasia is caused by the abnormality of FGFR3 and exhibits short stature. Hypofunction of growth hormone and thyroid hormone are associated with short stature as well.

  10. Effect of tibial dyschondroplasia on broiler growth and cancellous bone mechanical properties.

    PubMed

    Capps, S G

    1998-01-01

    The increased incidence of leg abnormalities, particularly tibial dyschondroplasia, in chickens could be related to changes in tibiotarsal cancellous bone properties. To explore this hypothesis, the relationship between lesion occurrence and various tibiotarsal growth parameters, and subchondral bone strength characteristics was investigated. A higher elastic modulus, meaning the cancellous bone was more rigid, was seen for tibiotarsal cancellous bone with lesions. Microfractures in cancellous bone, particularly in the medial growth plate region, may lead to overall bone conformation changes and therefore to lameness.

  11. Microarchitecture, but Not Bone Mechanical Properties, Is Rescued with Growth Hormone Treatment in a Mouse Model of Growth Hormone Deficiency

    PubMed Central

    Kristensen, Erika; Hallgrímsson, Benedikt; Morck, Douglas W.; Boyd, Steven K.

    2012-01-01

    Growth hormone (GH) deficiency is related to an increased fracture risk although it is not clear if this is due to compromised bone quality or a small bone size. We investigated the relationship between bone macrostructure, microarchitecture and mechanical properties in a GH-deficient (GHD) mouse model undergoing GH treatment commencing at an early (prepubertal) or late (postpubertal) time point. Microcomputed tomography images of the femur and L4 vertebra were obtained to quantify macrostructure and vertebral trabecular microarchitecture, and mechanical properties were determined using finite element analyses. In the GHD animals, bone macrostructure was 25 to 43% smaller as compared to the GH-sufficient (GHS) controls (P < 0.001). GHD animals had 20% and 19% reductions in bone volume ratio (BV/TV) and trabecular thickness (Tb.Th), respectively. Whole bone mechanical properties of the GHD mice were lower at the femur and vertebra (67% and 45% resp.) than the GHS controls (P < 0.001). Both early and late GH treatment partially recovered the bone macrostructure (15 to 32 % smaller than GHS controls) and the whole bone mechanical properties (24 to 43% larger than GHD animals) although there remained a sustained 27–52% net deficit compared to normal mice (P < 0.05). Importantly, early treatment with GH led to a recovery of BV/TV and Tb.Th with a concomitant improvement of trabecular mechanical properties. Therefore, the results suggest that GH treatment should start early, and that measurements of microarchitecture should be considered in the management of GHD. PMID:22505889

  12. Mesenchymal stem cell growth on and mechanical properties of fibrin-based biomimetic bone scaffolds.

    PubMed

    Linsley, Chase S; Wu, Benjamin M; Tawil, Bill

    2016-12-01

    Using the microenvironment of healing bone tissue as inspiration, this study utilized fibrin hydrogels combined with collagen type I and calcium phosphate ceramics to create a biomimetic bone scaffold. The contribution each component had on the growth of mesenchymal stem cells (hMSC) was assessed, and changes in the scaffold's mechanical properties were measured by indentation testing. The results show cell growth was greatest in scaffolds with lower concentrations of fibrinogen complex and followed a similar trend with the addition of collagen. However, cell growth was greatest in fibrin scaffolds with high concentrations of fibrinogen complex when combined with hydroxyapatite-β-tricalcium phosphate. The fibrin scaffold's stiffness does not significantly change over time, but the addition of collagen to scaffolds with low concentrations of fibrinogen complex had significant increases in stiffness by day 14. These results demonstrate that hMSC do not rapidly degrade fibrin and fibrin-collagen scaffolds in vitro. The data reported here can aid in the design and fabrication of fibrin-based engineered tissues and cell delivery vehicles that promote hMSC growth and viability as well as meet the mechanical requirements of native tissues. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2945-2953, 2016.

  13. Carcass composition, bone mechanical properties, and meat quality traits in relation to growth rate in rabbits.

    PubMed

    Gondret, F; Larzul, C; Combes, S; de Rochambeau, H

    2005-07-01

    The objective of this study was to characterize correlated responses in carcass composition, bone mechanical properties, and meat quality indicators to divergent selection for growth rate. Rabbits from low (LOW) or high (HIGH) lines divergently selected over five generations on 63-d BW and a control group (CONT) were used. Rabbits were slaughtered at an average BW of 2,306 +/- 65 g, corresponding to 63, 58, or 52 d of age in LOW (n = 41), CONT (n = 43), and HIGH (n = 44) groups, respectively. Postweaning ADG and G:F increased (P < 0.001) in the order LOW < CONT < HIGH groups. The lengths of the tibia and femur in rabbit legs decreased (P < 0.001) with increasing growth rate. Tibia and femur bone intrinsic stiffness, as assessed by a three-point flexure test, followed the order (P < 0.001) of HIGH < CONT < LOW groups. At the same BW, HIGH rabbits and CONT rabbits showed many similarities for dressing percent, carcass composition, and color and chemical composition of muscles or meat parts. In contrast, carcass yield and the relative proportion of hind part were 3% greater (P < 0.01) in LOW rabbits than in CONT and HIGH rabbits. The meat-to-bone ratio in the hind leg was 11% greater (P < 0.001) in the LOW group compared with the CONT and HIGH groups. Yellow color index and moisture content in LM, a fast-twitch glycolytic muscle, were lower (P < 0.05) in LOW rabbits than in HIGH rabbits, but ultimate pH, WHC, and cooking loss did not differ between the two growth-selected lines. Ultimate pH in semitendinosus, a mixed slow- and fast-twitch oxidoglycolytic muscle, was less (P < 0.001) in HIGH rabbits than in CONT and LOW rabbits. However, lactate dehydrogenase and isocitrate dehydrogenase activities in this muscle (n = 21 per group), assessed at the time of slaughter as markers of glycolytic and oxidative capacities, respectively, did not differ among groups. Growth rate did not modify mean cross-sectional area and type frequency of myofibers in semitendinosus muscle

  14. 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.

  15. Excessive growth hormone expression in male GH transgenic mice adversely alters bone architecture and mechanical strength.

    PubMed

    Lim, S V; Marenzana, M; Hopkinson, M; List, E O; Kopchick, J J; Pereira, M; Javaheri, B; Roux, J P; Chavassieux, P; Korbonits, M; Chenu, C

    2015-04-01

    Patients with acromegaly have a higher prevalence of vertebral fractures despite normal bone mineral density (BMD), suggesting that GH overexpression has adverse effects on skeletal architecture and strength. We used giant bovine GH (bGH) transgenic mice to analyze the effects of high serum GH levels on BMD, architecture, and mechanical strength. Five-month-old hemizygous male bGH mice were compared with age- and sex-matched nontransgenic littermates controls (NT; n=16/group). Bone architecture and BMD were analyzed in tibia and lumbar vertebrae using microcomputed tomography. Femora were tested to failure using three-point bending and bone cellular activity determined by bone histomorphometry. bGH transgenic mice displayed significant increases in body weight and bone lengths. bGH tibia showed decreases in trabecular bone volume fraction, thickness, and number compared with NT ones, whereas trabecular pattern factor and structure model index were significantly increased, indicating deterioration in bone structure. Although cortical tissue perimeter was increased in transgenic mice, cortical thickness was reduced. bGH mice showed similar trabecular BMD but reduced trabecular thickness in lumbar vertebra relative to controls. Cortical BMD and thickness were significantly reduced in bGH lumbar vertebra. Mechanical testing of femora confirmed that bGH femora have decreased intrinsic mechanical properties compared with NT ones. Bone turnover is increased in favor of bone resorption in bGH tibia and vertebra compared with controls, and serum PTH levels is also enhanced in bGH mice. These data collectively suggest that high serum GH levels negatively affect bone architecture and quality at multiple skeletal sites.

  16. Influence of physiological effort of growth and chemical composition on antler bone mechanical properties.

    PubMed

    Landete-Castillejos, T; Currey, J D; Estevez, J A; Gaspar-López, E; Garcia, A; Gallego, L

    2007-11-01

    Antler is a good model to study bone biology both because it is accessible and because it grows and is shed every year. Previous studies have shown that chemical composition changes as the antler is grown, implying constraints in mineral availability and the physiological effort made to grow it. This study aimed at examining antler mechanical properties to assess whether they reflect physiological effort and whether they are associated with precise mineral bone composition rather than just ash content, which is usually the main factor affecting mechanical properties. We examined Young's modulus of elasticity (E), strength, and work to maximum load, as well as bone mineral composition, along the antler shaft. Then we compared trends between antlers from two populations: captive, well-fed, health-managed deer (n=15), and free-ranging deer with lower food quality and no health treatment (n=10). Greater E, strength and work were found for better fed and health managed deer. In addition, antler chemical composition of both populations differed in Na, Mg, K, Fe and Si, and marginally in Zn, but not in ash or Ca content. Significant and clear divergent trends in mechanical properties supporting greater physiological exhaustion in free-ranging deer were found for all mechanical variables. Detailed models showed that, in addition to ash content, independent factors extracted from principal component analyses on composition affected E and strength, but not work to maximum load. The results suggest that there is an association between bone chemical composition and mechanical properties independently of ash content.

  17. Growth and bone development.

    PubMed

    Cooper, Cyrus; Harvey, Nicholas; Javaid, Kassim; Hanson, Mark; Dennison, Elaine

    2008-01-01

    Osteoporosis is a major cause of morbidity and mortality through its association with age-related fractures. Although most effort in fracture prevention has been directed at retarding the rate of age-related bone loss, and reducing the frequency and severity of trauma among elderly people, evidence is growing that peak bone mass is an important contributor to bone strength during later life. The normal patterns of skeletal growth have been well characterized in cross-sectional and longitudinal studies. It has been confirmed that boys have higher bone mineral content, but not volumetric bone density, than girls. Furthermore, there is a dissociation between the peak velocities for height gain and bone mineral accrual, in both genders. Puberty is the period during which volumetric density appears to increase in both axial and appendicular sites. Many factors influence the accumulation of bone mineral during childhood and adolescence, including heredity, gender, diet, physical activity, endocrine status, and sporadic risk factors such as cigarette smoking. In addition to these modifiable factors during childhood, evidence has also accrued that fracture risk might be programmed during intrauterine life. Epidemiological studies have demonstrated a relationship between birthweight, weight in infancy, and adult bone mass. This appears to be mediated through modulation of the set-point for basal activity of pituitary-dependent endocrine systems such as the hypothalamicpituitary-adrenal and growth hormone/insulin-like growth factor-1 axes. Maternal smoking, diet (particularly vitamin D deficiency), and physical activity also appear to modulate bone mineral acquisition during intrauterine life; furthermore, both low birth size and poor childhood growth are directly linked to the later risk of hip fracture. The optimization of maternal nutrition and intrauterine growth should also be included within preventive strategies against osteoporotic fracture, albeit for future

  18. Magneto-mechanical bone growth stimulation by actuation of highly porous ferromagnetic fiber arrays

    NASA Astrophysics Data System (ADS)

    Markaki, Athina E.; Clyne, Trevor W.

    2005-02-01

    This work relates to porous material made by bonding together fibres of a magnetic material. When subjected to a magnetic field, the array deforms, with individual fibres becoming magnetised along their length and then tending to line up locally with the direction of the field. An investigation is presented into the concept that this deformation could induce beneficial strains in bone tissue network in the early stages of growth as it grows into the porous fibre array. An analytical model has been developed, based on the deflection of individual fibre segments (between joints) experiencing bending moments as a result of the induced magnetic dipole. The model has been validated via measurements made on simple fibre assemblies and random fibre arrays. Work has also been done on the deformation characteristics of random fibre arrays with a matrix filling the inter-fibre space. This has the effect of reducing the fibre deflections. The extent of this reduction, and an estimate of the maximum strains induced in the space-filling material, can be obtained using a simple force balance approach. Predictions indicate that in-growing bone tissue, with a stiffness of around 0.01-0.1 GPa, could be strained to beneficial levels (~1 millistrain), using magnetic field strengths in current diagnostic use (~1 Tesla), provided the fibre segment aspect ratio is at least about 10. Such material has a low Young"s modulus, but the overall stiffness of a prosthesis could be matched to that of cortical bone by using an integrated design involving a porous magneto-active layer bonded to a dense non-magnetic core.

  19. [Molecular mechanisms of bone calcification].

    PubMed

    Hoshi, Kazuto; Ozawa, Hidehiro

    2003-04-01

    Bone matrix consists mainly of hydroxyapatite and organics. The latter include various substances which interact with minerals. Osteoblasts secrete these organic substances and control crystal formation and growth of hydroxyapatite. The authors discuss the molecular mechanisms of calcification by focusing on the mineral/organic interaction.

  20. Mechanical Signaling for Bone Modeling and Remodeling

    PubMed Central

    Robling, Alexander G.; Turner, Charles H.

    2012-01-01

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

  1. Effect of dietary boron on growth performance, calcium and phosphorus metabolism, and bone mechanical properties in growing barrows.

    PubMed

    Armstrong, T A; Spears, J W

    2001-12-01

    An experiment was conducted to evaluate the effects of dietary boron (B) on growth performance, bone mechanical properties, and calcium (Ca) and phosphorus (P) metabolism in pigs. Thirty-six barrows were weaned at approximately 21 d of age and randomly assigned to receive one of three dietary treatments. Treatments consisted of 1) low-B basal diet (control), 2) basal + 5 mg B/kg diet, and 3) basal + 15 mg B/kg diet. Boron was supplemented as sodium borate. Barrows remained on their respective experimental diets throughout the nursery (35 d) and growing (30 d) phases of production. Blood samples were obtained from each barrow at the end of each phase. Following the 30-d growing period, eight barrows per treatment were transferred to stainless steel metabolism crates. Barrows had an adjustment period of 7 d, followed by a 7-d total collection of urine and feces. All barrows were fed at 90% of the previous ad libitum grower intake of the control animals during the adjustment and collection periods. At the end of the 7-d collection period, barrows were killed and femurs and fibulas were harvested for the assessment of bone mechanical properties. During the nursery phase, ADG and ADFI were increased (P < 0.05) by B supplementation. Boron did not affect (P = 0.34) feed efficiency during the nursery phase. During the growing phase, ADG and ADFI were increased (P < 0.05) by B supplementation. Boron did not affect (P = 0.97) feed efficiency during the growing phase. Boron did not affect (P = 0.44) bone ash percentage, but B supplementation increased (P < 0.05) bone ash P. Ultimate shear force of the fibula was increased (P < 0.05) in barrows supplemented with 15 mg B/kg diet compared to barrows fed diets supplemented with 5 mg B/kg diet. Apparent absorption and retention of Ca and P were not affected (P > 0.05) by dietary B. These data indicate that B supplementation to pigs can increase growth and bone strength without greatly affecting Ca and P metabolism.

  2. Bone metastasis: mechanisms and therapeutic opportunities

    PubMed Central

    Suva, Larry J.; Washam, Charity; Nicholas, Richard W.; Griffin, Robert J.

    2011-01-01

    The skeleton is one of the most common sites for metastatic cancer, and tumors arising from the breast or prostate possess an increased propensity to spread to this site. The growth of disseminated tumor cells in the skeleton requires tumor cells to inhabit the bone marrow, from which they stimulate local bone cell activity. Crosstalk between tumor cells and resident bone and bone marrow cells disrupts normal bone homeostasis, which leads to tumor growth in bone. The metastatic tumor cells have the ability to elicit responses that stimulate bone resorption, bone formation or both. The net result of these activities is profound skeletal destruction that can have dire consequences for patients. The molecular mechanisms that underlie these painful and often incurable consequences of tumor metastasis to bone are beginning to be recognized, and they represent promising new molecular targets for therapy. PMID:21200394

  3. Mechanisms influencing bone metabolism in chronic illness.

    PubMed

    Daci, E; van Cromphaut, S; Bouillon, R

    2002-01-01

    Bone is permanently renewed by the coordinated actions of bone-resorbing osteoclasts and bone-forming osteoblasts, which model and remodel bone structure during growth and adult life. The origin of osteoblastic cells (osteoblasts, osteocytes and bone-lining cells) differs from that of osteoclasts, but both cell groups communicate with each other using cytokines and cell-cell contact as to optimally maintain bone homeostasis. This communication in many ways uses the same players as the communication between cells in the immune system. During acute life-threatening illness massive bone resorption is the rule, while bone formation is suppressed. During chronic illness, the balance between bone formation and bone resorption also shifts, frequently resulting in decreased bone mass and density. Several factors may contribute to the osteopenia that accompanies chronic illness, the most important being undernutrition and low body weight, inflammatory cytokines, disorders of the neuroendocrine axis (growth hormone/IGF-1 disturbances, thyroid and gonadal deficiency), immobilization, and the long-term use of glucocorticoids. Their combined effects not only influence the generation and activity of all bone cells involved, but probably also regulate their life span by apoptotic mechanisms. Osteopenia or even osteoporosis and bone fragility, and before puberty also decreased linear growth and lower peak bone mass are therefore frequent consequences of chronic illnesses.

  4. Digital electronic bone growth stimulator

    SciTech Connect

    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.

  5. 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.

  6. Bone's early responses to mechanical loading differ in distinct genetic strains of chick: selection for enhanced growth reduces skeletal adaptability.

    PubMed

    Pitsillides, A A; Rawlinson, S C; Mosley, J R; Lanyon, L E

    1999-06-01

    genetically selected, high growth rate chicks may reflect a compromised ability to respond to load; and that load-induced increases in osteoblastic G6PD activity appear to be closely associated with increased rates of NO release. It is probable that similar genetically related differences in bones' responsiveness to mechanical loading occur in other species.

  7. Disturbances of bone growth and development

    SciTech Connect

    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 the 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.

  8. Mechanical bone growth stimulation by magnetic fibre networks obtained through a competent finite element technique.

    PubMed

    Bosbach, Wolfram A

    2017-09-11

    Fibre networks combined with a matrix material in their void phase make the design of novel and smart composite materials possible. Their application is of great interest in the field of advanced paper or as bioactive tissue engineering scaffolds. In the present study, we analyse the mechanical interaction between metallic fibre networks under magnetic actuation and a matrix material. Experimentally validated FE models are combined for that purpose in one joint simulation. High performance computing facilities are used. The resulting strain in the composite's matrix is not uniform across the sample volume. Instead we show that boundary conditions and proximity to the fibre structure strongly influence the local strain magnitude. An analytical model of local strain magnitude is derived. The strain magnitude of 0.001 which is of particular interest for bone growth stimulation is achievable by this assembly. In light of these findings, the investigated composite structure is suitable for creating and for regulating contactless a stress field which is to be imposed on the matrix material. Topics for future research will be the advanced modelling of the biological components and the potential medical utilisation.

  9. 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

  10. Biomimetic growth and substrate dependent mechanical properties of bone like apatite nucleated on Ti and magnetron sputtered TiO2 nanostructure

    NASA Astrophysics Data System (ADS)

    Sarma, Bimal K.; Das, Apurba; Barman, Pintu; Pal, Arup R.

    2016-04-01

    This report presents findings on biomimetic growth of hydroxyapatite (HAp) nanocrystals on Ti and sputtered TiO2 substrates. The possibility of TiO2 nanostructure as candidate materials for future biomedical applications has been explored through the comparison of microstructural and mechanical properties of bone like apatite grown on Ti and nano-TiO2 surfaces. Raman spectroscopy and x-ray diffraction studies reveal formation of carbonate apatite with apparent domain size in the nanoscale range. A better interaction at the nano-TiO2/nano-HAp interface due to higher interfacial area could promote the growth of bone like apatite. The crystal phases, crystallinity, and surface morphology of nano-TiO2 are considered as parameters to understand the nucleation and growth of apatite with different mechanical properties at the nanoscale. The methodology of x-ray line profile analysis encompasses deconvolution of merged peaks by preserving broadening due to nanosized HAp aggregates. The Young’s modulus of bone like apatite exhibits crystallographic directional dependence which suggests the presence of elastic anisotropy in bone like apatite. The lattice contraction in the c-direction is associated with the degree of carbonate substitution in the apatite lattice. The role of residual stress is critical for the lattice distortion of HAp deposited at physiological conditions of temperature and pH of human blood plasma. The ion concentration is crucial for the uniformity, crystallinity, and mechanical behaviour of the apatite.

  11. Histomorphometric, physical, and mechanical effects of spaceflight and insulin-like growth factor-I on rat long bones.

    PubMed

    Bateman, T A; Zimmerman, R J; Ayers, R A; Ferguson, V L; Chapes, S K; Simske, S J

    1998-12-01

    Previous experiments have shown that skeletal unloading resulting from exposure to microgravity induces osteopenia in rats. In maturing rats, this is primarily a function of reduced formation, rather than increased resorption. Insulin-like growth factor-I (IGF-I) stimulates bone formation by increasing collagen synthesis by osteoblasts. The ability of IGF-I to prevent osteopenia otherwise caused by spaceflight was investigated in 12 rats flown for 10 days aboard the Space Shuttle, STS-77. The effect IGF-I had on cortical bone metabolism was generally anabolic. For example, humerus periosteal bone formation increased a significant 37.6% for the spaceflight animals treated with IGF-I, whereas the ground controls increased 24.7%. This increase in humeral bone formation at the periosteum is a result of an increased percent mineralizing perimeter (%Min.Pm), rather than mineral apposition rate (MAR), for both spaceflight and ground control rats. However, IGF-I did inhibit humerus endocortical bone formation in both the spaceflight and ground control rats (38.1% and 39.2%, respectively) by limiting MAR. This effect was verified in a separate ground-based study. Similar histomorphometric results for spaceflight and ground control rats suggest that IGF-I effects occur during normal weight bearing and during spaceflight. Microhardness measurements of the newly formed bone indicate that the quality of the bone formed during IGF-I treatment or spaceflight was not adversely altered. Spaceflight did not consistently change the structural (force-deflection) properties of the femur or humerus when tested in three-point bending. IGF-I significantly increased femoral maximum and fracture strength.

  12. Genetic selection for fast growth generates bone architecture characterised by enhanced periosteal expansion and limited consolidation of the cortices but a diminution in the early responses to mechanical loading.

    PubMed

    Rawlinson, Simon C F; Murray, Dianne H; Mosley, John R; Wright, Chris D P; Bredl, John C; Saxon, Leanne K; Loveridge, Nigel; Leterrier, Christine; Constantin, Paul; Farquharson, Colin; Pitsillides, Andrew A

    2009-08-01

    Bone strength is, in part, dependent on a mechanical input that regulates the (re)modelling of skeletal elements to an appropriate size and architecture to resist fracture during habitual use. The rate of longitudinal bone growth in juveniles can also affect fracture incidence in adulthood, suggesting an influence of growth rate on later bone quality. We have compared the effects of fast and slow growth on bone strength and architecture in the tibiotarsi of embryonic and juvenile birds. The loading-related biochemical responses (intracellular G6PD activity and NO release) to mechanical load were also determined. Further, we have analysed the proliferation and differentiation characteristics of primary tibiotarsal osteoblasts from fast and slow-growing strains. We found that bones from chicks with divergent growth rates display equal resistance to applied loads, but weight-correction revealed that the bones from juvenile fast growth birds are weaker, with reduced stiffness and lower resistance to fracture. Primary osteoblasts from slow-growing juvenile birds proliferated more rapidly and had lower alkaline phosphatase activity. Bones from fast-growing embryonic chicks display rapid radial expansion and incomplete osteonal infilling but, importantly, lack mechanical responsiveness. These findings are further evidence that the ability to respond to mechanical inputs is crucial to adapt skeletal architecture to generate a functionally appropriate bone structure and that fast embryonic and juvenile growth rates may predispose bone to particular architectures with increased fragility in the adult.

  13. Interaction of Mechanical Load with Growth Hormone (GH) and Insulin-Like Growth Factor I (IGF-I) on Slow-Twitch Skeletal Muscle and Bone

    NASA Technical Reports Server (NTRS)

    Linderman, Jon K.; Gosselink, Kristin L.; Wang, Tommy J.; Mukku, Venkat R.; Grindeland, Richard E.

    1994-01-01

    growth of hindlimb bones in the absence of mechanical load.

  14. Interaction of Mechanical Load with Growth Hormone (GH) and Insulin-Like Growth Factor I (IGF-I) on Slow-Twitch Skeletal Muscle and Bone

    NASA Technical Reports Server (NTRS)

    Linderman, Jon K.; Gosselink, Kristin L.; Wang, Tommy J.; Mukku, Venkat R.; Grindeland, Richard E.

    1994-01-01

    growth of hindlimb bones in the absence of mechanical load.

  15. Nanoscale deformation mechanisms in bone.

    PubMed

    Gupta, Himadri S; Wagermaier, Wolfgang; Zickler, Gerald A; Raz-Ben Aroush, D; Funari, Sérgio S; Roschger, Paul; Wagner, H Daniel; Fratzl, Peter

    2005-10-01

    Deformation mechanisms in bone matrix at the nanoscale control its exceptional mechanical properties, but the detailed nature of these processes is as yet unknown. In situ tensile testing with synchrotron X-ray scattering allowed us to study directly and quantitatively the deformation mechanisms at the nanometer level. We find that bone deformation is not homogeneous but distributed between a tensile deformation of the fibrils and a shearing in the interfibrillar matrix between them.

  16. 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.

  17. [Mechanisms of bone calcification].

    PubMed

    Hoshi, Kazuto

    2007-10-01

    In bone calcification, hydroxyapatite is crystallized on the type I collagen-based organic matrices. It occurs in the extracellular spaces. Osteoblasts trigger and promote the crystallization by the biological control to the secretion of various matrix proteins or enzymes. The author overviews the mineral and organic environments in calcification areas and the roles of osteoblasts in mineral/organic interaction.

  18. The biomechanical basis of bone strength development during growth.

    PubMed

    Kontulainen, Saija A; Hughes, Julie M; Macdonald, Heather M; Johnston, James D

    2007-01-01

    Understanding the development of the material composition and structure of bone during growth, both key determinants of bone strength, and identifying factors that regulate the development of these properties are important for developing effective lifestyle interventions to optimize peak bone strength. New imaging technologies provide the ability to measure estimates of both the material composition and structure of bone, and thus, estimates of whole bone strength. During childhood and adolescence, bone structure is altered by growth in length and width, which is associated with increases in mass, and alterations in tissue density. These processes lead to a bone with an optimal size, shape, and architecture to withstand the normal physiological loads imposed on it. Longitudinal bone growth is the result of endochondral ossification, a process that continues throughout childhood and rapidly increases during the adolescent growth spurt. Along the shaft, long bones continually grow in width, thus improving the resistance to bending forces by depositing new bone on the periosteal surface with simultaneous resorption on the endocortical surface. Sexual dimorphism in periosteal bone formation and endosteal bone resorption result in sex-specific differences in adult bone conformation. Changes in linear and periosteal growth are closely tied to changes in bone mass, with approximately one quarter of adult total body bone mineral accrued during the 2 years around the adolescent growth spurt. These structural and material changes are under mechanical regulation and influenced by the hormonal environment. Overall, bones must continually adapt their geometry and mass to withstand loads from increases in bone length, muscle mass and external forces during growth. However, the tempo, timing, and extent of such adaptations are also closely regulated by several systemic hormones.

  19. Regulation of bone mass by growth hormone.

    PubMed

    Olney, Robert C

    2003-09-01

    Growth hormone (GH) is a peptide hormone secreted from the pituitary gland under the control of the hypothalamus. It has a many actions in the body, including regulating a number of metabolic pathways. Some, but not all, of its effects are mediated through insulin-like growth factor-I (IGF-I). Both GH and IGF-I play significant roles in the regulation of growth and bone metabolism and hence are regulators of bone mass. Bone mass increases steadily through childhood, peaking in the mid 20s. Subsequently, there is a slow decline that accelerates in late life. During childhood, the accumulation in bone mass is a combination of bone growth and bone remodeling. Bone remodeling is the process of new bone formation by osteoblasts and bone resorption by osteoclasts. GH directly and through IGF-I stimulates osteoblast proliferation and activity, promoting bone formation. It also stimulates osteoclast differentiation and activity, promoting bone resorption. The result is an increase in the overall rate of bone remodeling, with a net effect of bone accumulation. The absence of GH results in a reduced rate of bone remodeling and a gradual loss of bone mineral density. Bone growth primarily occurs at the epiphyseal growth plates and is the result of the proliferation and differentiation of chondrocytes. GH has direct effects on these chondrocytes, but primarily regulates this function through IGF-I, which stimulates the proliferation of and matrix production by these cells. GH deficiency severely limits bone growth and hence the accumulation of bone mass. GH deficiency is not an uncommon complication in oncology and has long-term effects on bone health.

  20. Mechanism of Shortened Bones in Mucopolysaccharidosis VII

    PubMed Central

    Metcalf, Jason A.; Zhang, Yanming; Hilton, Matthew J.; Long, Fanxin; Ponder, Katherine P.

    2009-01-01

    Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease in which deficiency in β-glucuronidase results in glycosaminoglycan (GAG) accumulation in and around cells, causing shortened long bones through mechanisms that remain largely unclear. We demonstrate here that MPS VII mice accumulate massive amounts of the GAG chondroitin-4-sulfate (C4S) in their growth plates, the cartilaginous region near the ends of long bones responsible for growth. MPS VII mice also have only 60% of the normal number of chondrocytes in the growth plate and 55% of normal chondrocyte proliferation at 3 weeks of age. We hypothesized that this reduction in proliferation was due to C4S-mediated overactivation of fibroblast growth factor receptor 3 (FGFR3). However, MPS VII mice that were FGFR3-deficient still had shortened bones, suggesting that FGFR3 is not required for the bone defect. Further study revealed that MPS VII growth plates had reduced tyrosine phosphorylation of STAT3, a pro-proliferative transcription factor. This was accompanied by a decrease in expression of leukemia inhibitory factor (LIF) and other interleukin 6 family cytokines, and a reduction in phosphorylated tyrosine kinase 2 (TYK2), Janus kinase 1 (JAK1), and JAK2, known activators of STAT3 phosphorylation. Intriguingly, loss of function mutations in LIF and its receptor leads to shortened bones. This suggests that accumulation of C4S in the growth plate leads to reduced expression of LIF and reduced STAT3-tyrosine phosphorylation, which results in reduced chondrocyte proliferation and ultimately shortened bones. PMID:19375967

  1. Mechanism of shortened bones in mucopolysaccharidosis VII.

    PubMed

    Metcalf, Jason A; Zhang, Yanming; Hilton, Matthew J; Long, Fanxin; Ponder, Katherine P

    2009-07-01

    Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease in which deficiency in beta-glucuronidase results in glycosaminoglycan (GAG) accumulation in and around cells, causing shortened long bones through mechanisms that remain largely unclear. We demonstrate here that MPS VII mice accumulate massive amounts of the GAG chondroitin-4-sulfate (C4S) in their growth plates, the cartilaginous region near the ends of long bones responsible for growth. MPS VII mice also have only 60% of the normal number of chondrocytes in the growth plate and 55% of normal chondrocyte proliferation at 3weeks of age. We hypothesized that this reduction in proliferation was due to C4S-mediated overactivation of fibroblast growth factor receptor 3 (FGFR3). However, MPS VII mice that were FGFR3-deficient still had shortened bones, suggesting that FGFR3 is not required for the bone defect. Further study revealed that MPS VII growth plates had reduced tyrosine phosphorylation of STAT3, a pro-proliferative transcription factor. This was accompanied by a decrease in expression of leukemia inhibitory factor (LIF) and other interleukin 6 family cytokines, and a reduction in phosphorylated tyrosine kinase 2 (TYK2), Janus kinase 1 (JAK1), and JAK2, known activators of STAT3 phosphorylation. Intriguingly, loss of function mutations in LIF and its receptor leads to shortened bones. This suggests that accumulation of C4S in the growth plate leads to reduced expression of LIF and reduced STAT3 tyrosine phosphorylation, which results in reduced chondrocyte proliferation and ultimately shortened bones.

  2. The role of pressurized fluid in subchondral bone cyst growth.

    PubMed

    Cox, L G E; Lagemaat, M W; van Donkelaar, C C; van Rietbergen, B; Reilingh, M L; Blankevoort, L; van Dijk, C N; Ito, K

    2011-10-01

    Pressurized fluid has been proposed to play an important role in subchondral bone cyst development. However, the exact mechanism remains speculative. We used an established computational mechanoregulated bone adaptation model to investigate two hypotheses: 1) pressurized fluid causes cyst growth through altered bone tissue loading conditions, 2) pressurized fluid causes cyst growth through osteocyte death. In a 2D finite element model of bone microarchitecture, a marrow cavity was filled with fluid to resemble a cyst. Subsequently, the fluid was pressurized, or osteocyte death was simulated, or both. Rather than increasing the load, which was the prevailing hypothesis, pressurized fluid decreased the load on the surrounding bone, thereby leading to net bone resorption and growth of the cavity. In this scenario an irregularly shaped cavity developed which became rounded and obtained a rim of sclerotic bone after removal of the pressurized fluid. This indicates that cyst development may occur in a step-wise manner. In the simulations of osteocyte death, cavity growth also occurred, and the cavity immediately obtained a rounded shape and a sclerotic rim. Combining both mechanisms increased the growth rate of the cavity. In conclusion, both stress-shielding by pressurized fluid, and osteocyte death may cause cyst growth. In vivo observations of pressurized cyst fluid, dead osteocytes, and different appearances of cysts similar to our simulation results support the idea that both mechanisms can simultaneously play a role in the development and growth of subchondral bone cysts. Copyright © 2011 Elsevier Inc. All rights reserved.

  3. Bone marrow macrophages support prostate cancer growth in bone

    PubMed Central

    Soki, Fabiana N.; Cho, Sun Wook; Kim, Yeo Won; Jones, Jacqueline D.; Park, Serk In; Koh, Amy J.; Entezami, Payam; Daignault-Newton, Stephanie; Pienta, Kenneth J.; Roca, Hernan; McCauley, Laurie K.

    2015-01-01

    Resident macrophages in bone play important roles in bone remodeling, repair, and hematopoietic stem cell maintenance, yet their role in skeletal metastasis remains under investigated. The purpose of this study was to determine the role of macrophages in prostate cancer skeletal metastasis, using two in vivo mouse models of conditional macrophage depletion. RM-1 syngeneic tumor growth was analyzed in an inducible macrophage (CSF-1 receptor positive cells) ablation model (MAFIA mice). There was a significant reduction in tumor growth in the tibiae of macrophage-ablated mice, compared with control non-ablated mice. Similar results were observed when macrophage ablation was performed using liposome-encapsulated clodronate and human PC-3 prostate cancer cells where tumor-bearing long bones had increased numbers of tumor associated-macrophages. Although tumors were consistently smaller in macrophage-depleted mice, paradoxical results of macrophage depletion on bone were observed. Histomorphometric and micro-CT analyses demonstrated that clodronate-treated mice had increased bone volume, while MAFIA mice had reduced bone volume. These results suggest that the effect of macrophage depletion on tumor growth was independent of its effect on bone responses and that macrophages in bone may be more important to tumor growth than the bone itself. In conclusion, resident macrophages play a pivotal role in prostate cancer growth in bone. PMID:26459393

  4. Bone marrow macrophages support prostate cancer growth in bone.

    PubMed

    Soki, Fabiana N; Cho, Sun Wook; Kim, Yeo Won; Jones, Jacqueline D; Park, Serk In; Koh, Amy J; Entezami, Payam; Daignault-Newton, Stephanie; Pienta, Kenneth J; Roca, Hernan; McCauley, Laurie K

    2015-11-03

    Resident macrophages in bone play important roles in bone remodeling, repair, and hematopoietic stem cell maintenance, yet their role in skeletal metastasis remains under investigated. The purpose of this study was to determine the role of macrophages in prostate cancer skeletal metastasis, using two in vivo mouse models of conditional macrophage depletion. RM-1 syngeneic tumor growth was analyzed in an inducible macrophage (CSF-1 receptor positive cells) ablation model (MAFIA mice). There was a significant reduction in tumor growth in the tibiae of macrophage-ablated mice, compared with control non-ablated mice. Similar results were observed when macrophage ablation was performed using liposome-encapsulated clodronate and human PC-3 prostate cancer cells where tumor-bearing long bones had increased numbers of tumor associated-macrophages. Although tumors were consistently smaller in macrophage-depleted mice, paradoxical results of macrophage depletion on bone were observed. Histomorphometric and micro-CT analyses demonstrated that clodronate-treated mice had increased bone volume, while MAFIA mice had reduced bone volume. These results suggest that the effect of macrophage depletion on tumor growth was independent of its effect on bone responses and that macrophages in bone may be more important to tumor growth than the bone itself. In conclusion, resident macrophages play a pivotal role in prostate cancer growth in bone.

  5. Endochondral bone growth, bone calcium accretion, and bone mineral density: how are they related?

    PubMed

    Wongdee, Kannikar; Krishnamra, Nateetip; Charoenphandhu, Narattaphol

    2012-07-01

    Endochondral bone growth in young growing mammals or adult mammals with persistent growth plates progresses from proliferation, maturation and hypertrophy of growth plate chondrocytes to mineralization of cartilaginous matrix to form an osseous tissue. This complex process is tightly regulated by a number of factors with different impacts, such as genetics, endocrine/paracrine factors [e.g., PTHrP, 1,25(OH)(2)D(3), IGF-1, FGFs, and prolactin], and nutritional status (e.g., dietary calcium and vitamin D). Despite a strong link between growth plate function and elongation of the long bone, little is known whether endochondral bone growth indeed determines bone calcium accretion, bone mineral density (BMD), and/or peak bone mass. Since the process ends with cartilaginous matrix calcification, an increase in endochondral bone growth typically leads to more calcium accretion in the primary spongiosa and thus higher BMD. However, in lactating rats with enhanced trabecular bone resorption, bone elongation is inversely correlated with BMD. Although BMD can be increased by factors that enhance endochondral bone growth, the endochondral bone growth itself is unlikely to be an important determinant of peak bone mass since it is strongly determined by genetics. Therefore, endochondral bone growth and bone elongation are associated with calcium accretion only in a particular subregion of the long bone, but do not necessarily predict BMD and peak bone mass.

  6. Digital electronic bone growth stimulator

    DOEpatents

    Kronberg, J.W.

    1993-01-01

    The present invention relates to the electrical treatment of biological tissue. In particular, the present invention discloses a device that produces discrete electrical pulse trains for treating osteoporosis and accelerating bone growth. According to its major aspects and broadly stated, the present invention consists of an electrical circuit configuration capable of generating Bassett-type waveforms shown with alternative signals provide for the treatment of either fractured bones or osteoporosis. The signal generator comprises a quartz clock, an oscillator circuit, a binary divider chain, and a plurality of simple, digital logic gates. Signals are delivered efficiently, with little or no distortion, and uniformly distributed throughout the area of injury. Perferably, power is furnished by widely available and inexpensive radio batteries, needing replacement only once in several days. The present invention can be affixed to a medical cast without a great increase in either weight or bulk. Also, the disclosed stimulator can be used to treat osteoporosis or to strengthen a healing bone after the cast has been removed by attaching the device to the patient`s skin or clothing.

  7. Inhibition of bone resorption and growth of breast cancer in the bone microenvironment.

    PubMed

    Buijs, Jeroen T; Que, Ivo; Löwik, Clemens W G M; Papapoulos, Socrates E; van der Pluijm, Gabri

    2009-02-01

    Breast cancer frequently metastasizes to bone, where tumor cells induce osteoclasts to locally destroy bone. During bone resorption, growth factors are locally released that may support bone metastatic growth. Differently from most other tissues, drugs that can limit local turnover, such as bisphosphonates and osteoprotegerin (OPG), are available for bone. We examined the hypothesis that inhibition of bone resorption by two different mechanisms may also affect the growth of cancer cells in bone. For this, we tested the effects of high doses of OPG and zoledronic acid (ZOL) on progression of MDA-231-B/Luc+ breast cancer cells in the bone microenvironment using whole body bioluminescent reporter imaging (BLI). Both treatments significantly inhibited the development of radiographically detectable osteolytic lesions. Histologic examination corroborated the radiographic findings, showing that both treatments preserved the integrity of bone trabeculae and prevented bone destruction (significantly higher trabecular bone volumes vs. vehicle). However, whereas practically no TRAcP-positive osteoclasts were observed in tibiae preparations of animals treated with Fc-OPG, TRAcP-positive osteoclasts were still present in the animals treated with ZOL. Intra-bone tumor burden was reduced with ZOL and Fc-OPG treatment. Although there appeared to be a trend for less overall total tumor burden upon treatment with both compounds, this was not significant as assessed by BLI and histomorphometric analysis due to the extramedullary growth of cancer cells which was not affected by these treatments. Collectively, anti-resorptive agents with different mechanisms of action - ZOL and OPG - significantly reduced cancer-induced osteolysis and intra-osseous tumor burden, but failed to restrain local tumor growth. However, interference with the bone micro-environmental growth support could still be of therapeutic relevance when given to patients early in the course of bone metastatic disease.

  8. The dynamics of bone structure development during pubertal growth.

    PubMed

    Rauch, F

    2012-03-01

    The pubertal growth spurt is a time of rapid changes in bone length, mass and structure, followed by the cessation of longitudinal growth. The two best studied anatomical areas in this respect are the metaphyses and the diaphyses of peripheral long bones. A model is presented here in which the speed of longitudinal growth and the resulting age gradient in metaphyseal bone are key factors in explaining the high incidence of distal radius fractures during puberty. As growth in length accelerates, the age of the bone structural elements at a given distance to the growth plate decreases, leaving less time for cortical thickening through trabecular coalescence. This leads to a discrepancy between stagnant metaphyseal bone strength and increasing mechanical requirements in the case of accidents. In comparison to the metaphysis, diaphyseal bone develops more in line with the increasing mechanical requirements, presumably because the bone formation rates needed for diaphyseal growth in width are only a fraction of the apposition rates in the metaphysis. It remains largely unexplored how local and systemic signals are integrated to achieve site-specific changes in bone structure.

  9. Mechanisms of gut microbiota-mediated bone remodeling.

    PubMed

    Yan, Jing; Takakura, Ayumi; Zandi-Nejad, Kambiz; Charles, Julia F

    2017-09-29

    The mechanisms underlying the systemic effects mediated by gut microbiota are under active investigation. In addition to local, direct effects of gut microbiota on the host, metabolic products from microbiota may act peripherally, reaching distal organs through the circulation. In our recent publication we demonstrated that gut microbiota influence bone remodeling distally, promoting both bone resorption and formation. We proposed that these effects are mediated, at least in part, by the induction of insulin like growth factor (IGF-1) by the microbiota metabolite short chain fatty acids (SCFA). Here we explore additional mechanisms by which microbial metabolites could directly or indirectly alter host bone remodeling. We discuss whether SCFA directly modulate bone resorption by their actions on osteoclasts, and test the possibility that serotonin is another gut microbiota derived long-distance mediator of effects on bone remodeling. A detailed understanding of the mechanisms of microbiota effect on bone remodeling could help establish potential therapeutic strategies to promote bone health.

  10. Short Anabolic Peptides for Bone Growth.

    PubMed

    Amso, Zaid; Cornish, Jillian; Brimble, Margaret A

    2016-07-01

    Loss of bone occurs in the age-related skeletal disorder, osteoporosis, leading to bone fragility and increased incidence of fractures, which are associated with enormous costs and substantial morbidity and mortality. Recent data indicate that osteoporotic fractures are more common than other diseases, which usually attract public attention (e.g., heart attack and breast cancer). The prevention and treatment of this skeletal disorder are therefore of paramount importance. Majority of osteoporosis medications restore skeletal balance by reducing osteoclastic activity, thereby reducing bone resorption. These agents, however, do not regenerate damaged bone tissue, leaving limited options for patients once bone loss has occurred. Recently, attention has turned to bone-anabolic agents. Such agents have the ability to increase bone mass and strength, potentially reversing structural damage. To date, only one bone-anabolic drug is available in the market. The discovery of more novel, cost-effective bone anabolic agents is therefore a priority to treat those suffering from this disabling condition. Short peptides offer an important alternative for the development of novel bone-anabolic agents given their high target binding specificity, which translates into potent activity with limited side effects. This review summarizes attempts in the identification of bone-anabolic peptides, and their development for promoting bone growth. © 2016 Wiley Periodicals, Inc.

  11. Effects of testosterone and growth hormone on the structural and mechanical properties of bone by micro-MRI in the distal tibia of men with hypopituitarism.

    PubMed

    Al Mukaddam, Mona; Rajapakse, Chamith S; Bhagat, Yusuf A; Wehrli, Felix W; Guo, Wensheng; Peachey, Helen; LeBeau, Shane O; Zemel, Babette S; Wang, Christina; Swerdloff, Ronald S; Kapoor, Shiv C; Snyder, Peter J

    2014-04-01

    Severe deficiencies of testosterone (T) and GH are associated with low bone mineral density (BMD) and increased fracture risk. Replacement of T in hypogonadal men improves several bone parameters. Replacement of GH in GH-deficient men improves BMD. Our objective was to determine whether T and GH treatment together improves the structural and mechanical parameters of bone more than T alone in men with hypopituitarism. This randomized, prospective, 2-year study included 32 men with severe deficiencies of T and GH due to panhypopituitarism. Subjects were randomized to receive T alone (n = 15) or T and GH (n = 17) for 2 years. We evaluated magnetic resonance microimaging-derived structural (bone volume fraction [BVF] and trabecular thickness) and mechanical (axial stiffness [AS], a measure of bone strength) properties of the distal tibia at baseline and after 1 and 2 years of treatment. Treatment with T and GH did not affect BVF, thickness, or AS differently from T alone. T treatment in all subjects for 2 years increased trabecular BVF by 9.6% (P < .0001), trabecular thickness by 2.6% (P < .001), and trabecular AS by 9.8% (P < .001). In contrast, testosterone treatment in all subjects significantly increased cortical thickness by 2.4% (P < .01) but decreased cortical BVF by -4.7% (P < .01) and cortical AS by -6.9% (P < .01). Combined T and GH treatment of men with hypopituitarism for 2 years did not improve the measured structural or mechanical parameters of the distal tibia more than T alone. However, testosterone significantly increased the structural and mechanical properties of trabecular bone but decreased most of these properties of cortical bone, illustrating the potential importance of assessing trabecular and cortical bone separately in future studies of the effect of testosterone on bone.

  12. Molecular Mechanisms That Contribute to Bone Marrow Pain

    PubMed Central

    Ivanusic, Jason J.

    2017-01-01

    Pain associated a bony pathology puts a significant burden on individuals, society, and the health-care systems worldwide. Pathology that involves the bone marrow activates sensory nerve terminal endings of peripheral bone marrow nociceptors, and is the likely trigger for pain. This review presents our current understanding of how bone marrow nociceptors are influenced by noxious stimuli presented in pathology associated with bone marrow. A number of ion channels and receptors are emerging as important modulators of the activity of peripheral bone marrow nociceptors. Nerve growth factor (NGF) sequestration has been trialed for the management of inflammatory bone pain (osteoarthritis), and there is significant evidence for interaction of NGF with bone marrow nociceptors. Activation of transient receptor potential cation channel subfamily V member 1 sensitizes bone marrow nociceptors and could contribute to increased sensitivity of patients to noxious stimuli in various bony pathologies. Acid-sensing ion channels sense changes to tissue pH in the bone marrow microenvironment and could be targeted to treat pathology that involves acidosis of the bone marrow. Piezo2 is a mechanically gated ion channel that has recently been reported to be expressed by most myelinated bone marrow nociceptors and might be a target for treatments directed against mechanically induced bone pain. These ion channels and receptors could be useful targets for the development of peripherally acting drugs to treat pain of bony origin. PMID:28955292

  13. Molecular Mechanisms That Contribute to Bone Marrow Pain.

    PubMed

    Ivanusic, Jason J

    2017-01-01

    Pain associated a bony pathology puts a significant burden on individuals, society, and the health-care systems worldwide. Pathology that involves the bone marrow activates sensory nerve terminal endings of peripheral bone marrow nociceptors, and is the likely trigger for pain. This review presents our current understanding of how bone marrow nociceptors are influenced by noxious stimuli presented in pathology associated with bone marrow. A number of ion channels and receptors are emerging as important modulators of the activity of peripheral bone marrow nociceptors. Nerve growth factor (NGF) sequestration has been trialed for the management of inflammatory bone pain (osteoarthritis), and there is significant evidence for interaction of NGF with bone marrow nociceptors. Activation of transient receptor potential cation channel subfamily V member 1 sensitizes bone marrow nociceptors and could contribute to increased sensitivity of patients to noxious stimuli in various bony pathologies. Acid-sensing ion channels sense changes to tissue pH in the bone marrow microenvironment and could be targeted to treat pathology that involves acidosis of the bone marrow. Piezo2 is a mechanically gated ion channel that has recently been reported to be expressed by most myelinated bone marrow nociceptors and might be a target for treatments directed against mechanically induced bone pain. These ion channels and receptors could be useful targets for the development of peripherally acting drugs to treat pain of bony origin.

  14. Consequences of Daily Administered Parathyroid Hormone on Myeloma Growth, Bone Disease, and Molecular Profiling of Whole Myelomatous Bone

    PubMed Central

    Pennisi, Angela; Ling, Wen; Li, Xin; Khan, Sharmin; Wang, Yuping; Barlogie, Bart; Shaughnessy, John D.; Yaccoby, Shmuel

    2010-01-01

    Background Induction of osteolytic bone lesions in multiple myeloma is caused by an uncoupling of osteoclastic bone resorption and osteoblastic bone formation. Current management of myeloma bone disease is limited to the use of antiresorptive agents such as bisphosphonates. Methodology/Principal Findings We tested the effects of daily administered parathyroid hormone (PTH) on bone disease and myeloma growth, and we investigated molecular mechanisms by analyzing gene expression profiles of unique myeloma cell lines and primary myeloma cells engrafted in SCID-rab and SCID-hu mouse models. PTH resulted in increased bone mineral density of myelomatous bones and reduced tumor burden, which reflected the dependence of primary myeloma cells on the bone marrow microenvironment. Treatment with PTH also increased bone mineral density of uninvolved murine bones in myelomatous hosts and bone mineral density of implanted human bones in nonmyelomatous hosts. In myelomatous bone, PTH markedly increased the number of osteoblasts and bone-formation parameters, and the number of osteoclasts was unaffected or moderately reduced. Pretreatment with PTH before injecting myeloma cells increased bone mineral density of the implanted bone and delayed tumor progression. Human global gene expression profiling of myelomatous bones from SCID-hu mice treated with PTH or saline revealed activation of multiple distinct pathways involved in bone formation and coupling; involvement of Wnt signaling was prominent. Treatment with PTH also downregulated markers typically expressed by osteoclasts and myeloma cells, and altered expression of genes that control oxidative stress and inflammation. PTH receptors were not expressed by myeloma cells, and PTH had no effect on myeloma cell growth in vitro. Conclusions/Significance We conclude that PTH-induced bone formation in myelomatous bones is mediated by activation of multiple signaling pathways involved in osteoblastogenesis and attenuated bone resorption

  15. Equine cortical bone exhibits rising R-curve fracture mechanics.

    PubMed

    Malik, C L; Stover, S M; Martin, R B; Gibeling, J C

    2003-02-01

    Previous studies of the fracture properties of cortical bone have suggested that the fracture toughness increases with crack length, which is indicative of rising R-curve behavior. Based on this indirect evidence and the similarity of bone to ceramic matrix composites, we hypothesized that bone would exhibit rising R-curve behavior in the transverse orientation and that the characteristics of the R-curves would be regionally dependent within the cortex due to variations in bone microstructure and toughening mechanisms. To test these hypotheses, we conducted R-curve experiments on specimens from equine third metacarpal bones using standard fracture mechanics testing methods. Compact type specimens from the dorsal and lateral regions in the middle of the diaphysis were oriented for crack propagation transverse to the longitudinal axis of the bone. The test results demonstrate that equine cortical bone exhibits rising R-curve behavior during transverse crack propagation as hypothesized. Statistical analyses of the crack growth initiation toughness, K0, the peak toughness, Kpeak, and the crack extension at peak toughness, deltaa, revealed significant regional differences in these characteristics. Specifically, the lateral cortex displayed higher crack growth initiation and peak toughnesses. The dorsal cortex exhibited greater crack extension at the peak of crack growth resistance. Scanning electron microscopy revealed osteon pullout on fracture surfaces from the dorsal cortex and but not in the lateral cortex. Taken together, the significant differences in R-curves and the SEM fractography indicate that the fracture mechanisms acting in equine cortical bone are regionally dependent.

  16. Residual bone growth after lengthening procedures.

    PubMed

    Journeau, Pierre; Lascombes, Pierre; Barbier, Dominique; Popkov, Dmitry

    2016-12-01

    The prognosis of limb length discrepancy is a major subject in paediatric orthopaedic surgery. The strategy depends on the prognosis and must be adapted to each patient. The residual growth of the lengthened segment often remains unknown, but is dependent on age, the percentage of lengthening and other factors. Using a large cohort of 150 children who had undergone bone lengthening procedures, we describe five patterns of post-intervention growth and identify factors that are favourable for normal residual growth. The criteria for bone lengthening which should maintain good residual growth are-bone age at lengthening should be before the pubertal growth spurt; the interval between two lengthening procedures should be over three years; the percentage of lengthening should be <30% of the initial segment; and no more than two lengthening procedures should be carried out during infancy.

  17. PROSPECT - GROWTH FACTOR CONTROL OF BONE MASS

    PubMed Central

    Canalis, Ernesto

    2010-01-01

    Bone formation is determined by the number and function of osteoblasts. Cell number is governed by factors that regulate the replication and differentiation of pre-osteoblasts and factors that regulate osteoblastic cell death. Cell function is controlled by signals acting on the mature osteoblast. Platelet derived and fibroblast growth factors are bone cell mitogens. Bone morphogenetic proteins (BMP) and Wnt induce the differentiation of mesenchymal cells toward osteoblasts, and insulin-like growth factor (IGF)-I stimulates the function of mature osteoblasts and prevents their death. The activity of BMP, Wnt and IGF-I is modulated by extracellular antagonists or binding proteins. Changes in growth factor synthesis and activity may play a role in the pathogenesis of selected forms of osteoporosis, and alterations in the expression or binding of the extracellular antagonists can be associated with changes in bone mass. Current approaches to bone anabolic therapies for osteoporosis include the administration of a growth factor, such as IGF-I, or the neutralization of an antagonist. Ideally, the targeting of an anabolic agent should be specific to bone to preclude non-skeletal unwanted side effects. Clinical trials are needed to determine the long-term effectiveness and safety of novel anabolic agents for the management of osteoporosis. PMID:19718659

  18. Molecular Mechanisms of Bone Metastasis.

    PubMed

    Weidle, Ulrich H; Birzele, Fabian; Kollmorgen, Gwendlyn; Rüger, Rüdiger

    2016-01-01

    Metastasis of breast and prostate cancer as well as multiple myeloma to the bones represents a significant medical problem. We herein discuss the molecular basis of the creation of pre-metastatic niches, the process of bone metastasis and the phenomenon of tumor dormancy in the bone marrow as well as its regulation. We describe the identification and validation of genes mediating bone metastasis by use of pre-clinical models of bone metastasis. Additionally, we discuss the role of small integrin binding N-linked glycoproteins (SIBLINGS), the chemokine/chemokine receptor CXCL12/CXCR4 pathway and the role of micro RNAs (miRNAs) as mediators of bone metastasis. Finally, we summarize clinical achievements for the treatment of bone metastases.

  19. 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.

  20. Mechanotransduction and the functional response of bone to mechanical strain

    NASA Technical Reports Server (NTRS)

    Duncan, R. L.; Turner, C. H.

    1995-01-01

    Mechanotransduction plays a crucial role in the physiology of many tissues including bone. Mechanical loading can inhibit bone resorption and increase bone formation in vivo. In bone, the process of mechanotransduction can be divided into four distinct steps: (1) mechanocoupling, (2) biochemical coupling, (3) transmission of signal, and (4) effector cell response. In mechanocoupling, mechanical loads in vivo cause deformations in bone that stretch bone cells within and lining the bone matrix and create fluid movement within the canaliculae of bone. Dynamic loading, which is associated with extracellular fluid flow and the creation of streaming potentials within bone, is most effective for stimulating new bone formation in vivo. Bone cells in vitro are stimulated to produce second messengers when exposed to fluid flow or mechanical stretch. In biochemical coupling, the possible mechanisms for the coupling of cell-level mechanical signals into intracellular biochemical signals include force transduction through the integrin-cytoskeleton-nuclear matrix structure, stretch-activated cation channels within the cell membrane, G protein-dependent pathways, and linkage between the cytoskeleton and the phospholipase C or phospholipase A pathways. The tight interaction of each of these pathways would suggest that the entire cell is a mechanosensor and there are many different pathways available for the transduction of a mechanical signal. In the transmission of signal, osteoblasts, osteocytes, and bone lining cells may act as sensors of mechanical signals and may communicate the signal through cell processes connected by gap junctions. These cells also produce paracrine factors that may signal osteoprogenitors to differentiate into osteoblasts and attach to the bone surface. Insulin-like growth factors and prostaglandins are possible candidates for intermediaries in signal transduction. In the effector cell response, the effects of mechanical loading are dependent upon the

  1. Mechanotransduction and the functional response of bone to mechanical strain

    NASA Technical Reports Server (NTRS)

    Duncan, R. L.; Turner, C. H.

    1995-01-01

    Mechanotransduction plays a crucial role in the physiology of many tissues including bone. Mechanical loading can inhibit bone resorption and increase bone formation in vivo. In bone, the process of mechanotransduction can be divided into four distinct steps: (1) mechanocoupling, (2) biochemical coupling, (3) transmission of signal, and (4) effector cell response. In mechanocoupling, mechanical loads in vivo cause deformations in bone that stretch bone cells within and lining the bone matrix and create fluid movement within the canaliculae of bone. Dynamic loading, which is associated with extracellular fluid flow and the creation of streaming potentials within bone, is most effective for stimulating new bone formation in vivo. Bone cells in vitro are stimulated to produce second messengers when exposed to fluid flow or mechanical stretch. In biochemical coupling, the possible mechanisms for the coupling of cell-level mechanical signals into intracellular biochemical signals include force transduction through the integrin-cytoskeleton-nuclear matrix structure, stretch-activated cation channels within the cell membrane, G protein-dependent pathways, and linkage between the cytoskeleton and the phospholipase C or phospholipase A pathways. The tight interaction of each of these pathways would suggest that the entire cell is a mechanosensor and there are many different pathways available for the transduction of a mechanical signal. In the transmission of signal, osteoblasts, osteocytes, and bone lining cells may act as sensors of mechanical signals and may communicate the signal through cell processes connected by gap junctions. These cells also produce paracrine factors that may signal osteoprogenitors to differentiate into osteoblasts and attach to the bone surface. Insulin-like growth factors and prostaglandins are possible candidates for intermediaries in signal transduction. In the effector cell response, the effects of mechanical loading are dependent upon the

  2. Spaceflight alters bone mechanics and modeling drifts in growing rats.

    PubMed

    Vajda, E G; Wronski, T J; Halloran, B P; Bachus, K N; Miller, S C

    2001-08-01

    Alterations in bone metabolism may be a particularly serious consequence of spaceflight and a major obstacle to long-term space exploration. The effects of spaceflight on bone mechanics are unclear. This study examined the effects of spaceflight on bone mechanics in a growing rat model during a 17-d mission aboard the space shuttle (STS-78). There were 18 rats that were divided into 3 experimental groups: flight rats (n = 6), ground-based control rats housed in an animal enclosure module (AEM, n = 6), and ground-based control rats housed in standard vivarium caging (n = 6). At the conclusion of the mission, rat femurs were tested in three-point bending followed by static and dynamic bone histomorphometry. Maximum stress was unaffected by spaceflight, but flexural rigidity was significantly decreased in flight animals. Much of the decrease appeared to be the result of decreases in tissue properties (elastic modulus) rather than structural changes within the bone. No significant differences in cortical bone mass or geometry were observed. In contrast, endocortical resorption was significantly decreased in flight rats accompanied by a nonsignificant decrease in periosteal bone formation, suggesting alterations in bone modeling drifts during spaceflight. For nearly all measured indices, ground-based AEM rats displayed values intermediate to flight and ground-based vivarium rats. Spaceflight can impair tissue properties in femoral cortical bone during growth without significant decreases in bone mass or geometry.

  3. Effects of Growth Hormone on Bone.

    PubMed

    Tritos, Nicholas A; Klibanski, Anne

    2016-01-01

    Describe the effects of growth hormone (GH) and insulin-like growth factor 1 (IGF-1) on the skeleton. The GH and IGF-1 axis has pleiotropic effects on the skeleton throughout the lifespan by influencing bone formation and resorption. GH deficiency leads to decreased bone turnover, delayed statural growth in children, low bone mass, and increased fracture risk in adults. GH replacement improves adult stature in GH deficient children, increases bone mineral density (BMD) in adults, and helps to optimize peak bone acquisition in patients, during the transition from adolescence to adulthood, who have persistent GH deficiency. Observational studies suggest that GH replacement may mitigate the excessive fracture risk associated with GH deficiency. Acromegaly, a state of GH and IGF-1 excess, is associated with increased bone turnover and decreased BMD in the lumbar spine observed in some studies, particularly in patients with hypogonadism. In addition, patients with acromegaly appear to be at an increased risk of morphometric-vertebral fractures, especially in the presence of active disease or concurrent hypogonadism. GH therapy also has beneficial effects on statural growth in several conditions characterized by GH insensitivity, including chronic renal failure, Turner syndrome, Prader-Willi syndrome, postnatal growth delay in patients with intrauterine growth retardation who do not demonstrate catchup growth, idiopathic short stature, short stature homeobox-containing (SHOX) gene mutations, and Noonan syndrome. GH and IGF-1 have important roles in skeletal physiology, and GH has an important therapeutic role in both GH deficiency and insensitivity states. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Platelet leukocyte gel facilitates bone substitute growth and autologous bone growth in a goat model.

    PubMed

    Everts, Peter A M; Delawi, Diyar; Mahoney, Christine Brown; van Erp, Albert; Overdevest, Eddy P; van Zundert, André; Knape, Johannes T A; Dhert, Wouter J A

    2010-02-01

    The aim of this study is to evaluate multiple conditions on the formation of bone growth in a goat model. We prepared from a unit of whole blood, platelet-leukocyte gel (PLG) to stimulate bone formation, based on the release of platelet growth factors. Two 3-compartment cages containing autologous bone, calcium phosphate, and trabecular metal were implanted onto goat spinal transverse processes. One cage was treated with PLG, prepared according to a standardized protocol. An untreated cage served as a control. To monitor bone formation overtime, fluorochrome markers were administered at 2, 3, and 5 weeks. Animals were sacrificed at 9 weeks after implantation. Bone growth in these 3-compartments cages was examined by histology and histomorphometry of nondecalcified sections using traditional light and epifluorescent microscopy. Compared to the control samples, bone growth in the PLG-treated autologous bone and calcium phosphate samples was significantly more. Fairly little bone growth was seen in PLG treated or untreated trabecular metal scaffolds. The results obtained from this goat model suggest a potential role for the application of autologous PLG during surgeries in which autologous bone grafts or calcium phosphate scaffolds are used.

  5. The influence of growth hormone on bone and adipose programming.

    PubMed

    Oberbauer, Anita M

    2014-01-01

    In utero growth hormone exposure is associated with distinct immediate growth responses and long term impacts on adult physiological parameters that include obesity, insulin resistance, and bone function. Growth hormone accelerates cellular proliferation in many tissues but is exemplified by increases in the number of cells within the cartilaginous growth plate of bone. In some cases growth hormone also potentiates differentiation as seen in the differentiation of adipocytes that rapidly fill upon withdrawal of growth hormone. Growth hormone provokes these changes either by direct action or through intermediaries such as insulin-like growth factor-I and other downstream effector molecules. The specific mechanism used by growth hormone in programming tissues is not yet fully characterized and likely represents a multipronged approach involving DNA modification, altered adult hormonal milieu, and the development of an augmented stem cell pool capable of future engagement as is seen in adipose accrual. This review summarizes findings of growth hormone's influence on in utero and neonatal cellular and metabolic profiles related to bone and adipose tissue.

  6. Exposure to omega-3 fatty acids at early age accelerate bone growth and improve bone quality.

    PubMed

    Koren, Netta; Simsa-Maziel, Stav; Shahar, Ron; Schwartz, Betty; Monsonego-Ornan, Efrat

    2014-06-01

    Omega-3 fatty acids (FAs) are essential nutritional components that must be obtained from foods. Increasing evidence validate that omega-3 FAs are beneficial for bone health, and several mechanisms have been suggested to mediate their effects on bone, including alterations in calcium absorption and urinary calcium loss, prostaglandin synthesis, lipid oxidation, osteoblast formation and inhibition of osteoclastogenesis. However, to date, there is scant information regarding the effect of omega-3 FAs on the developing skeleton during the rapid growth phase. In this study we aim to evaluate the effect of exposure to high levels of omega-3 FAs on bone development and quality during prenatal and early postnatal period. For this purpose, we used the fat-1 transgenic mice that have the ability to convert omega-6 to omega-3 fatty acids and the ATDC5 chondrogenic cell line as models. We show that exposure to high concentrations of omega-3 FAs at a young age accelerates bone growth through alterations of the growth plate, associated with increased chondrocyte proliferation and differentiation. We further propose that those effects are mediated by the receptors G-protein coupled receptor 120 (GPR120) and hepatic nuclear factor 4α, which are expressed by chondrocytes in culture. Additionally, using a combined study on the structural and mechanical bone parameters, we show that high omega-3 levels contribute to superior trabecular and cortical structure, as well as to stiffer bones and improved bone quality. Most interestingly, the fat-1 model allowed us to demonstrate the role of maternal high omega-3 concentration on bone growth during the gestation and postnatal period.

  7. Transforming growth factor alpha controls the transition from hypertrophic cartilage to bone during endochondral bone growth.

    PubMed

    Usmani, Shirine E; Pest, Michael A; Kim, Gunwoo; Ohora, Sara N; Qin, Ling; Beier, Frank

    2012-07-01

    We have recently identified transforming growth factor alpha (TGFα) as a novel growth factor involved in the joint disease osteoarthritis. The role of TGFα in normal cartilage and bone physiology however, has not been well defined. The objective of this study was to determine the role of TGFα in bone development through investigation of the Tgfa knockout mouse. The gross skeletons as well as the cartilage growth plates of Tgfa knockout mice and their control littermates were examined during several developmental stages ranging from newborn to ten weeks old. Knockout mice experienced skeletal growth retardation and expansion of the hypertrophic zone of the growth plate. These phenotypes were transient and spontaneously resolved by ten weeks of age. Tgfa knockout growth plates also had fewer osteoclasts along the cartilage/bone interface. Furthermore, knockout mice expressed less RUNX2, RANKL, and MMP13 mRNA in their cartilage growth plates than controls did. Tgfa knockout mice experience a delay in bone development, specifically the conversion of hypertrophic cartilage to true bone. The persistence of the hypertrophic zone of the growth plate appears to be mediated by a decrease in MMP13 and RANKL expression in hypertrophic chondrocytes and a resulting reduction in osteoclast recruitment. Overall, TGFα appears to be an important growth factor regulating the conversion of cartilage to bone during the process of endochondral ossification. Copyright © 2012 Elsevier Inc. All rights reserved.

  8. Bacterially induced bone destruction: mechanisms and misconceptions.

    PubMed Central

    Nair, S P; Meghji, S; Wilson, M; Reddi, K; White, P; Henderson, B

    1996-01-01

    Normal bone remodelling requires the coordinated regulation of the genesis and activity of osteoblast and osteoclast lineages. Any interference with these integrated cellular systems can result in dysregulation of remodelling with the consequent loss of bone matrix. Bacteria are important causes of bone pathology in common conditions such as periodontitis, dental cysts, bacterial arthritis, and osteomyelitis. It is now established that many of the bacteria implicated in bone diseases contain or produce molecules with potent effects on bone cells. Some of these molecules, such as components of the gram-positive cell walls (lipoteichoic acids), are weak stimulators of bone resorption in vitro, while others (PMT, cpn60) are as active as the most active mammalian osteolytic factors such as cytokines like IL-1 and TNF. The complexity of the integration of bone cell lineage development means that there are still question marks over the mechanism of action of many well-known bone-modulatory molecules such as parathyroid hormone. The key questions which must be asked of the now-recognized bacterial bone-modulatory molecules are as follows: (i) what cell population do they bind to, (ii) what is the nature of the receptor and postreceptor events, and (iii) is their action direct or dependent on the induction of secondary extracellular bone-modulating factors such as cytokines, eicosanoids, etc. In the case of LPS, this ubiquitous gram-negative polymer probably binds to osteoblasts or other cells in bone through the CD14 receptor and stimulates them to release cytokines and eicosanoids which then induce the recruitment and activation of osteoclasts. This explains the inhibitor effects of nonsteroidal and anticytokine agents on LPS-induced bone resorption. However, other bacterial factors such as the potent toxin PMT may act by blocking the normal maturation pathway of the osteoblast lineage, thus inducing dysregulation in the tightly regulated process of resorption and

  9. The fracture mechanics of human bone: influence of disease and treatment

    PubMed Central

    Zimmermann, Elizabeth A; Busse, Björn; Ritchie, Robert O

    2015-01-01

    Aging and bone diseases are associated with increased fracture risk. It is therefore pertinent to seek an understanding of the origins of such disease-related deterioration in bone's mechanical properties. The mechanical integrity of bone derives from its hierarchical structure, which in healthy tissue is able to resist complex physiological loading patterns and tolerate damage. Indeed, the mechanisms through which bone derives its mechanical properties make fracture mechanics an ideal framework to study bone's mechanical resistance, where crack-growth resistance curves give a measure of the intrinsic resistance to the initiation of cracks and the extrinsic resistance to the growth of cracks. Recent research on healthy cortical bone has demonstrated how this hierarchical structure can develop intrinsic toughness at the collagen fibril scale mainly through sliding and sacrificial bonding mechanisms that promote plasticity. Furthermore, the bone-matrix structure develops extrinsic toughness at much larger micrometer length-scales, where the structural features are large enough to resist crack growth through crack-tip shielding mechanisms. Although healthy bone tissue can generally resist physiological loading environments, certain conditions such as aging and disease can significantly increase fracture risk. In simple terms, the reduced mechanical integrity originates from alterations to the hierarchical structure. Here, we review how human cortical bone resists fracture in healthy bone and how changes to the bone structure due to aging, osteoporosis, vitamin D deficiency and Paget's disease can affect the mechanical integrity of bone tissue. PMID:26380080

  10. The fracture properties and toughening mechanisms of bone and dentin

    NASA Astrophysics Data System (ADS)

    Koester, Kurt John

    The mechanical properties of bone and dentin and in particular their fracture properties, are the subject of intense research. The relevance of these properties is increasing as our population ages and fracture incidence impacts the lives of a greater portion of the population. A robust framework is needed to understand the fracture properties of bone and dentin to guide researchers as they attempt to characterize the effects of aging, disease, and pharmaceutical treatments on the properties of these mineralized tissues. In the present work, this framework is provided and applied to human bone, human dentin, and animal bone. In situ electron microscopy was also used to identify the salient toughening mechanisms in bone and dentin. It was found that bone and dentin are extrinsically toughened materials and consequently their fracture properties are best characterized utilizing a crack-growth resistance approach. A description of the different mechanical measurements commonly employed when using small animal models (rats and mice) to evaluate the influence of drug therapies on bone fragility is provided. A study where these properties were measured for a large population of wild-type rats and mice was also conducted. Given my findings, it was determined that for the most complete understanding of small animal bone it was necessary to measure strength and toughness. Strength measurements probe the flaw distribution and toughness measurements to evaluate the resistance to facture in the presence of a single dominant worst-case flaw.

  11. 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.

  12. Nutrition and bone growth and development.

    PubMed

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

    2006-11-01

    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.

  13. Growth Plate Mechanics and Mechanobiology. A Survey of Present Understanding

    PubMed Central

    VILLEMURE, Isabelle; STOKES, Ian A.F.

    2009-01-01

    The longitudinal growth of long bones occurs in growth plates where chondrocytes synthesize cartilage that is subsequently ossified. Altered growth and subsequent deformity resulting from abnormal mechanical loading is often referred to as mechanical modulation of bone growth. This phenomenon has key implications in the progression of infant and juvenile musculoskeletal deformities, such as adolescent idiopathic scoliosis, hyperkyphosis, genus varus/valgus, tibia vara/valga, as well as neuromuscular diseases and clinical management of these deformities is often directed at modifying the mechanical environment of affected bones. However, there is limited quantitative and physiological understanding of how bone growth is regulated in response to mechanical loading. This review of published work addresses the state of knowledge concerning key questions about the mechanisms underlying biomechanical modulation of bone growth. The longitudinal growth of bones is apparently controlled by modifying the numbers of growth plate chondrocytes in the proliferative zone, their rate of proliferation, the amount of chondrocytic hypertrophy and the controlled synthesis and degradation of matrix throughout the growth plate. These variables may be modulated to produce a change in growth rate in the presence of sustained or cyclic mechanical load. Tissue and cellular deformations involved in the transduction of mechanical stimuli depend on the growth plate tissue material properties that are highly anisotropic, time-dependent, and that differ in different zones of the growth plate and with developmental stages. There is little information about the effects of time-varying changes in volume, water content, osmolarity of matrix, etc. on differentiation, maturation and metabolic activity of chondrocytes. Also, the effects of shear forces and torsion on the growth plate are incompletely characterized. Future work on growth plate mechanobiology should distinguish between changes in the

  14. Growth plate mechanics and mechanobiology. A survey of present understanding.

    PubMed

    Villemure, Isabelle; Stokes, Ian A F

    2009-08-25

    The longitudinal growth of long bones occurs in growth plates where chondrocytes synthesize cartilage that is subsequently ossified. Altered growth and subsequent deformity resulting from abnormal mechanical loading is often referred to as mechanical modulation of bone growth. This phenomenon has key implications in the progression of infant and juvenile musculoskeletal deformities, such as adolescent idiopathic scoliosis, hyperkyphosis, genu varus/valgus and tibia vara/valga, as well as neuromuscular diseases. Clinical management of these deformities is often directed at modifying the mechanical environment of affected bones. However, there is limited quantitative and physiological understanding of how bone growth is regulated in response to mechanical loading. This review of published work addresses the state of knowledge concerning key questions about mechanisms underlying biomechanical modulation of bone growth. The longitudinal growth of bones is apparently controlled by modifying the numbers of growth plate chondrocytes in the proliferative zone, their rate of proliferation, the amount of chondrocytic hypertrophy and the controlled synthesis and degradation of matrix throughout the growth plate. These variables may be modulated to produce a change in growth rate in the presence of sustained or cyclic mechanical load. Tissue and cellular deformations involved in the transduction of mechanical stimuli depend on the growth plate tissue material properties that are highly anisotropic, time-dependent, and that differ in different zones of the growth plate and with developmental stages. There is little information about the effects of time-varying changes in volume, water content, osmolarity of matrix, etc. on differentiation, maturation and metabolic activity of chondrocytes. Also, the effects of shear forces and torsion on the growth plate are incompletely characterized. Future work on growth plate mechanobiology should distinguish between changes in the

  15. FGF signalling regulates bone growth through autophagy.

    PubMed

    Cinque, Laura; Forrester, Alison; Bartolomeo, Rosa; Svelto, Maria; Venditti, Rossella; Montefusco, Sandro; Polishchuk, Elena; Nusco, Edoardo; Rossi, Antonio; Medina, Diego L; Polishchuk, Roman; De Matteis, Maria Antonietta; Settembre, Carmine

    2015-12-10

    Skeletal growth relies on both biosynthetic and catabolic processes. While the role of the former is clearly established, how the latter contributes to growth-promoting pathways is less understood. Macroautophagy, hereafter referred to as autophagy, is a catabolic process that plays a fundamental part in tissue homeostasis. We investigated the role of autophagy during bone growth, which is mediated by chondrocyte rate of proliferation, hypertrophic differentiation and extracellular matrix (ECM) deposition in growth plates. Here we show that autophagy is induced in growth-plate chondrocytes during post-natal development and regulates the secretion of type II collagen (Col2), the major component of cartilage ECM. Mice lacking the autophagy related gene 7 (Atg7) in chondrocytes experience endoplasmic reticulum storage of type II procollagen (PC2) and defective formation of the Col2 fibrillary network in the ECM. Surprisingly, post-natal induction of chondrocyte autophagy is mediated by the growth factor FGF18 through FGFR4 and JNK-dependent activation of the autophagy initiation complex VPS34-beclin-1. Autophagy is completely suppressed in growth plates from Fgf18(-/-) embryos, while Fgf18(+/-) heterozygous and Fgfr4(-/-) mice fail to induce autophagy during post-natal development and show decreased Col2 levels in the growth plate. Strikingly, the Fgf18(+/-) and Fgfr4(-/-) phenotypes can be rescued in vivo by pharmacological activation of autophagy, pointing to autophagy as a novel effector of FGF signalling in bone. These data demonstrate that autophagy is a developmentally regulated process necessary for bone growth, and identify FGF signalling as a crucial regulator of autophagy in chondrocytes.

  16. Molecular mechanisms of bone formation in spondyloarthritis.

    PubMed

    González-Chávez, Susana Aideé; Quiñonez-Flores, Celia María; Pacheco-Tena, César

    2016-07-01

    Spondyloarthritis comprise a group of inflammatory rheumatic diseases characterized by its association to HLA-B27 and the presence of arthritis and enthesitis. The pathogenesis involves both an inflammatory process and new bone formation, which eventually lead to ankylosis of the spine. To date, the intrinsic mechanisms of the pathogenic process have not been fully elucidated, and our progress is remarkable in the identification of therapeutic targets to achieve the control of the inflammatory process, yet our ability to inhibit the excessive bone formation is still insufficient. The study of new bone formation in spondyloarthritis has been mostly conducted in animal models of the disease and only few experiments have been done using human biopsies. The deregulation and overexpression of molecules involved in the osteogenesis process have been observed in bone cells, mesenchymal cells, and fibroblasts. The signaling associated to the excessive bone formation is congruent with those involved in the physiological processes of bone remodeling. Bone morphogenetic proteins and Wnt pathways have been found deregulated in this disease; however, the cause for uncontrolled stimulation remains unknown. Mechanical stress appears to play an important role in the pathological osteogenesis process; nevertheless, the association of other important factors, such as the presence of HLA-B27 and environmental factors, remains uncertain. The present review summarizes the experimental findings that describe the signaling pathways involved in the new bone formation process in spondyloarthritis in animal models and in human biopsies. The role of mechanical stress as the trigger of these pathways is also reviewed.

  17. Expression of CD31, Met/hepatocyte growth factor receptor and bone morphogenetic protein in bone metastasis of osteosarcoma.

    PubMed

    Arihiro, K; Inai, K

    2001-02-01

    The mechanism of metastasis of osteosarcoma cells to other bones has not yet fully been clarified. The purpose of the present study was to examine whether various factors involve the formation of osteosarcoma metastatic foci in other bones. Immunohistochemically, CD31 expression in osteosarcoma with no bone metastasis and osteosarcoma with bone metastasis was noted in 10 and 75% of cases, respectively. Met/hepatocyte growth factor (HGF) receptor expression in osteosarcoma with no bone metastasis and osteosarcoma with bone metastasis was noted in 90 and 25% of cases, respectively. Bone morphogenetic protein (BMP) expression in osteosarcoma with no bone metastasis and osteosarcoma with bone metastasis was noted in 20 and 75% of cases, respectively. Metastasis of osteosarcoma cells to other bones was significantly correlated with expression of BMP and CD31 and with no expression of Met/HGF receptor protein in osteosarcoma cells. In contrast, expression of insulin-like growth factor receptor in osteosarcoma cells did not correlate significantly with bone metastasis. These results suggest that formation of metastatic foci of osteosarcoma cells in other bones is regulated by CD31, which is associated with migration between endothelial cells, by BMP, which can induce and activate various mesenchymal cells affecting bone formation, and by escape of effect by HGF, which promotes differentiation of osteosarcoma cells.

  18. Mechanical signals as anabolic agents in bone.

    PubMed

    Ozcivici, Engin; Luu, Yen Kim; Adler, Ben; Qin, Yi-Xian; Rubin, Janet; Judex, Stefan; Rubin, Clinton T

    2010-01-01

    Aging and a sedentary lifestyle conspire to reduce bone quantity and quality, decrease muscle mass and strength, and undermine postural stability, culminating in an elevated risk of skeletal fracture. Concurrently, a marked reduction in the available bone-marrow-derived population of mesenchymal stem cells (MSCs) jeopardizes the regenerative potential that is critical to recovery from musculoskeletal injury and disease. A potential way to combat the deterioration involves harnessing the sensitivity of bone to mechanical signals, which is crucial in defining, maintaining and recovering bone mass. To effectively utilize mechanical signals in the clinic as a non-drug-based intervention for osteoporosis, it is essential to identify the components of the mechanical challenge that are critical to the anabolic process. Large, intense challenges to the skeleton are generally presumed to be the most osteogenic, but brief exposure to mechanical signals of high frequency and extremely low intensity, several orders of magnitude below those that arise during strenuous activity, have been shown to provide a significant anabolic stimulus to bone. Along with positively influencing osteoblast and osteocyte activity, these low-magnitude mechanical signals bias MSC differentiation towards osteoblastogenesis and away from adipogenesis. Mechanical targeting of the bone marrow stem-cell pool might, therefore, represent a novel, drug-free means of slowing the age-related decline of the musculoskeletal system.

  19. Mechanical signals as anabolic agents in bone

    PubMed Central

    Ozcivici, Engin; Luu, Yen Kim; Adler, Ben; Qin, Yi-Xian; Rubin, Janet; Judex, Stefan; Rubin, Clinton T.

    2013-01-01

    Aging and a sedentary lifestyle conspire to reduce bone quantity and quality, decrease muscle mass and strength, and undermine postural stability, culminating in an elevated risk of skeletal fracture. Concurrently, a marked reduction in the available bone-marrow-derived population of mesenchymal stem cells (MSCs) jeopardizes the regenerative potential that is critical to recovery from musculoskeletal injury and disease. A potential way to combat the deterioration involves harnessing the sensitivity of bone to mechanical signals, which is crucial in defining, maintaining and recovering bone mass. To effectively utilize mechanical signals in the clinic as a non-drug-based intervention for osteoporosis, it is essential to identify the components of the mechanical challenge that are critical to the anabolic process. Large, intense challenges to the skeleton are generally presumed to be the most osteogenic, but brief exposure to mechanical signals of high frequency and extremely low intensity, several orders of magnitude below those that arise during strenuous activity, have been shown to provide a significant anabolic stimulus to bone. Along with positively influencing osteoblast and osteocyte activity, these low-magnitude mechanical signals bias MSC differentiation towards osteoblastogenesis and away from adipogenesis. Mechanical targeting of the bone marrow stem-cell pool might, therefore, represent a novel, drug-free means of slowing the age-related decline of the musculoskeletal system. PMID:20046206

  20. 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

  1. 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

  2. Suppression of mammalian bone growth by membrane transport inhibitors.

    PubMed

    Loqman, Mohamad Y; Bush, Peter G; Farquharson, Colin; Hall, Andrew C

    2013-03-01

    Bone lengthening during skeletal growth is driven primarily by the controlled enlargement of growth plate (GP) chondrocytes. The cellular mechanisms are unclear but membrane transporters are probably involved. We investigated the role of the Na(+)/H(+) antiporter (NHE1) and anion exchanger (AE2) in bone lengthening and GP chondrocyte hypertrophy in Sprague-Dawley 7-day-old rat (P7) bone rudiments using the inhibitors EIPA (5-(N-ethyl-N-isopropyl)amiloride) and DIDS (4,4-diidothiocyano-2,2-stilbenedisulphonate), respectively. We have also determined cell-associated levels of these transporters along the GP using fluorescent immunohistochemistry (FIHC). Culture of bones with EIPA or DIDS inhibited rudiment growth (50% at approx. 250 and 25 µM, respectively). Both decreased the size of the hypertrophic zone (P < 0.05) but had no effect on overall length or cell density of the GP. In situ chondrocyte volume in proliferative and hypertrophic zones was decreased (P < 0.01) with EIPA but not DIDS. FIHC labeling of NHE1 was relatively high and constant along the GP but declined steeply in the late hypertrophic zone. In contrast, AE2 labeling was relatively low in proliferative zone cells but increased (P < 0.05) reaching a maximum in the early hypertrophic zone, before falling rapidly in the late hypertrophic zone suggesting AE2 might regulate the transition phase of chondrocytes between proliferative and hypertrophic zones. The inhibition of bone growth by EIPA may be due to a reduction to chondrocyte volume set-point. However the effect of DIDS was unclear but could result from inhibition of AE2 and blocking of the transition phase. These results demonstrate that NHE1 and AE2 are important regulators of bone growth. Copyright © 2012 Wiley Periodicals, Inc.

  3. In vivo dynamic bone growth modulation is less detrimental but as effective as static growth modulation.

    PubMed

    Valteau, Barthélémy; Grimard, Guy; Londono, Irène; Moldovan, Florina; Villemure, Isabelle

    2011-11-01

    Longitudinal bone growth, which occurs in growth plates, has important implications in pediatric orthopedics. Mechanical loads are essential to normal bone growth, but excessive loads can lead to progressive deformities. In order to compare the effects of in vivo static and dynamic loading on bone growth rate and growth plate histomorphometry, a finely controlled, normalized and equivalent compression was applied for a period of two weeks on the seventh caudal vertebra (Cd7) of rats during their pubertal growth spurt. The load was sustained (0.2MPa, 0.0Hz) in the static group and sinusoidally oscillating (0.2MPa±30%, 0.1Hz) in the dynamic group. Control and sham (operated but no load applied) groups were also studied. Cd7 growth rate was statistically reduced by 19% (p<0.001) for both static and dynamic groups when compared to the sham group. Loading effects on growth plate histomorphometry were greater in the static than dynamic groups with significant reductions (p<0.001) observed for growth plate thickness, proliferative chondrocyte number per column and hypertrophic chondrocyte height in the static group when compared to the sham group. Significant differences (p<0.01) were also found between static and dynamic groups for growth plate thickness and proliferative chondrocyte number per column while the difference nearly reached significance (p=0.014) for hypertrophic chondrocyte height. This in vivo study shows that static and dynamic loading are equally effective in modulating bone growth of rat caudal vertebrae. However, dynamic loading causes less detrimental effects on growth plate histomorphometry compared to static loading. This knowledge is greatly relevant for the improvement and/or development of new minimally invasive approaches, which are based on the local modulation of bone growth, to correct several progressive musculoskeletal deformities.

  4. Insulin-Like Growth Factor-Independent Effects of Growth Hormone on Growth Plate Chondrogenesis and Longitudinal Bone Growth.

    PubMed

    Wu, Shufang; Yang, Wei; De Luca, Francesco

    2015-07-01

    GH stimulates growth plate chondrogenesis and longitudinal bone growth directly at the growth plate. However, it is not clear yet whether these effects are entirely mediated by the local expression and action of IGF-1 and IGF-2. To determine whether GH has any IGF-independent growth-promoting effects, we generated (TamCart)Igf1r(flox/flox) mice. The systemic injection of tamoxifen in these mice postnatally resulted in the excision of the IGF-1 receptor (Igf1r) gene exclusively in the growth plate. (TamCart)Igf1r(flox/flox) tamoxifen-treated mice [knockout (KO) mice] and their Igf1r(flox/flox) control littermates (C mice) were injected for 4 weeks with GH. At the end of the 4-week period, the tibial growth and growth plate height of GH-treated KO mice were greater than those of untreated C or untreated KO mice. The systemic injection of GH increased the phosphorylation of Janus kinase 2 and signal transducer and activator of transcription 5B in the tibial growth plate of the C and KO mice. In addition, GH increased the mRNA expression of bone morphogenetic protein-2 and the mRNA expression and protein phosphorylation of nuclear factor-κB p65 in both C and KO mice. In cultured chondrocytes transfected with Igf1r small interfering RNA, the addition of GH in the culture medium significantly induced thymidine incorporation and collagen X mRNA expression. In conclusion, our findings demonstrate that GH can promote growth plate chondrogenesis and longitudinal bone growth directly at the growth plate, even when the local effects of IGF-1 and IGF-2 are prevented. Further studies are warranted to elucidate the intracellular molecular mechanisms mediating the IGF-independent, growth-promoting GH effects.

  5. HOW DO BONE CELLS SENSE MECHANICAL LOADING?

    PubMed Central

    Gusmão, Carlos Vinícius Buarque de; Belangero, William Dias

    2015-01-01

    Influenced by gravidity, bone tissue experiences stronger or lighter deformation according to the strength of the activities of daily life. Activities resulting in impact are particularly known to stimulate osteogenesis, thus reducing bone mass loss. Knowing how bone cells recognize the mechanical deformation imposed to the bone and trigger a series of biochemical chain reactions is of crucial importance for the development of therapeutic and preventive practices in orthopaedic activity. There is still a long way to run until we can understand the whole process, but current knowledge has shown a strong progression, with researches being conducted focused on therapies. For a mechanical sign to be transformed into a biological one (mechanotransduction), it must be amplified at cell level by the histological structure of bone tissue, producing tensions in cell membrane proteins (integrins) and changing their spatial structure. Such change activates bindings between these and the cytoskeleton, producing focal adhesions, where cytoplasmatic proteins are recruited to enable easier biochemical reactions. Focal adhesion kinase (FAK) is the most important one being self-activated when its structure is changed by integrins. Activated FAK triggers a cascade of reactions, resulting in the activation of ERK-1/2 and Akt, which are proteins that, together with FAK, regulate the production of bone mass. Osteocytes are believed to be the mechanosensor cells of the bone and to transmit the mechanical deformation to osteoblasts and osteoclasts. Ionic channels and gap junctions are considered as intercellular communication means for biochemical transmission of a mechanical stimulus. These events occur continuously on bone tissue and regulate bone remodeling. PMID:27022510

  6. The mechanism of shock wave treatment in bone healing

    NASA Astrophysics Data System (ADS)

    Wang, Ching-Jen

    2005-04-01

    The purpose of this study was to investigate the biological mechanism of shock wave treatment in bone healing in rabbits. A closed fracture of the right femur was created with a three-point bend method and the fracture was stabilized with an intra-medullary pin. Shock waves were applied one week after the fracture. Twenty-four New Zealand white rabbits were randomly divided into 3 groups. Group 1 (the control) received no shock waves; group 2 received low-energy and group 3 high-energy shock waves. The animals were sacrificed at 24 weeks, and a 5-cm segment of the femur bone including the callus was harvested. The specimens were studied with histomorphological examination, biomechanical analysis and immunohistochemical stains. The results showed that high-energy shock waves improved bone healing with significant increases in cortical bone formation and the number neovascularization in histomorphology, better bone strength and bone mass in biomechanics, and increased expressions of angiogenic growth markers including BMP-2, eNOS, VEGF and PCNA than the control and low-energy shock wave groups. The effect of shock wave treatment appears to be dose-dependent. In conclusion, high-energy shock waves promote bone healing associated with ingrowth of neovascularization and increased expressions of angiogenic growth factors.

  7. Transduction of mechanical strain in bone

    NASA Technical Reports Server (NTRS)

    Duncan, R. L.

    1995-01-01

    One physiologic consequence of extended periods of weightlessness is the rapid loss of bone mass associated with skeletal unloading. Conversely, mechanical loading has been shown to increase bone formation and stimulate osteoblastic function. The mechanisms underlying mechanotransduction, or how the osteoblast senses and converts biophysical stimuli into cellular responses has yet to be determined. For non-innervated mechanosensitive cells like the osteoblast, mechanotransduction can be divided into four distinct phases: 1) mechanocoupling, or the characteristics of the mechanical force applied to the osteoblast, 2) biochemical coupling, or the mechanism through which mechanical strain is transduced into a cellular biochemical signal, 3) transmission of signal from sensor to effector cell and 4) the effector cell response. This review examines the characteristics of the mechanical strain encountered by osteoblasts, possible biochemical coupling mechanisms, and how the osteoblast responds to mechanical strain. Differences in osteoblastic responses to mechanical strain are discussed in relation to the types of strain encountered and the possible transduction pathways involved.

  8. Transduction of mechanical strain in bone

    NASA Technical Reports Server (NTRS)

    Duncan, R. L.

    1995-01-01

    One physiologic consequence of extended periods of weightlessness is the rapid loss of bone mass associated with skeletal unloading. Conversely, mechanical loading has been shown to increase bone formation and stimulate osteoblastic function. The mechanisms underlying mechanotransduction, or how the osteoblast senses and converts biophysical stimuli into cellular responses has yet to be determined. For non-innervated mechanosensitive cells like the osteoblast, mechanotransduction can be divided into four distinct phases: 1) mechanocoupling, or the characteristics of the mechanical force applied to the osteoblast, 2) biochemical coupling, or the mechanism through which mechanical strain is transduced into a cellular biochemical signal, 3) transmission of signal from sensor to effector cell and 4) the effector cell response. This review examines the characteristics of the mechanical strain encountered by osteoblasts, possible biochemical coupling mechanisms, and how the osteoblast responds to mechanical strain. Differences in osteoblastic responses to mechanical strain are discussed in relation to the types of strain encountered and the possible transduction pathways involved.

  9. Mechanisms of age-related bone loss.

    PubMed

    Mosekilde, L

    2001-01-01

    The human skeleton is formed and modelled during childhood and youth through the influence of hormones and daily mechanical usage. Around the age of 20-25 years, the skeleton achieves its maximum mass and strength. Thereafter, and throughout adult life, bone is lost at an almost constant rate due to the dynamic bone turnover process: the remodelling process. During this process, small packets of bone are renewed by teams of bone cells coupled together in time and space. In an adult human skeleton there will be 1-2 million active remodelling sites at any time point. The vast number of turnover units combined with a slightly negative balance at the completion of each process leads to the age-related loss of bone mass mentioned above and, concomitantly, to loss of structural continuity and strength. The magnitude of this loss will be determined by hormonal factors, nutrition and mechanical usage. As a consequence of the remodelling process, the bone tissue of the skeleton will always be younger than the age of the individual. However, as a consequence of the remodelling process, osteopenia and osteoporotic fractures will also occur. In this article, the remodelling-induced changes in the human spine will be used as an example of ageing bone.

  10. Lactoferrin – A Novel Bone Growth Factor

    PubMed Central

    Naot, Dorit; Grey, Andrew; Reid, Ian R; Cornish, Jillian

    2005-01-01

    Lactoferrin is an iron-binding glycoprotein that belongs to the transferrin family. It is present in breast milk, in epithelial secretions, and in the secondary granules of neutrophils. In healthy subjects lactoferrin circulates at concentrations of 2–7 x 10−6 g/ml. Lactoferrin is a pleiotropic factor with potent antimicrobial and immunomodulatory activities. Recently, we have shown that lactoferrin can also promote bone growth. At physiological concentrations, lactoferrin potently stimulates the proliferation and differentiation of primary osteoblasts and also acts as a survival factor inhibiting apoptosis induced by serum withdrawal. Lactoferrin also affects osteoclast formation and, in murine bone marrow culture, lactoferrin potently inhibits osteoclastogenesis. In vivo, local injection of lactoferrin above the hemicalvaria of adult mice results in substantial increases in the dynamic histomorphometric indices of bone formation and bone area. The mitogenic effect of lactoferrin in osteoblast-like cells is mediated mainly through LRP1, a member of the family of low-density lipoprotein receptor-related proteins that are primarily known as endocytic receptors. Using confocal laser scanning microscopy, we demonstrated that fluorescently labeled lactoferrin is endocytosed and can be visualized in the cytoplasm of primary osteoblastic cells. Lactoferrin also induces activation of p42/44 MAPK signaling in primary osteoblasts, but the two pathways seem to operate independently as activation of MAPK signaling, but not endocytosis, is necessary for the mitogenic effect of lactoferrin. We conclude that lactoferrin may have a physiological role in bone growth and healing, and a potential therapeutic role as an anabolic factor in osteoporosis. PMID:16012127

  11. Determinants of the mechanical properties of bones

    NASA Technical Reports Server (NTRS)

    Martin, R. B.

    1991-01-01

    The mechanical properties of bones are governed by the same principles as those of man-made load-bearing structures, but the organism is able to adapt its bone structure to changes in skeletal loading. In this overview of the determinants of the strength and stiffness of bone, a continuum approach has been taken, in which the behavior of a macroscopic structure depends on its shape and size, and on the mechanical properties of the material within. The latter are assumed to depend on the composition (porosity and mineralization) and organization (trabecular or cortical bone architecture, collagen fiber orientation, fatigue damage) of the bone. The effects of each of these factors are reviewed. Also, the possible means of non-invasively estimating the strength or other mechanical properties of a bone are reviewed, including quantitative computed tomography, photon absorptiometry, and ultrasonic measurements. The best estimates of strength have been obtained with photon absorptiometry and computed tomography, which at best are capable of accounting for 90% of the strength variability in a simple in vitro test, but results from different laboratories have been highly variable.

  12. Bone and muscle: Interactions beyond mechanical.

    PubMed

    Brotto, Marco; Bonewald, Lynda

    2015-11-01

    The musculoskeletal system is significantly more complex than portrayed by traditional reductionist approaches that have focused on and studied the components of this system separately. While bone and skeletal muscle are the two largest tissues within this system, this system also includes tendons, ligaments, cartilage, joints and other connective tissues along with vascular and nervous tissues. Because the main function of this system is locomotion, the mechanical interaction among the major players of this system is essential for the many shapes and forms observed in vertebrates and even in invertebrates. Thus, it is logical that the mechanical coupling theories of musculoskeletal development exert a dominant influence on our understanding of the biology of the musculoskeletal system, because these relationships are relatively easy to observe, measure, and perturb. Certainly much less recognized is the molecular and biochemical interaction among the individual players of the musculoskeletal system. In this brief review article, we first introduce some of the key reasons why the mechanical coupling theory has dominated our view of bone-muscle interactions followed by summarizing evidence for the secretory nature of bones and muscles. Finally, a number of highly physiological questions that cannot be answered by the mechanical theories alone will be raised along with different lines of evidence that support both a genetic and a biochemical communication between bones and muscles. It is hoped that these discussions will stimulate new insights into this fertile and promising new way of defining the relationships between these closely related tissues. Understanding the cellular and molecular mechanisms responsible for biochemical communication between bone and muscle is important not only from a basic research perspective but also as a means to identify potential new therapies for bone and muscle diseases, especially for when they co-exist. This article is part of a

  13. Growth and differentiation of a long bone in limb development, repair and regeneration.

    PubMed

    Egawa, Shiro; Miura, Shinichirou; Yokoyama, Hitoshi; Endo, Tetsuya; Tamura, Koji

    2014-06-01

    Repair from traumatic bone fracture is a complex process that includes mechanisms of bone development and bone homeostasis. Thus, elucidation of the cellular/molecular basis of bone formation in skeletal development would provide valuable information on fracture repair and would lead to successful skeletal regeneration after limb amputation, which never occurs in mammals. Elucidation of the basis of epimorphic limb regeneration in amphibians would also provide insights into skeletal regeneration in mammals, since the epimorphic regeneration enables an amputated limb to re-develop the three-dimensional structure of bones. In the processes of bone development, repair and regeneration, growth of the bone is achieved through several events including not only cell proliferation but also aggregation of mesenchymal cells, enlargement of cells, deposition and accumulation of extracellular matrix, and bone remodeling. © 2014 The Authors Development, Growth & Differentiation © 2014 Japanese Society of Developmental Biologists.

  14. Mechanical Regulation of Signaling Pathways in Bone

    PubMed Central

    Thompson, William R.; Rubin, Clinton T.; Rubin, Janet

    2012-01-01

    A wide range of cell types depend on mechanically induced signals to enable appropriate physiological responses. The skeleton is particularly dependent on mechanical information to guide the resident cell population towards adaptation, maintenance and repair. Research at the organ, tissue, cell and molecular levels has improved our understanding of how the skeleton can recognize the functional environment, and how these challenges are translated into cellular information that can site-specifically alter phenotype. This review first considers those cells within the skeleton that are responsive to mechanical signals, including osteoblasts, osteoclasts, osteocytes and osteoprogenitors. This is discussed in light of a range of experimental approaches that can vary parameters such as strain, fluid shear stress, and pressure. The identity of mechanoreceptor candidates is approached, with consideration of integrins, pericellular tethers, focal adhesions, ion channels, cadherins, connexins, and the plasma membrane including caveolar and non-caveolar lipid rafts and their influence on integral signaling protein interactions. Several mechanically regulated intracellular signaling cascades are detailed including activation of kinases (Akt, MAPK, FAK), β-catenin, GTPases, and calcium signaling events. While the interaction of bone cells with their mechanical environment is complex, an understanding of mechanical regulation of bone signaling is crucial to understanding bone physiology, the etiology of diseases such as osteoporosis, and to the development of interventions to improve bone strength. PMID:22575727

  15. Bone and Muscle: Interactions beyond Mechanical

    PubMed Central

    Brotto, Marco

    2015-01-01

    The musculoskeletal system is significantly more complex than portrayed by traditional reductionist approaches that have focused on and studied the components of this system separately. While bone and skeletal muscle are the two largest tissues within this system, this system also includes tendons, ligaments, cartilage, joints and other connective tissue along with vascular and nervous tissue. Because the main function of this system is locomotion, the mechanical interaction among the major players of this system is essential for the many shapes and forms observed in vertebrates and even in invertebrates. Thus, it is logical that the mechanical coupling theories of musculoskeletal development exert a dominant influence on our understanding of the biology of the musculoskeletal system, because these relationships are relatively easy to observe, measure, and perturb. Certainly much less recognized is the molecular and biochemical interaction among the individual players of the musculoskeletal system. In this brief review article, we first introduce some of the key reasons why the mechanical coupling theory has dominated our view of bone-muscle interactions followed by summarizing evidence for the secretory nature of bones and muscles. Finally, a number of highly physiological questions that cannot be answered by the mechanical theories alone will be raised along with different lines of evidence that support both a genetic and a biochemical communication between bones and muscles. It is hoped that these discussions will stimulate new insights into this fertile and promising new way of defining the relationships between these closely related tissues. Understanding the cellular and molecular mechanisms responsible for biochemical communication between bone and muscle is important not only from a basic research perspective but also as a means to identify potential new therapies for bone and muscle diseases, especially for when they co-exist. PMID:26453500

  16. The mechanical integrity of in vivo engineered heterotopic bone.

    PubMed

    Warnke, Patrick H; Springer, Ingo N; Acil, Yahya; Julga, Gerrit; Wiltfang, Jörg; Ludwig, Klaus; Russo, Paul A J; Sherry, Eugene; Sivananthan, Sureshan; Hedderich, Jürgen; Terheyden, Hendrik

    2006-03-01

    Recent advances in tissue engineering have aroused interest in growth of heterotopic bone for the repair of skeletal defects. This study demonstrates an in vivo method in minipigs of engineering individual human-sized mandible replacements of heterotopic bone with a mechanical integrity similar to natural bone. Ten individualized mandible replacement scaffolds were created using computer-aided design (CAD) techniques. Five had a resorbable external scaffold made of polylactite mesh (test group 1) and five had had a non-resorbable external scaffold of titanium mesh (test group 2). The mesh scaffolds were loaded each with five BioOss blocks serving as internal scaffolds and 3.5 mg recombinant human Bone Morphogenetic Protein-7. The loaded mesh scaffolds were implanted into the latissimus dorsi muscles of five infant minipigs. After 6 weeks the mandible replacements were harvested. Core biopsy cylinders were taken from the replacements of both test groups and from the natural pig mandibles (control 1). Also, core biopsies from plain BioOss Blocks were gained (control 2). The core biopsy cylinders were loaded axially into a compression test device to evaluate the mechanical compression resistance. Additional specimen underwent histological examination. Both test groups resulted in successful bone induction with degrees of compression resistance [Test 1: 1.62 MPa (SD+/-0.73); Test 2: 1.51 MPa (SD+/-0.56)] statistically insignificant when compared to natural porcine mandibular bone [1.75 MPa (SD+/-0.69)]. This differed significantly from the much lower compression resistance seen in the unadulterated BioOss [0.92 MPa (SD+/-0.04)]. Following this, the in vivo engineered bone has a similar mechanical compression stability as natural bone.

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

    PubMed

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

    2015-01-01

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

  18. Vitamin D and bone health: potential mechanisms.

    PubMed

    Laird, Eamon; Ward, Mary; McSorley, Emeir; Strain, J J; Wallace, Julie

    2010-07-01

    Osteoporosis is associated with increased morbidity, mortality and significant economic and health costs. Vitamin D is a secosteriod hormone essential for calcium absorption and bone mineralization which is positively associated with bone mineral density [BMD]. It is well-established that prolonged and severe vitamin D deficiency leads to rickets in children and osteomalacia in adults. Sub-optimal vitamin D status has been reported in many populations but it is a particular concern in older people; thus there is clearly a need for effective strategies to optimise bone health. A number of recent studies have suggested that the role of vitamin D in preventing fractures may be via its mediating effects on muscle function (a defect in muscle function is one of the classical signs of rickets) and inflammation. Studies have demonstrated that vitamin D supplementation can improve muscle strength which in turn contributes to a decrease in incidence of falls, one of the largest contributors to fracture incidence. Osteoporosis is often considered to be an inflammatory condition and pro-inflammatory cytokines have been associated with increased bone metabolism. The immunoregulatory mechanisms of vitamin D may thus modulate the effect of these cytokines on bone health and subsequent fracture risk. Vitamin D, therefore, may influence fracture risk via a number of different mechanisms.

  19. 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.

  20. 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

  1. Heterogeneity of tumor cells in the bone microenvironment: Mechanisms and therapeutic targets for bone metastasis of prostate or breast cancer.

    PubMed

    Futakuchi, Mitsuru; Fukamachi, Katsumi; Suzui, Masumi

    2016-04-01

    Bone is the most common target organ of metastasis of prostate and breast cancers. This produces considerable morbidity due to skeletal-related events, SREs, including bone pain, hypercalcemia, pathologic fracture, and compression of the spinal cord. The mechanism of bone metastasis is complex and involves cooperative reciprocal interaction among tumor cells, osteoblasts, osteoclasts, and the mineralized bone matrix. The interaction between the metastatic tumor and bone stromal cells has been commonly referred to as the "vicious cycle". Tumor cells stimulate osteoblasts, which in turn stimulate osteoclasts through the secretion of cytokines such as the TNF family member receptor activator of nuclear κB ligand (RANKL). Activated osteoclasts degrade the bone matrix by producing strong acid and proteinases. Bone degradation by osteoclasts releases TGFβ and other growth factors stored in the bone matrix, that further stimulate tumor cells. Bone modifying agents, targeting osteoclast activity, such as bisphosphonate and RANKL antibodies are considered as the standard of care for reducing SREs of patients with bone metastatic diseases. These agents decrease osteoclast activity and delay worsening of skeletal pain and aggravation of bone metastatic diseases. While the management of SREs by these agents may improve patients' lives, this treatment does not address the specific issues of the patients with bone metastasis such as tumor dormancy, drug resistance, or improvement of survival. Here, we review the mechanisms of bone metastasis formation, tumor heterogeneity in the bone microenvironment, and conventional therapy for bone metastatic diseases and discuss the potential development of new therapies targeting tumor heterogeneity in the bone microenvironment.

  2. Long bone histology and growth patterns in ankylosaurs: implications for life history and evolution.

    PubMed

    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.

  3. 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

  4. [Mechanism of bone mass regulation by mechanical stress].

    PubMed

    Komori, Toshihisa

    2013-11-01

    Osteocytes establish an extensive intercellular and extracellular communication system via gap junction-coupled cell processes and canaliculi, through which cell processes pass throughout bone, and the communication system is extended to osteoblasts on the bone surface. The lacunocanalicular network formed by osteocytes is thought to be an ideal mechanosensory system and suitable for mechanotransduction, by which mechanical energy is converted into electrical and/or biochemical signals. The function of osteocytes cannot be estimated based on the events caused by osteocyte death, because apoptotic osteocytes are not phagocytosed, undergo secondary necrosis, and trigger a process of repair to replace the damaged bone. The analysis of the mice, in which both intercellular and extracellular communication systems are disturbed, shows that the osteocyte network mildly inhibits bone formation and mildly stimulates bone resorption in physiological condition. In unloaded condition, the functions of the osteocyte network are augmented, and it strongly inhibits bone formation and strongly stimulates bone resorption, at least in part, through the induction of Sost in osteocytes and Rankl in osteoblasts.

  5. Effect of rearing environment on bone growth of pullets.

    PubMed

    Regmi, P; Deland, T S; Steibel, J P; Robison, C I; Haut, R C; Orth, M W; Karcher, D M

    2015-03-01

    Alternative housing systems for laying hens provide mechanical loading and help reduce bone loss. Moreover, achieving greater peak bone mass during pullet phase can be crucial to prevent fractures in the production period. The aim of this study was to determine the housing system effects on bone quality of pullets. Tibiae and humeri of White Leghorn pullets reared in conventional cages (CCs) and a cage-free aviary (AV) system were studied. At 16 wk, 120 birds at random from each housing system were euthanized. Right and left tibiae and humeri were collected and further analyzed. Cortical bone density and thickness were measured using computed tomography. Periosteal and endosteal dimensions were measured at the fracture site during mechanical testing. At 4, 8, 12, and 16 wk, serum concentrations of osteocalcin and hydroxylysyl pyridinoline were analyzed as markers of bone formation and resorption. Cortical bone density was higher (P<0.05) in humeri of AV pullets, and tibiae were denser (P<0.05) for AV pullets in the distal section of the bone compared to CC pullets. Ash content was higher (P<0.05) in AV humeri with no difference in tibiae ash content. Tibiae and humeri of AV pullets had a thicker cortex than the CC pullets (P<0.05). Additionally, the tibiae and humeri of AV pullets had greater (P<0.05) second moment of areas than the CC pullets. While some bone material properties between groups were different (P<0.05), the differences were so small (<7%) that they likely have no clinical significance. Serum osteocalcin concentrations were not different between the treatments, but hydroxylsyl pyridinoline concentrations were higher in CC pullets at 12 wk compared to the AV pullets and the effect reversed at 16 wk (P<0.05). These findings indicate that tibiae and humeri respond differently to load bearing activities during growth. The improved load bearing capability and stiffness in bones of AV pullets were related to increased cross-sectional geometry. © The

  6. Mechanical basis of bone strength: influence of bone material, bone structure and muscle action

    PubMed Central

    Hart, N.H.; Nimphius, S.; Rantalainen, T.; Ireland, A.; Siafarikas, A.; Newton, R.U.

    2017-01-01

    This review summarises current understanding of how bone is sculpted through adaptive processes, designed to meet the mechanical challenges it faces in everyday life and athletic pursuits, serving as an update for clinicians, researchers and physical therapists. Bone’s ability to resist fracture under the large muscle and locomotory forces it experiences during movement and in falls or collisions is dependent on its established mechanical properties, determined by bone’s complex and multidimensional material and structural organisation. At all levels, bone is highly adaptive to habitual loading, regulating its structure according to components of its loading regime and mechanical environment, inclusive of strain magnitude, rate, frequency, distribution and deformation mode. Indeed, the greatest forces habitually applied to bone arise from muscular contractions, and the past two decades have seen substantial advances in our understanding of how these forces shape bone throughout life. Herein, we also highlight the limitations of in vivo methods to assess and understand bone collagen, and bone mineral at the material or tissue level. The inability to easily measure or closely regulate applied strain in humans is identified, limiting the translation of animal studies to human populations, and our exploration of how components of mechanical loading regimes influence mechanoadaptation. PMID:28860414

  7. Mechanism of cellular growth

    NASA Astrophysics Data System (ADS)

    David, Shaquan D.

    The purpose of this thesis is to investigate the effects of weak static and inhomogeneous magnetic fields on the growth and behavior of living organisms. We studied three common bacterial species of human flora in attempt to relate the effect of bacteria to human health. We measured the effects of various intensities of electromagnetic and randomly distributed fields to the physiological adaptation of the bacteria in relation to its environment. We also notice the different growth patterns of the three bacteria species when exposed to magnetic fields at a fixed temperature. The application of quantum electrodynamics describes the electrochemical interaction between the molecular bonding of the ions within the cell membrane and inorganic ions extracellular to the membrane. External magnetic fields contribute to the breaking and forming of covalent bonds to modify the time difference of DNA replication and metabolism of nutrients available for growth and sustainability. In short, we conclude that weak magnetic fields in a controlled environment affect the physiology and growth of cells.

  8. Parallel mechanisms suppress cochlear bone remodeling to protect hearing.

    PubMed

    Jáuregui, Emmanuel J; Akil, Omar; Acevedo, Claire; Hall-Glenn, Faith; Tsai, Betty S; Bale, Hrishikesh A; Liebenberg, Ellen; Humphrey, Mary Beth; Ritchie, Robert O; Lustig, Lawrence R; Alliston, Tamara

    2016-08-01

    Bone remodeling, a combination of bone resorption and formation, requires precise regulation of cellular and molecular signaling to maintain proper bone quality. Whereas osteoblasts deposit and osteoclasts resorb bone matrix, osteocytes both dynamically resorb and replace perilacunar bone matrix. Osteocytes secrete proteases like matrix metalloproteinase-13 (MMP13) to maintain the material quality of bone matrix through perilacunar remodeling (PLR). Deregulated bone remodeling impairs bone quality and can compromise hearing since the auditory transduction mechanism is within bone. Understanding the mechanisms regulating cochlear bone provides unique ways to assess bone quality independent of other aspects that contribute to bone mechanical behavior. Cochlear bone is singular in its regulation of remodeling by expressing high levels of osteoprotegerin. Since cochlear bone expresses a key PLR enzyme, MMP13, we examined whether cochlear bone relies on, or is protected from, osteocyte-mediated PLR to maintain hearing and bone quality using a mouse model lacking MMP13 (MMP13(-/-)). We investigated the canalicular network, collagen organization, lacunar volume via micro-computed tomography, and dynamic histomorphometry. Despite finding defects in these hallmarks of PLR in MMP13(-/-) long bones, cochlear bone revealed no differences in these markers, nor hearing loss as measured by auditory brainstem response (ABR) or distortion product oto-acoustic emissions (DPOAEs), between wild type and MMP13(-/-) mice. Dynamic histomorphometry revealed abundant PLR by tibial osteocytes, but near absence in cochlear bone. Cochlear suppression of PLR corresponds to repression of several key PLR genes in the cochlea relative to long bones. These data suggest that cochlear bone uniquely maintains bone quality and hearing independent of MMP13-mediated osteocytic PLR. Furthermore, the cochlea employs parallel mechanisms to inhibit remodeling by osteoclasts and osteoblasts, and by

  9. Trabecular Bone Mechanical Properties and Fractal Dimension

    NASA Technical Reports Server (NTRS)

    Hogan, Harry A.

    1996-01-01

    Countermeasures for reducing bone loss and muscle atrophy due to extended exposure to the microgravity environment of space are continuing to be developed and improved. An important component of this effort is finite element modeling of the lower extremity and spinal column. These models will permit analysis and evaluation specific to each individual and thereby provide more efficient and effective exercise protocols. Inflight countermeasures and post-flight rehabilitation can then be customized and targeted on a case-by-case basis. Recent Summer Faculty Fellowship participants have focused upon finite element mesh generation, muscle force estimation, and fractal calculations of trabecular bone microstructure. Methods have been developed for generating the three-dimensional geometry of the femur from serial section magnetic resonance images (MRI). The use of MRI as an imaging modality avoids excessive exposure to radiation associated with X-ray based methods. These images can also detect trabecular bone microstructure and architecture. The goal of the current research is to determine the degree to which the fractal dimension of trabecular architecture can be used to predict the mechanical properties of trabecular bone tissue. The elastic modulus and the ultimate strength (or strain) can then be estimated from non-invasive, non-radiating imaging and incorporated into the finite element models to more accurately represent the bone tissue of each individual of interest. Trabecular bone specimens from the proximal tibia are being studied in this first phase of the work. Detailed protocols and procedures have been developed for carrying test specimens through all of the steps of a multi-faceted test program. The test program begins with MRI and X-ray imaging of the whole bones before excising a smaller workpiece from the proximal tibia region. High resolution MRI scans are then made and the piece further cut into slabs (roughly 1 cm thick). The slabs are X-rayed again

  10. 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

    2017-04-13

    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.

  11. Pain and nociception: mechanisms of cancer-induced bone pain.

    PubMed

    Falk, Sarah; Dickenson, Anthony H

    2014-06-01

    Cancer pain, especially pain caused by metastasis to bone, is a severe type of pain, and unless the cause and consequences can be resolved, the pain will become chronic. As detection and survival among patients with cancer have improved, pain has become an increasing challenge, because traditional therapies are often only partially effective. Until recently, knowledge of cancer pain mechanisms was poor compared with understanding of neuropathic and inflammatory pain states. We now view cancer-induced bone pain as a complex pain state involving components of both inflammatory and neuropathic pain but also exhibiting elements that seem unique to cancer pain. In addition, the pain state is often unpredictable, and the intensity of the pain is highly variable, making it difficult to manage. The establishment of translational animal models has started to reveal some of the molecular components involved in cancer pain. We present the essential pharmacologic and neurobiologic mechanisms involved in the generation and continuance of cancer-induced bone pain and discuss these in the context of understanding and treating patients. We discuss changes in peripheral signaling in the area of tumor growth, examine spinal cord mechanisms of sensitization, and finally address central processing. Our aim is to provide a mechanistic background for the sensory characteristics of cancer-induced bone pain as a basis for better understanding and treating this condition.

  12. IL-1RI participates in normal growth plate development and bone modeling.

    PubMed

    Simsa-Maziel, Stav; Zaretsky, Janna; Reich, Adi; Koren, Yoav; Shahar, Ron; Monsonego-Ornan, Efrat

    2013-07-01

    The proinflammatory cytokine interleukin-1 (IL-1) signals through IL-1 receptor type I (IL-1RI) and induces osteoclastogenesis and bone resorption mainly during pathological conditions. Little is known about the effect of excess or absence of IL-1 signaling on the physiological development of the growth plate and bone. In this study, we examine growth plate morphology, bone structure, and mechanical properties as well as osteoclast number in IL-1RI knockout mice to evaluate the role of IL-1RI in the normal development of the growth plate and bone. We show for the first time that IL-1RI knockout mice have narrower growth plates due to a smaller hypertrophic zone, suggesting a role for this cytokine in hypertrophic differentiation, together with higher proteoglycan content. The bones of theses mice exhibit higher trabecular and cortical mass, increased mineral density, and superior mechanical properties. In addition, IL-1RI knockout mice have significantly reduced osteoclast numbers in the chondro-osseous junction, trabecular bone, and cortical bone. These results suggest that IL-1RI is involved in normal growth plate development and ECM homeostasis and that it is significant in the physiological process of bone modeling.

  13. Adverse Effects of Osteocytic Constitutive Activation of ß-Catenin on Bone Strength and Bone Growth.

    PubMed

    Chen, Sixu; Feng, Jianquan; Bao, Quanwei; Li, Ang; Zhang, Bo; Shen, Yue; Zhao, Yufeng; Guo, Qingshan; Jing, Junjun; Lin, Shuxian; Zong, Zhaowen

    2015-07-01

    The activation of the canonical Wnt/β-catenin signaling pathway in both mesenchymal stem cells and osteoblasts has been demonstrated to increase bone mass, showing promise for the treatment of low bone volume conditions such as osteoporosis. However, the possible side effects of manipulating this pathway have not been fully addressed. Previously, we reported that the constitutive activation of ß-catenin in osteoblasts impaired vertebral linear growth. In the present study, β-catenin was constitutively activated in osteocytes by crossing Catnb+/lox(exon 3) mice with dentin matrix protein 1(DMP1)-Cre transgenic mice, and the effects of this activation on bone mass, bone growth and bone strength were then observed. DMP1-Cre was found to be predominantly expressed in osteocytes, with weak expression in a small portion of osteoblasts and growth plate chondrocytes. After the activation, the cancellous bone mass was dramatically increased, almost filling the entire bone marrow cavity in long bones. However, bone strength decreased significantly. Thinner and more porous cortical bone along with impaired mineralization were responsible for the decrease in bone strength. Furthermore, the mice showed shorter stature with impaired linear growth of the long bones. Moreover, the concentration of serum phosphate decreased significantly after the activation of ß-catenin, and a high inorganic phosphate (Pi) diet could partially rescue the phenotype of decreased mineralization level and impaired linear growth. Taken together, the constitutive activation of β-catenin in osteocytes may increase cancellous bone mass; however, the activation also had adverse effects on bone strength and bone growth. These adverse effects should be addressed before the adoption of any therapeutic clinical application involving adjustment of the Wnt/β-catenin signaling pathway.

  14. Porcine Bone Scaffolds Adsorb Growth Factors Secreted by MSCs and Improve Bone Tissue Repair.

    PubMed

    Mijiritsky, Eitan; Ferroni, Letizia; Gardin, Chiara; Bressan, Eriberto; Zanette, Gastone; Piattelli, Adriano; Zavan, Barbara

    2017-09-08

    An ideal tissue-engineered bone graft should have both excellent pro-osteogenesis and pro-angiogenesis properties to rapidly realize the bone regeneration in vivo. To meet this goal, in this work a porcine bone scaffold was successfully used as a Trojan horse to store growth factors produced by mesenchymal stem cells (MSCs). This new scaffold showed a time-dependent release of bioactive growth factors, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), in vitro. The biological effect of the growth factors-adsorbed scaffold on the in vitro commitment of MSCs into osteogenic and endothelial cell phenotypes has been evaluated. In addition, we have investigated the activity of growth factor-impregnated granules in the repair of critical-size defects in rat calvaria by means of histological, immunohistochemical, and molecular biology analyses. Based on the results of our work bone tissue formation and markers for bone and vascularization were significantly increased by the growth factor-enriched bone granules after implantation. This suggests that the controlled release of active growth factors from porcine bone granules can enhance and promote bone regeneration.

  15. Growth hormone therapy and craniofacial bones: a comprehensive review.

    PubMed

    Litsas, G

    2013-09-01

    Growth hormone (GH) has significant effects on linear bone growth, bone mass and bone metabolism. The primary role of GH supplementation in children with GH deficiency, those born small for gestational age or with other types of disorders in somatic development is to increase linear growth. However, GH therapy seems to elicit varying responses in the craniofacial region. Whereas the effects of GH administration on somatic development are well documented, comparatively little is known of its effects on the craniofacial region. The purpose of this review was to search the literature and compile results from both animal and human studies related to the impact of GH on craniofacial growth.

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

    PubMed

    Hu, Kai; Olsen, Bjorn R

    2016-10-01

    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.

  17. Predicting Bone Mechanical Properties of Cancellous Bone from DXA, MRI, and Fractal Dimensional Measurements

    NASA Technical Reports Server (NTRS)

    Harrigan, Timothy P.; Ambrose, Catherine G.; Hogan, Harry A.; Shackleford, Linda; Webster, Laurie; LeBlanc, Adrian; Lin, Chen; Evans, Harlan

    1997-01-01

    This project was aimed at making predictions of bone mechanical properties from non-invasive DXA and MRI measurements. Given the bone mechanical properties, stress calculations can be made to compare normal bone stresses to the stresses developed in exercise countermeasures against bone loss during space flight. These calculations in turn will be used to assess whether mechanical factors can explain bone loss in space. In this study we assessed the use of T2(sup *) MRI imaging, DXA, and fractal dimensional analysis to predict strength and stiffness in cancellous bone.

  18. Paradoxical Response to Mechanical Unloading in Bone Loss, Microarchitecture, and Bone Turnover Markers

    PubMed Central

    Sun, Xiaodi; Yang, Kaiyun; Wang, Chune; Cao, Sensen; Merritt, Mackenzie; Hu, Yingwei; Xu, Xin

    2015-01-01

    Background: Sclerostin, encoded by the SOST gene, has been implicated in the response to mechanical loading in bone. Some studies demonstrated that unloading leads to up-regulated SOST expression, which may induce bone loss. Purpose: Most reported studies regarding the changes caused by mechanical unloading were only based on a single site. Considering that the longitudinal bone growth leads to cells of different age with different sensitivity to unloading, we hypothesized that bone turnover in response to unloading is site specific. Methods: We established a disuse rat model by sciatic neurectomy in tibia. In various regions at two time-points, we evaluated the bone mass and microarchitecture in surgically-operated rats and control rats by micro-Computed Tomography (micro-CT) and histology, sclerostin/SOST by immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), and quantitative reverse transcription polymerase chain reaction (qPCR), tartrate resistant acid phosphatase 5b (TRAP 5b) by ELISA and TRAP staining, and other bone markers by ELISA. Results: Micro-CT and histological analysis confirmed bone volume in the disuse rats was significantly decreased compared with those in the time-matched control rats, and microarchitecture also changed 2 and 8 weeks after surgery. Compared with the control groups, SOST mRNA expression in the diaphysis was down-regulated at both week 2 and 8. On the contrary, the percentage of sclerostin-positive osteocytes showed an up-regulated response in the 5 - 6 mm region away from the growth plate, while in the 2.5 - 3.5 mm region, the percentage was no significant difference. Nevertheless, in 0.5 - 1.5 mm region, the percentage of sclerostin-positive osteocytes decreased after 8 weeks, consistent with serum SOST level. Besides, the results of TRAP also suggested that the expression in response to unloading may be opposite in different sites or system. Conclusion: Our data indicated that unloading-induced changes in bone

  19. Effects of Phlomis umbrosa Root on Longitudinal Bone Growth Rate in Adolescent Female Rats.

    PubMed

    Lee, Donghun; Kim, Young-Sik; Song, Jungbin; Kim, Hyun Soo; Lee, Hyun Jung; Guo, Hailing; Kim, Hocheol

    2016-04-07

    This study aimed to investigate the effects of Phlomis umbrosa root on bone growth and growth mediators in rats. Female adolescent rats were administered P. umbrosa extract, recombinant human growth hormone or vehicle for 10 days. Tetracycline was injected intraperitoneally to produce a glowing fluorescence band on the newly formed bone on day 8, and 5-bromo-2'-deoxyuridine was injected to label proliferating chondrocytes on days 8-10. To assess possible endocrine or autocrine/paracrine mechanisms, we evaluated insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein-3 (IGFBP-3) or bone morphogenetic protein-2 (BMP-2) in response to P. umbrosa administration in either growth plate or serum. Oral administration of P. umbrosa significantly increased longitudinal bone growth rate, height of hypertrophic zone and chondrocyte proliferation of the proximal tibial growth plate. P. umbrosa also increased serum IGFBP-3 levels and upregulated the expressions of IGF-1 and BMP-2 in growth plate. In conclusion, P. umbrosa increases longitudinal bone growth rate by stimulating proliferation and hypertrophy of chondrocyte with the increment of circulating IGFBP-3. Regarding the immunohistochemical study, the effect of P. umbrosa may also be attributable to upregulation of local IGF-1 and BMP-2 expressions in the growth plate, which can be considered as a GH dependent autocrine/paracrine pathway.

  20. 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.

  1. Mechanically induced alterations in cultured skeletal muscle growth

    NASA Technical Reports Server (NTRS)

    Vandenburgh, H. H.; Hatfaludy, S.; Karlisch, P.; Shansky, J.

    1991-01-01

    Model systems are available for mechanically stimulating cultured skeletal muscle cells by passive tensile forces which simulate those found in vivo. When applied to embryonic muscle cells in vitro these forces induce tissue organogenesis, metabolic adaptations, and muscle cell growth. The mechanical stimulation of muscle cell growth correlates with stretch-induced increases in the efflux of prostaglandins PGE2 and PGF2(alpha) in a time and frequency dependent manner. These prostaglandins act as mechanical 'second messengers' regulating skeletal muscle protein turnover rates. Since they also effect bone remodelling in response to tissue loading and unloading, secreted prostaglandins may serve as paracrine growth factors, coordinating the growth rates of muscle and bone in response to external mechanical forces. Cell culture model systems will supplement other models in understanding mechanical transduction processes at the molecular level.

  2. Mechanically induced alterations in cultured skeletal muscle growth

    NASA Technical Reports Server (NTRS)

    Vandenburgh, H. H.; Hatfaludy, S.; Karlisch, P.; Shansky, J.

    1991-01-01

    Model systems are available for mechanically stimulating cultured skeletal muscle cells by passive tensile forces which simulate those found in vivo. When applied to embryonic muscle cells in vitro these forces induce tissue organogenesis, metabolic adaptations, and muscle cell growth. The mechanical stimulation of muscle cell growth correlates with stretch-induced increases in the efflux of prostaglandins PGE2 and PGF2(alpha) in a time and frequency dependent manner. These prostaglandins act as mechanical 'second messengers' regulating skeletal muscle protein turnover rates. Since they also effect bone remodelling in response to tissue loading and unloading, secreted prostaglandins may serve as paracrine growth factors, coordinating the growth rates of muscle and bone in response to external mechanical forces. Cell culture model systems will supplement other models in understanding mechanical transduction processes at the molecular level.

  3. Bioresorbability, porosity and mechanical strength of bone substitutes: what is optimal for bone regeneration?

    PubMed

    Hannink, Gerjon; Arts, J J Chris

    2011-09-01

    Bone repair is a multi-dimensional process that requires osteogenic cells, an osteoconductive matrix, osteoinductive signalling, mechanical stability and vascularization. In clinical practice, bone substitute materials are being used for reconstructive purposes, bone stock augmentation, and bone repair. Over the last decade, the use of calcium phosphate (CaP) based bone substitute materials has increased exponentially. These bone substitute materials vary in composition, mechanical strength and biological mechanism of function, each having their own advantages and disadvantages. It is known that intrinsic material properties of CaP bone substitutes have a profound effect on their mechanical and biological behaviour and associated biodegradation. These material properties of bone substitutes, such as porosity, composition and geometry change the trade-off between mechanical and biological performance. The choice of the optimal bone substitutes is therefore not always an easy one, and largely depends on the clinical application and its associated biological and mechanical needs. Not all bone graft substitutes will perform the same way, and their performance in one clinical site may not necessarily predict their performance in another site. CaP bone substitutes unfortunately have yet to achieve optimal mechanical and biological performance and to date each material has its own trade-off between mechanical and biological performance. This review describes the effect of intrinsic material properties on biological performance, mechanical strength and biodegradability of CaP bone substitutes. Copyright © 2011 Elsevier Ltd. All rights reserved.

  4. Mechanisms by which nutritional disorders cause reduced bone mass in adults.

    PubMed

    Miller, Karen K

    2003-03-01

    Nutritional disorders that cause bone loss in adults include disordered eating behaviors (female athlete triad and anorexia nervosa), gastrointestinal diseases (celiac sprue, inflammatory bowel disease, and other malabsorption syndromes), alcoholism, and hypervitaminosis A. These disorders exert their effects on bone through a number of mechanisms, including estrogen deficiency. Deficiencies of anabolic hormones may also be important, including insulin-like growth factor I (IGF-I), a nutritionally regulated bone trophic factor. In addition, low weight itself is a risk factor for bone loss and decreased bone formation. Reduced calcium and vitamin D availability, with resultant secondary hyperparathyroidism, is another important mechanism of bone loss in nutritional disorders. This review discusses nutritional causes of reduced bone mass in adults and how nutritional disorders exert deleterious effects on the skeleton.

  5. Growth of long bones in renal failure: roles of hyperparathyroidism, growth hormone and calcitriol.

    PubMed

    Sanchez, C P; Salusky, I B; Kuizon, B D; Abdella, P; Jüppner, H; Goodman, W G

    1998-12-01

    The treatment of secondary hyperparathyroidism (2 degrees HPT) associated with chronic renal failure adversely affects skeletal growth. We assessed epiphyseal growth plate morphology by quantitative histology and measured mRNA levels for selected markers of chondrocyte proliferation and differentiation by in situ hybridization in the growth plate cartilage of subtotally nephrectomized rats with either mild or advanced 2 degrees HPT. The width of the growth plate cartilage in the proximal tibia and mRNA levels for PTH/PTHrP receptor were unchanged in rats with mild 2 degrees HPT, however, they were markedly less in nephrectomized rats with advanced 2 degrees HPT than in intact controls. Treatment with growth hormone 10 IU/kg/day increased growth plate thickness both in mild and in advanced 2 degrees HPT and raised mRNA levels for type II and type X collagen in rats with advanced 2 degrees HPT. The administration of calcitriol 50 ng/kg/day attenuated these responses in animals with advanced 2 degrees HPT. Overall, PTH/PTHrP receptor mRNA levels did not correspond to the serum levels of PTH indicating that PTH/PTHrP receptor expression is down-regulated in renal failure by a PTH-independent mechanism. Calcitriol counteracts the trophic actions of growth hormone on epiphyseal growth plate cartilage and modifies chondrocyte differentiation in vivo, and these mechanisms may contribute to disturbances in longitudinal bone growth in renal failure.

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

    PubMed

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

    2015-08-01

    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

  7. 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

  8. An adaptation model for trabecular bone at different mechanical levels

    PubMed Central

    2010-01-01

    Background Bone has the ability to adapt to mechanical usage or other biophysical stimuli in terms of its mass and architecture, indicating that a certain mechanism exists for monitoring mechanical usage and controlling the bone's adaptation behaviors. There are four zones describing different bone adaptation behaviors: the disuse, adaptation, overload, and pathologic overload zones. In different zones, the changes of bone mass, as calculated by the difference between the amount of bone formed and what is resorbed, should be different. Methods An adaptation model for the trabecular bone at different mechanical levels was presented in this study based on a number of experimental observations and numerical algorithms in the literature. In the proposed model, the amount of bone formation and the probability of bone remodeling activation were proposed in accordance with the mechanical levels. Seven numerical simulation cases under different mechanical conditions were analyzed as examples by incorporating the adaptation model presented in this paper with the finite element method. Results The proposed bone adaptation model describes the well-known bone adaptation behaviors in different zones. The bone mass and architecture of the bone tissue within the adaptation zone almost remained unchanged. Although the probability of osteoclastic activation is enhanced in the overload zone, the potential of osteoblasts to form bones compensate for the osteoclastic resorption, eventually strengthening the bones. In the disuse zone, the disuse-mode remodeling removes bone tissue in disuse zone. Conclusions The study seeks to provide better understanding of the relationships between bone morphology and the mechanical, as well as biological environments. Furthermore, this paper provides a computational model and methodology for the numerical simulation of changes of bone structural morphology that are caused by changes of mechanical and biological environments. PMID:20598128

  9. MECHANISMS OF BONE METASTASES OF BREAST CANCER

    PubMed Central

    Suva, Larry J.; Griffin, Robert J.; Makhoul, Issam

    2010-01-01

    Cancer development is a multistep process driven by genetic alterations that elicit the progressive transformation of normal human cells into highly malignant derivatives. The altered cell proliferation phenotype of cancer involves a poorly characterized sequence of molecular events, which often result in the development of distant metastasis. In the case of breast cancer, the skeleton is amongst the most common of metastatic sites. In spite of its clinical importance, the underlying cellular and molecular mechanisms driving bone metastasis remain elusive. Despite advances in our understanding of the phenotype of cancer cells, the increased focus on the contribution of the tumor microenvironment and the recent revival of interest in the role of tumor propagating cells (so called cancer stem cells) that may originate or be related to normal stem cells produced in the bone marrow, many important questions remain unanswered. As such, a more complete understanding of the influences of both the microenvironment and tumor phenotype that impact the entire multi-step metastatic cascade is required. In this review the importance of tumor heterogeneity, tumor propagating cells, the microenvironment of breast cancer metastasis to bone as well as many current endocrine therapies for the prevention and treatment of metastatic breast cancer are discussed. PMID:19443538

  10. ON THE MECHANISMS OF BONE RESORPTION

    PubMed Central

    Vaes, Gilbert

    1968-01-01

    Bone resorption, characterized by the solubilization of both the mineral and the organic components of the osseous matrix, was obtained in tissue culture under the action of parathyroid hormone (PTH). It was accompanied by the excretion of six lysosomal acid hydrolases, which was in good correlation with the progress of the resorption evaluated by the release of phosphate, calcium 45 or hydroxyproline from the explants; there was no increased excretion of two nonlysosomal enzymes, alkaline phosphatase, and catalase. Balance studies and experiments with inhibitors of protein synthesis indicated that the intracellular stores of the acid hydrolases excreted were maintained by new synthesis. The release was not due to a direct disruption of the lysosomal membrane by PTH; it is presumed to result from an exocytosis of the whole lysosomal content and to involve mechanisms similar to those controlling the secretion of this content into digestive vacuoles. The resorbing explants acidified their culture fluids at a faster rate and released more lactate and citrate than the controls; this release was in good correlation, in the PTH-treated cultures, with the resorption of the bone mineral, but the amount of citrate released was considerably smaller than that of lactate. The acid released could account for the resorption of the mineral. It is proposed, as a working hypothesis, that the acid hydrolases of the lysosomes are active in the resorption of the organic matrix of bone and that acid, originating possibly from the stimulation of glycolysis, cares for the concomitant solubilization of bone mineral while also favoring the hydrolytic action of the lysosomal enzymes. PMID:5699937

  11. In vivo measurement of mechanical impedance of bone

    NASA Technical Reports Server (NTRS)

    Young, D. R.; Thompson, G.

    1974-01-01

    System of measurement provides indications of ulnar properties independent of characteristics of surrounding soft tissue and other bones. Mechanical modal approximated ulnar response so average bending rigidity could be determined to provide direct index of bone resistance to bending loading.

  12. Bone growth and turnover in progesterone receptor knockout mice.

    SciTech Connect

    Rickard, David J.; Iwaniec, Urszula T.; Evans, Glenda; Hefferan, Theresa E.; Hunter, Jaime C.; Waters, Katrina M.; Lydon, John P.; O'Malley, Bert W.; Khosla, Sundeep; Spelsberg, Thomas C.; Turner, Russell T.

    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 bones 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.

  13. Osteoinductive small molecules: growth factor alternatives for bone tissue engineering.

    PubMed

    Aravamudhan, Aja; Ramos, Daisy M; Nip, Jonathan; Subramanian, Aditi; James, Roshan; Harmon, Matthew D; Yu, Xiaojun; Kumbar, Sangamesh G

    2013-01-01

    Tissue engineering aims to repair, restore, and regenerate lost or damaged tissues by using biomaterials, cells, mechanical forces and factors (chemical and biological) alone or in combination. Growth factors are routinely used in the tissue engineering approach to expedite the process of regeneration. The growth factor approach has been hampered by several complications including high dose requirements, lower half-life, protein instability, higher costs and undesired side effects. Recently a variety of alternative small molecules of both natural and synthetic origin have been explored as alternatives to growth factors for tissue regeneration applications. Small molecules are simple biochemical components that elicit certain cellular responses through signaling cascades. Small molecules present a viable alternative to biological factors. Small molecule strategies can reduce various side effects, maintain bioactivity in a biological environment and minimize cost issues associated with complex biological growth factors. This manuscript focuses on three-osteoinductive small molecules, namely melatonin, resveratrol (from natural sources) and purmorphamine (synthetically designed) as inducers of bone formation and osteogenic differentiation of stem cells. Efforts have been made to summarize possible biological pathways involved in the action of each of these drugs. Melatonin is known to affect Mitogen Activated Protein (MAP) kinase, Bone morphogenic protein (BMP) and canonical wnt signaling. Resveratrol is known to activate cascades involving Wnt and NAD-dependent deacetylase sirtuin-1 (Sirt1). Purmorphamine is a Hedgehog (Hh) pathway agonist as it acts on Smoothened (Smo) receptors. These mechanisms and the way they are affected by the respective small molecules will also be discussed in the manuscript.

  14. Osteocytic Connexin Hemichannels Suppress Breast Cancer Growth and Bone Metastasis

    PubMed Central

    Zhou, Jade Z.; Riquelme, Manuel A.; Gu, Sumin; Kar, Rekha; Gao, Xiaoli; Sun, LuZhe; Jiang, Jean X.

    2016-01-01

    Although the skeleton is one of predominant sites for breast cancer metastasis, why breast cancer cells often become dormant after homing to bone is not well understood. Here, we reported an intrinsic self-defense mechanism of bone cells against breast cancer cells: a critical role of connexin (Cx) 43 hemichannels in osteocytes in the suppression of breast cancer bone metastasis. Cx43 hemichannels allow passage of small molecules between the intracellular and extracellular environments. The treatment of bisphosphonate drugs, either alendronate (ALN) or zoledronic acid (ZOL), opened Cx43 hemichannels in osteocytes. Conditioned media (CM) collected from MLO-Y4 osteocyte cells treated with bisphosphonates inhibited the anchorage-independent growth, migration and invasion of MDA-MB-231 human breast cancer cells and Py8119 mouse mammary carcinoma cells and this inhibitory effect was attenuated with Cx43(E2), a specific hemichannel blocking antibody. The opening of osteocytic Cx43 hemichannels by mechanical stimulation had similar inhibitory effects on breast cancer cells and this inhibition was attenuated by Cx43(E2) antibody as well. These inhibitory effects on cancer cells were mediated by ATP released from osteocyte Cx43 hemichannels. Furthermore, both Cx43 osteocyte-specific knockout mice and osteocyte-specific Δ130–136 transgenic mice with impaired Cx43 gap junctions and hemichannels showed significantly increased tumor growth and attenuated the inhibitory effect of ZOL. However, R76W transgenic mice with functional hemichannels but not gap junctions in osteocytes did not display a significant difference. Together, our studies establish the specific inhibitory role of osteocytic Cx43 hemichannels, and exploiting the activity of this channel could serve as a de novo therapeutic strategy. PMID:27041582

  15. Finite element prediction of fatigue damage growth in cancellous bone.

    PubMed

    Hambli, Ridha; Frikha, Sana; Toumi, Hechmi; Tavares, João Manuel R S

    2016-01-01

    Cyclic stresses applied to bones generate fatigue damage that affects the bone stiffness and its elastic modulus. This paper proposes a finite element model for the prediction of fatigue damage accumulation and failure in cancellous bone at continuum scale. The model is based on continuum damage mechanics and incorporates crack closure effects in compression. The propagation of the cracks is completely simulated throughout the damaged area. In this case, the stiffness of the broken element is reduced by 98% to ensure no stress-carrying capacities of completely damaged elements. Once a crack is initiated, the propagation direction is simulated by the propagation of the broken elements of the mesh. The proposed model suggests that damage evolves over a real physical time variable (cycles). In order to reduce the computation time, the integration of the damage growth rate is based on the cycle blocks approach. In this approach, the real number of cycles is reduced (divided) into equivalent blocks of cycles. Damage accumulation is computed over the cycle blocks and then extrapolated over the corresponding real cycles. The results show a clear difference between local tensile and compressive stresses on damage accumulation. Incorporating stiffness reduction also produces a redistribution of the peak stresses in the damaged region, which results in a delay in damage fracture.

  16. Cellular and molecular mechanisms for the bone response to mechanical loading

    NASA Technical Reports Server (NTRS)

    Bloomfield, S. A.

    2001-01-01

    To define the cellular and molecular mechanisms for the osteogenic response of bone to increased loading, several key steps must be defined: sensing of the mechanical signal by cells in bone, transduction of the mechanical signal to a biochemical one, and transmission of that biochemical signal to effector cells. Osteocytes are likely to serve as sensors of loading, probably via interstitial fluid flow produced during loading. Evidence is presented for the role of integrins, the cell's actin cytoskeleton, G proteins, and various intracellular signaling pathways in transducing that mechanical signal to a biochemical one. Nitric oxide, prostaglandins, and insulin-like growth factors all play important roles in these pathways. There is growing evidence for modulation of these mechanotransduction steps by endocrine factors, particularly parathyroid hormone and estrogen. The efficiency of this process is also impaired in the aged animal, yet what remains undefined is at what step mechanotransduction is affected.

  17. Cellular and molecular mechanisms for the bone response to mechanical loading

    NASA Technical Reports Server (NTRS)

    Bloomfield, S. A.

    2001-01-01

    To define the cellular and molecular mechanisms for the osteogenic response of bone to increased loading, several key steps must be defined: sensing of the mechanical signal by cells in bone, transduction of the mechanical signal to a biochemical one, and transmission of that biochemical signal to effector cells. Osteocytes are likely to serve as sensors of loading, probably via interstitial fluid flow produced during loading. Evidence is presented for the role of integrins, the cell's actin cytoskeleton, G proteins, and various intracellular signaling pathways in transducing that mechanical signal to a biochemical one. Nitric oxide, prostaglandins, and insulin-like growth factors all play important roles in these pathways. There is growing evidence for modulation of these mechanotransduction steps by endocrine factors, particularly parathyroid hormone and estrogen. The efficiency of this process is also impaired in the aged animal, yet what remains undefined is at what step mechanotransduction is affected.

  18. [Bone defects in revision knee arthroplasty: filling with bone allograft plus platelet-derived growth factors].

    PubMed

    Macule-Beneyto, Francisco; Segur-Vilalta, Josep; Vilchez-Cavazos, Felix; Esteban-Navarro, Pedro; Vidal-Sicart, Sergi; Acosta-Olivo, Carlos

    2014-01-01

    One of the most challenging aspects of a revision knee arthroplasty is the management of bone loss. The OBJECTIVE of the study is to show the capability to augment bone mineral density in areas with bone loss with platelet-derived growth factors. Randomized, prospective, blinded study in patients who underwent a total knee replacement revision with tibial-damaged metaphyseal bone were randomly allocated to have a revision total knee arthroplasty and to fill the bone defects with lyophilized bone allograft mixed with platelet growth factors (experimental group, n= 9) or with lyophilized bone allograft alone (control group, n= 7). To evaluate bone mineral density between groups, dual-energy X-ray absorptiometry (DEXA) was performed preoperatively, at 1 month, 6 months and 1 year after surgery. The study was comprised of a total of 16 patients. We found no significant differences observed during the follow-up between groups in mineral bone density. Use of platelet-derived growth factors does not improve bone mineral density in patients with revision knee arthroplasty.

  19. Growth Hormone Regulates the Balance Between Bone Formation and Bone Marrow Adiposity

    PubMed Central

    Menagh, Philip J; Turner, Russell T; Jump, Donald B; Wong, Carmen P; Lowry, Malcolm B; Yakar, Shoshana; Rosen, Clifford J; Iwaniec, Urszula T

    2010-01-01

    Cancellous bone decreases and bone marrow fat content increases with age. Osteoblasts and adipocytes are derived from a common precursor, and growth hormone (GH), a key hormone in integration of energy metabolism, regulates the differentiation and function of both cell lineages. Since an age-related decline in GH is associated with bone loss, we investigated the relationship between GH and bone marrow adiposity in hypophysectomized (HYPOX) rats and in mice with defects in GH signaling. HYPOX dramatically reduced body weight gain, bone growth and mineralizing perimeter, serum insulin-like growth factor 1 (IGF-1) levels, and mRNA levels for IGF-1 in liver and bone. Despite reduced body mass and adipocyte precursor pool size, HYPOX resulted in a dramatic increase in bone lipid levels, as reflected by increased bone marrow adiposity and bone triglyceride and cholesterol content. GH replacement normalized bone marrow adiposity and precursor pool size, as well as mineralizing perimeter in HYPOX rats. In contrast, 17β -estradiol, IGF-1, thyroxine, and cortisone were ineffective. Parathyroid hormone (PTH) reversed the inhibitory effects of HYPOX on mineralizing perimeter but had no effect on adiposity. Finally, bone marrow adiposity was increased in mice deficient in GH and IGF-1 but not in mice deficient in serum IGF-1. Taken together, our findings indicate that the reciprocal changes in bone and fat mass in GH signaling-deficient rodents are not directly coupled with one another. Rather, GH enhances adipocyte as well as osteoblast precursor pool size. However, GH increases osteoblast differentiation while suppressing bone marrow lipid accumulation. © 2010 American Society for Bone and Mineral Research PMID:19821771

  20. Biocompatibility of calcium phosphate bone cement with optimised mechanical properties: an in vivo study.

    PubMed

    Palmer, Iwan; Nelson, John; Schatton, Wolfgang; Dunne, Nicholas J; Buchanan, Fraser; Clarke, Susan A

    2016-12-01

    This work establishes the in vivo performance of modified calcium phosphate bone cements for vertebroplasty of spinal fractures using a lapine model. A non-modified calcium phosphate bone cement and collagen-calcium phosphate bone cements composites with enhanced mechanical properties, utilising either bovine collagen or collagen from a marine sponge, were compared to a commercial poly(methyl methacrylate) cement. Conical cement samples (8 mm height × 4 mm base diameter) were press-fit into distal femoral condyle defects in New Zealand White rabbits and assessed after 5 and 10 weeks. Bone apposition and tartrate-resistant acid phosphatase activity around cements were assessed. All implants were well tolerated, but bone apposition was higher on calcium phosphate bone cements than on poly(methyl methacrylate) cement. Incorporation of collagen showed no evidence of inflammatory or immune reactions. Presence of positive tartrate-resistant acid phosphatase staining within cracks formed in calcium phosphate bone cements suggested active osteoclasts were present within the implants and were actively remodelling within the cements. Bone growth was also observed within these cracks. These findings confirm the biological advantages of calcium phosphate bone cements over poly(methyl methacrylate) and, coupled with previous work on enhancement of mechanical properties through collagen incorporation, suggest collagen-calcium phosphate bone cement composite may offer an alternative to calcium phosphate bone cements in applications where low setting times and higher mechanical stability are important.

  1. Bone quality is affected by food restriction and by nutrition-induced catch-up growth.

    PubMed

    Pando, Rakefet; Masarwi, Majdi; Shtaif, Biana; Idelevich, Anna; Monsonego-Ornan, Efrat; Shahar, Ron; Phillip, Moshe; Gat-Yablonski, Galia

    2014-12-01

    Growth stunting constitutes the most common effect of malnutrition. When the primary cause of malnutrition is resolved, catch-up (CU) growth usually occurs. In this study, we have explored the effect of food restriction (RES) and refeeding on bone structure and mechanical properties. Sprague-Dawley male rats aged 24 days were subjected to 10 days of 40% RES, followed by refeeding for 1 (CU) or 26 days long-term CU (LTCU). The rats fed ad libitum served as controls. The growth plates were measured, osteoclasts were identified using tartrate-resistant acid phosphatase staining, and micro-computed tomography (CT) scanning and mechanical testing were used to study structure and mechanical properties. Micro-CT analysis showed that RES led to a significant reduction in trabecular BV/TV and trabecular number (Tb.N), concomitant with an increase in trabecular separation (Tb.Sp). Trabecular BV/TV and Tb.N were significantly greater in the CU group than in the RES in both short- and long-term experiments. Mechanical testing showed that RES led to weaker and less compliant bones; interestingly, bones of the CU group were also more fragile after 1 day of CU. Longer term of refeeding enabled correction of the bone parameters; however, LTCU did not achieve full recovery. These results suggest that RES in young rats attenuated growth and reduced trabecular bone parameters. While nutrition-induced CU growth led to an immediate increase in epiphyseal growth plate height and active bone modeling, it was also associated with a transient reduction in bone quality. This should be taken into consideration when treating children undergoing CU growth. © 2014 Society for Endocrinology.

  2. Human Placenta-Derived Adherent Cells Prevent Bone loss, Stimulate Bone formation, and Suppress Growth of Multiple Myeloma in Bone

    PubMed Central

    Li, Xin; Ling, Wen; Pennisi, Angela; Wang, Yuping; Khan, Sharmin; Heidaran, Mohammad; Pal, Ajai; Zhang, Xiaokui; He, Shuyang; Zeitlin, Andy; Abbot, Stewart; Faleck, Herbert; Hariri, Robert; Shaughnessy, John D.; van Rhee, Frits; Nair, Bijay; Barlogie, Bart; Epstein, Joshua; Yaccoby, Shmuel

    2011-01-01

    Human placenta has emerged as a valuable source of transplantable cells of mesenchymal and hematopoietic origin for multiple cytotherapeutic purposes, including enhanced engraftment of hematopoietic stem cells, modulation of inflammation, bone repair, and cancer. Placenta-derived adherent cells (PDACs) are mesenchymal-like stem cells isolated from postpartum human placenta. Multiple myeloma is closely associated with induction of bone disease and large lytic lesions, which are often not repaired and are usually the sites of relapses. We evaluated the antimyeloma therapeutic potential, in vivo survival, and trafficking of PDACs in the severe combined immunodeficiency (SCID)–rab model of medullary myeloma-associated bone loss. Intrabone injection of PDACs into non-myelomatous and myelomatous implanted bone in SCID-rab mice promoted bone formation by stimulating endogenous osteoblastogenesis, and most PDACs disappeared from bone within 4 weeks. PDACs inhibitory effects on myeloma bone disease and tumor growth were dose-dependent and comparable with those of fetal human mesenchymal stem cells (MSCs). Intrabone, but not subcutaneous, engraftment of PDACs inhibited bone disease and tumor growth in SCID-rab mice. Intratumor injection of PDACs had no effect on subcutaneous growth of myeloma cells. A small number of intravenously injected PDACs trafficked into myelomatous bone. Myeloma cell growth rate in vitro was lower in coculture with PDACs than with MSCs from human fetal bone or myeloma patients. PDACs also promoted apoptosis in osteoclast precursors and inhibited their differentiation. This study suggests that altering the bone marrow microenvironment with PDAC cytotherapy attenuates growth of myeloma and that PDAC cytotherapy is a promising therapeutic approach for myeloma osteolysis. PMID:21732484

  3. Mechanical integrity of subchondral bone in osteochondral autografts and allografts

    PubMed Central

    Wohl, Greg; Goplen, Gordon; Ford, Jason; Novak, Kelli; Hurtig, Mark; McPherson, Roger; McGann, Locksley; Schachar, Norman; Zernicke, Ronald F.

    1998-01-01

    Objective To assess the influence of osteochondral graft preservation techniques on post-transplant biomechanics of graft and host subchondral bone in the knee joint. Design An experimental animal model (sheep), specifically the weight-bearing articular surface of the medial femoral condyle of the knee joints. Intervention Each sheep received, in the ipsilateral knee, an allograft that was (a) frozen without dimethyl sulfoxide (DMSO), (b) snap-frozen in liquid nitrogen or (c) frozen with DMSO. The contralateral knee received an autograft that was (a) snap-frozen, (b) treated with DMSO or (c) left untreated (fresh). Main outcome measures Mechanical and material properties of bone, including maximal compression stress, modulus of elasticity and bone mineral ash content of subchondral bone cores (from the graft centre and surrounding host bone). Results No significant differences were found in the mechanical properties of the subchondral bone under the graft, but there were significant changes in surrounding bone. Bone surrounding the grafts that were snap-frozen or frozen without DMSO was significantly stronger than the normal control bone. However, bone surrounding fresh autografts and cryoprotected allografts was not significantly different from normal control bone. Conclusions The changes in the mechanical behaviour of the host bone may be associated with graft cell viability. The greater stiffness of the subchondral host bone may have consequences for long-term graft integrity and for the development of degenerative osteoarthritis. PMID:9627549

  4. Mechanisms of Guided Bone Regeneration: A Review

    PubMed Central

    Liu, Jie; Kerns, David G

    2014-01-01

    Post-extraction crestal bone resorption is common and unavoidable which can lead to significant ridge dimensional changes. To regenerate enough bone for successful implant placement, Guided Bone Regeneration (GBR) is often required. GBR is a surgical procedure that uses barrier membranes with or without particulate bone grafts or/and bone substitutes. There are two approaches of GBR in implant therapy: GBR at implant placement (simultaneous approach) and GBR before implant placement to increase the alveolar ridge or improve ridge morphology (staged approach). Angiogenesis and ample blood supply play a critical role in promoting bone regeneration. PMID:24894890

  5. Mechanical stimulation of bone marrow in situ induces bone formation in trabecular explants.

    PubMed

    Birmingham, E; Kreipke, T C; Dolan, E B; Coughlin, T R; Owens, P; McNamara, L M; Niebur, G L; McHugh, P E

    2015-04-01

    Low magnitude high frequency (LMHF) loading has been shown to have an anabolic effect on trabecular bone in vivo. However, the precise mechanical signal imposed on the bone marrow cells by LMHF loading, which induces a cellular response, remains unclear. This study investigates the influence of LMHF loading, applied using a custom designed bioreactor, on bone adaptation in an explanted trabecular bone model, which isolated the bone and marrow. Bone adaptation was investigated by performing micro CT scans pre and post experimental LMHF loading, using image registration techniques. Computational fluids dynamic models were generated using the pre-experiment scans to characterise the mechanical stimuli imposed by the loading regime prior to adaptation. Results here demonstrate a significant increase in bone formation in the LMHF loaded group compared to static controls and media flow groups. The calculated shear stress in the marrow was between 0.575 and 0.7 Pa, which is within the range of stimuli known to induce osteogenesis by bone marrow mesenchymal stem cells in vitro. Interestingly, a correlation was found between the bone formation balance (bone formation/resorption), trabecular number, trabecular spacing, mineral resorption rate, bone resorption rate and mean shear stresses. The results of this study suggest that the magnitude of the shear stresses generated due to LMHF loading in the explanted bone cores has a contributory role in the formation of trabecular bone and improvement in bone architecture parameters.

  6. Role of Osteogenic Growth Peptide (OGP) and OGP(10-14) in Bone Regeneration: A Review.

    PubMed

    Pigossi, Suzane C; Medeiros, Marcell C; Saska, Sybele; Cirelli, Joni A; Scarel-Caminaga, Raquel M

    2016-11-22

    Bone regeneration is a process that involves several molecular mediators, such as growth factors, which directly affect the proliferation, migration and differentiation of bone-related cells. The osteogenic growth peptide (OGP) and its C-terminal pentapeptide OGP(10-14) have been shown to stimulate the proliferation, differentiation, alkaline phosphatase activity and matrix mineralization of osteoblastic lineage cells. However, the exact molecular mechanisms that promote osteoblastic proliferation and differentiation are not completely understood. This review presents the main chemical characteristics of OGP and/or OGP(10-14), and also discusses the potential molecular pathways induced by these growth factors to promote proliferation and differentiation of osteoblasts. Furthermore, since these peptides have been extensively investigated for bone tissue engineering, the clinical applications of these peptides for bone regeneration are discussed.

  7. Role of Osteogenic Growth Peptide (OGP) and OGP(10–14) in Bone Regeneration: A Review

    PubMed Central

    Pigossi, Suzane C.; Medeiros, Marcell C.; Saska, Sybele; Cirelli, Joni A.; Scarel-Caminaga, Raquel M.

    2016-01-01

    Bone regeneration is a process that involves several molecular mediators, such as growth factors, which directly affect the proliferation, migration and differentiation of bone-related cells. The osteogenic growth peptide (OGP) and its C-terminal pentapeptide OGP(10–14) have been shown to stimulate the proliferation, differentiation, alkaline phosphatase activity and matrix mineralization of osteoblastic lineage cells. However, the exact molecular mechanisms that promote osteoblastic proliferation and differentiation are not completely understood. This review presents the main chemical characteristics of OGP and/or OGP(10–14), and also discusses the potential molecular pathways induced by these growth factors to promote proliferation and differentiation of osteoblasts. Furthermore, since these peptides have been extensively investigated for bone tissue engineering, the clinical applications of these peptides for bone regeneration are discussed. PMID:27879684

  8. 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

  9. Molecular mechanism of action of fluoride on bone cells.

    PubMed

    Lau, K H; Baylink, D J

    1998-11-01

    Fluoride is an effective anabolic agent to increase spinal bone density by increasing bone formation, and at therapeutically relevant (i.e., micromolar) concentrations, it stimulates bone cell proliferation and activities in vitro and in vivo. However, the fluoride therapy of osteoporosis has been controversial, in large part because of a lack of consistent antifracture efficacy. However, information regarding the molecular mechanism of action of fluoride may improve its optimum and correct usage and may disclose potential targets for the development of new second generation drugs that might have a better efficacy and safety profile. Accordingly, this review will address the molecular mechanisms of the osteogenic action of fluoride. In this regard, we and other workers have proposed two competing models, both of which involve the mitogen activated protein kinase (MAPK) mitogenic signal transduction pathway. Our model involves a fluoride inhibition of a unique fluoride-sensitive phosphotyrosine phosphatase (PTP) in osteoblasts, which results in a sustained increase in the tyrosine phosphorylation level of the key signaling proteins of the MAPK mitogenic transduction pathway, leading to the potentiation of the bone cell proliferation initiated by growth factors. The competing model proposes that fluoride acts in coordination with aluminum to form fluoroaluminate, which activates a pertussis toxin-sensitive Gi/o protein on bone cell membrane, leading to an activation of cellular protein tyrosine kinases (PTKs), which in turn leads to increases in the tyrosine phosphorylation of signaling proteins of the MAPK mitogenic signal transduction pathway, ultimately leading to a stimulation of cell proliferation. A benefit of our model, but not the other model, is that it accounts for all the unique properties of the osteogenic action of fluoride. These include the low effective fluoride dose, the skeletal tissue specificity, the requirement of PTK-activating growth factors

  10. Differentiation and growth of bone ornamentation in vertebrates: a comparative histological study among the Crocodylomorpha.

    PubMed

    de Buffrénil, V; Clarac, F; Fau, M; Martin, S; Martin, B; Pellé, E; Laurin, M

    2015-04-01

    Bone ornamentation, that is, hollow (pits and grooves) or protruding (ridges) repetitive reliefs on the surface of dermal bones, is a frequent, though poorly studied and understood, feature in vertebrates. One of the most typical examples of this characteristic is given by the Crurotarsi, a taxon formed by the crocodilians and their closest allies, which generally display deep ornamentation on skull roof and osteoderms. However, the ontogenetic process responsible for the differentiation and development of this character remains controversial. This study was conducted to settle the question on histological and microanatomical evidence in several crurotarsan taxa. Observational and experimental data in extant and extinct crocodyliforms show that bone ornamentation is initially created, and later maintained during somatic growth (that is indefinite in crocodilians), by a complex process of bone remodeling comprising local resorption of superficial bone cortices, followed by partial reconstruction. The superficial reliefs of crocodilian dermal bones are thus permanently modified through pit enlargement, drift, stretching, shrinking, or complete filling. Ridges are also remodeled in corresponding ways. These processes allow accommodation of unitary ornamental motifs to the overall dimensions of the bones during growth. A parsimony optimization based on the results of this study, but integrating also published data on bone histology in non-crocodyliform crurotarsans and some non-crurotarsan taxa, suggests that the peculiar mechanism described above for creating and maintaining bone ornamentation is a general feature of the Crurotarsi and is quite distinct from that attributed by previous authors to other vertebrates. © 2014 Wiley Periodicals, Inc.

  11. Transforming growth factor-beta1 to the bone.

    PubMed

    Janssens, Katrien; ten Dijke, Peter; Janssens, Sophie; Van Hul, Wim

    2005-10-01

    TGF-beta1 is a ubiquitous growth factor that is implicated in the control of proliferation, migration, differentiation, and survival of many different cell types. It influences such diverse processes as embryogenesis, angiogenesis, inflammation, and wound healing. In skeletal tissue, TGF-beta1 plays a major role in development and maintenance, affecting both cartilage and bone metabolism, the latter being the subject of this review. Because it affects both cells of the osteoblast and osteoclast lineage, TGF-beta1 is one of the most important factors in the bone environment, helping to retain the balance between the dynamic processes of bone resorption and bone formation. Many seemingly contradictory reports have been published on the exact functioning of TGF-beta1 in the bone milieu. This review provides an overall picture of the bone-specific actions of TGF-beta1 and reconciles experimental discrepancies that have been reported for this multifunctional cytokine.

  12. 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

  13. The role of estrogen receptor α in the regulation of bone and growth plate cartilage.

    PubMed

    Börjesson, A E; Lagerquist, M K; Windahl, S H; Ohlsson, C

    2013-11-01

    Estrogens are important endocrine regulators of skeletal growth and maintenance in both females and males. Studies have demonstrated that the estrogen receptor (ER)-α is the main mediator of these estrogenic effects in bone. Therefore, estrogen signaling via ERα is a target both for affecting longitudinal bone growth and bone remodeling. However, treatment with estradiol (E2) leads to an increased risk of side effects such as venous thromboembolism and breast cancer. Thus, an improved understanding of the signaling pathways of ERα will be essential in order to find better bone specific treatments with minimal adverse effects for different estrogen-related bone disorders. This review summarizes the recent data regarding the intracellular signaling mechanisms, in vivo, mediated by the ERα activation functions (AFs), AF-1 and AF-2, and the effect on bone, growth plate and other estrogen responsive tissues. In addition, we review the recent cell-specific ERα-deleted mouse models lacking ERα specifically in neuronal cells or growth plate cartilage. The newly characterized signaling pathways of estrogen, described in this review, provide a better understanding of the ERα signaling pathways, which may facilitate the design of new, bone-specific treatment strategies with minimal adverse effects.

  14. Connecting Mechanics and Bone Cell Activities in the Bone Remodeling Process: An Integrated Finite Element Modeling

    PubMed Central

    Hambli, Ridha

    2014-01-01

    Bone adaptation occurs as a response to external loadings and involves bone resorption by osteoclasts followed by the formation of new bone by osteoblasts. It is directly triggered by the transduction phase by osteocytes embedded within the bone matrix. The bone remodeling process is governed by the interactions between osteoblasts and osteoclasts through the expression of several autocrine and paracrine factors that control bone cell populations and their relative rate of differentiation and proliferation. A review of the literature shows that despite the progress in bone remodeling simulation using the finite element (FE) method, there is still a lack of predictive models that explicitly consider the interaction between osteoblasts and osteoclasts combined with the mechanical response of bone. The current study attempts to develop an FE model to describe the bone remodeling process, taking into consideration the activities of osteoclasts and osteoblasts. The mechanical behavior of bone is described by taking into account the bone material fatigue damage accumulation and mineralization. A coupled strain–damage stimulus function is proposed, which controls the level of autocrine and paracrine factors. The cellular behavior is based on Komarova et al.’s (2003) dynamic law, which describes the autocrine and paracrine interactions between osteoblasts and osteoclasts and computes cell population dynamics and changes in bone mass at a discrete site of bone remodeling. Therefore, when an external mechanical stress is applied, bone formation and resorption is governed by cells dynamic rather than adaptive elasticity approaches. The proposed FE model has been implemented in the FE code Abaqus (UMAT routine). An example of human proximal femur is investigated using the model developed. The model was able to predict final human proximal femur adaptation similar to the patterns observed in a human proximal femur. The results obtained reveal complex spatio-temporal bone

  15. Connecting mechanics and bone cell activities in the bone remodeling process: an integrated finite element modeling.

    PubMed

    Hambli, Ridha

    2014-01-01

    Bone adaptation occurs as a response to external loadings and involves bone resorption by osteoclasts followed by the formation of new bone by osteoblasts. It is directly triggered by the transduction phase by osteocytes embedded within the bone matrix. The bone remodeling process is governed by the interactions between osteoblasts and osteoclasts through the expression of several autocrine and paracrine factors that control bone cell populations and their relative rate of differentiation and proliferation. A review of the literature shows that despite the progress in bone remodeling simulation using the finite element (FE) method, there is still a lack of predictive models that explicitly consider the interaction between osteoblasts and osteoclasts combined with the mechanical response of bone. The current study attempts to develop an FE model to describe the bone remodeling process, taking into consideration the activities of osteoclasts and osteoblasts. The mechanical behavior of bone is described by taking into account the bone material fatigue damage accumulation and mineralization. A coupled strain-damage stimulus function is proposed, which controls the level of autocrine and paracrine factors. The cellular behavior is based on Komarova et al.'s (2003) dynamic law, which describes the autocrine and paracrine interactions between osteoblasts and osteoclasts and computes cell population dynamics and changes in bone mass at a discrete site of bone remodeling. Therefore, when an external mechanical stress is applied, bone formation and resorption is governed by cells dynamic rather than adaptive elasticity approaches. The proposed FE model has been implemented in the FE code Abaqus (UMAT routine). An example of human proximal femur is investigated using the model developed. The model was able to predict final human proximal femur adaptation similar to the patterns observed in a human proximal femur. The results obtained reveal complex spatio-temporal bone

  16. Molecular Genetic Studies of Bone Mechanical Strain and of Pedigrees with Very High Bone Density

    DTIC Science & Technology

    2007-11-01

    30-46 Col8a1 EphA3 Pit1 Increased in bone in response to mechanical loading. Involved in tooth development. Mediates bone formation by...osteoclast resorption . KO mice show increased bone density and cortical thickness. Involved in MEKK3 signaling and apoptosis. Important in...osteoclastogenesis. Involved in tooth development. Involved in angiogenesis of bone. Involved in skeletal development. 18 15-40 Lox Pdgfrb Adrb2 Mc4r

  17. Local Mechanical Stimuli Regulate Bone Formation and Resorption in Mice at the Tissue Level

    PubMed Central

    Schulte, Friederike A.; Ruffoni, Davide; Lambers, Floor M.; Christen, David; Webster, Duncan J.; Kuhn, Gisela; Müller, Ralph

    2013-01-01

    Bone is able to react to changing mechanical demands by adapting its internal microstructure through bone forming and resorbing cells. This process is called bone modeling and remodeling. It is evident that changes in mechanical demands at the organ level must be interpreted at the tissue level where bone (re)modeling takes place. Although assumed for a long time, the relationship between the locations of bone formation and resorption and the local mechanical environment is still under debate. The lack of suitable imaging modalities for measuring bone formation and resorption in vivo has made it difficult to assess the mechanoregulation of bone three-dimensionally by experiment. Using in vivo micro-computed tomography and high resolution finite element analysis in living mice, we show that bone formation most likely occurs at sites of high local mechanical strain (p<0.0001) and resorption at sites of low local mechanical strain (p<0.0001). Furthermore, the probability of bone resorption decreases exponentially with increasing mechanical stimulus (R2 = 0.99) whereas the probability of bone formation follows an exponential growth function to a maximum value (R2 = 0.99). Moreover, resorption is more strictly controlled than formation in loaded animals, and ovariectomy increases the amount of non-targeted resorption. Our experimental assessment of mechanoregulation at the tissue level does not show any evidence of a lazy zone and suggests that around 80% of all (re)modeling can be linked to the mechanical micro-environment. These findings disclose how mechanical stimuli at the tissue level contribute to the regulation of bone adaptation at the organ level. PMID:23637993

  18. Mechanical loading, damping, and load-driven bone formation in mouse tibiae.

    PubMed

    Dodge, Todd; Wanis, Mina; Ayoub, Ramez; Zhao, Liming; Watts, Nelson B; Bhattacharya, Amit; Akkus, Ozan; Robling, Alexander; Yokota, Hiroki

    2012-10-01

    Mechanical loads play a pivotal role in the growth and maintenance of bone and joints. Although loading can activate anabolic genes and induce bone remodeling, damping is essential for preventing traumatic bone injury and fracture. In this study we investigated the damping capacity of bone, joint tissue, muscle, and skin using a mouse hindlimb model of enhanced loading in conjunction with finite element modeling to model bone curvature. Our hypothesis was that loads were primarily absorbed by the joints and muscle tissue, but that bone also contributed to damping through its compression and natural bending. To test this hypothesis, fresh mouse distal lower limb segments were cyclically loaded in axial compression in sequential bouts, with each subsequent bout having less surrounding tissue. A finite element model was generated to model effects of bone curvature in silico. Two damping-related parameters (phase shift angle and energy loss) were determined from the output of the loading experiments. Interestingly, the experimental results revealed that the knee joint contributed to the largest portion of the damping capacity of the limb, and bone itself accounted for approximately 38% of the total phase shift angle. Computational results showed that normal bone curvature enhanced the damping capacity of the bone by approximately 40%, and the damping effect grew at an accelerated pace as curvature was increased. Although structural curvature reduces critical loads for buckling in beam theory, evolution apparently favors maintaining curvature in the tibia. Histomorphometric analysis of the tibia revealed that in response to axial loading, bone formation was significantly enhanced in the regions that were predicted to receive a curvature-induced bending moment. These results suggest that in addition to bone's compressive damping capacity, surrounding tissues, as well as naturally-occurring bone curvature, also contribute to mechanical damping, which may ultimately affect

  19. Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover.

    PubMed

    Street, John; Bao, Min; deGuzman, Leo; Bunting, Stuart; Peale, Franklin V; Ferrara, Napoleone; Steinmetz, Hope; Hoeffel, John; Cleland, Jeffrey L; Daugherty, Ann; van Bruggen, Nicholas; Redmond, H Paul; Carano, Richard A D; Filvaroff, Ellen H

    2002-07-23

    Several growth factors are expressed in distinct temporal and spatial patterns during fracture repair. Of these, vascular endothelial growth factor, VEGF, is of particular interest because of its ability to induce neovascularization (angiogenesis). To determine whether VEGF is required for bone repair, we inhibited VEGF activity during secondary bone healing via a cartilage intermediate (endochondral ossification) and during direct bone repair (intramembranous ossification) in a novel mouse model. Treatment of mice with a soluble, neutralizing VEGF receptor decreased angiogenesis, bone formation, and callus mineralization in femoral fractures. Inhibition of VEGF also dramatically inhibited healing of a tibial cortical bone defect, consistent with our discovery of a direct autocrine role for VEGF in osteoblast differentiation. In separate experiments, exogenous VEGF enhanced blood vessel formation, ossification, and new bone (callus) maturation in mouse femur fractures, and promoted bony bridging of a rabbit radius segmental gap defect. Our results at specific time points during the course of healing underscore the role of VEGF in endochondral vs. intramembranous ossification, as well as skeletal development vs. bone repair. The responses to exogenous VEGF observed in two distinct model systems and species indicate that a slow-release formulation of VEGF, applied locally at the site of bone damage, may prove to be an effective therapy to promote human bone repair.

  20. Mechanical stimulation of tissue repair in the hydraulic bone chamber.

    PubMed

    Guldberg, R E; Caldwell, N J; Guo, X E; Goulet, R W; Hollister, S J; Goldstein, S A

    1997-08-01

    A hydraulically activated bone chamber model was utilized to investigate cellular and microstructural mechanisms of mechanical adaptation during bone repair. Woven trabecular bone and fibrotic granulation tissue filled the initially empty chambers by 8 weeks postimplantation into canine tibial and femoral metaphyses. Without mechanical stimulation, active bone remodeling to lamellar trabecular bone and reconstitution of marrow elements were observed between 8 and 24 weeks. In subsequent loading studies, the hydraulic mechanism was activated on one randomly chosen side of 10 dogs following 8 weeks of undisturbed bone repair. The loading treatment applied an intermittent compressive force (18 N, 1.0 Hz, 1800 cycles/day) for durations of a few days up to 12 weeks. Stereological analysis of three-dimensional microcomputed tomography images revealed an increase in trabecular plate thickness and connectivity associated with the loaded repair tissue microstructure relative to unloaded contralateral controls. These microstructural alterations corresponded to an over 600% increase in the apparent modulus of the loaded bone tissue. A significant increase in the percentage of trabecular surfaces lined by osteoblasts immunopositive for type I procollagen after a few days of loading provided further evidence for mechanical stimulation of bone matrix synthesis. The local principal tissue strains associated with these adaptive changes were estimated to range from approximately -2000 to +3000 mustrain using digital image-based finite element methods. This study demonstrates the sensitivity of bone tissue and cells to a controlled in vivo mechanical stimulus and identifies microstructural mechanisms of mechanical adaptation during bone repair. The hydraulic bone chamber is introduced as an efficient experimental model to study the effects of mechanical and biological factors on bone repair and regeneration.

  1. Mechanical response tissue analyzer for estimating bone strength

    NASA Technical Reports Server (NTRS)

    Arnaud, Sara B.; Steele, Charles; Mauriello, Anthony

    1991-01-01

    One of the major concerns for extended space flight is weakness of the long bones of the legs, composed primarily of cortical bone, that functions to provide mechanical support. The strength of cortical bone is due to its complex structure, described simplistically as cylinders of parallel osteons composed of layers of mineralized collagen. The reduced mechanical stresses during space flight or immobilization of bone on Earth reduces the mineral content, and changes the components of its matrix and structure so that its strength is reduced. Currently, the established clinical measures of bone strength are indirect. The measures are based on determinations of mineral density by means of radiography, photon absorptiometry, and quantitative computer tomography. While the mineral content of bone is essential to its strength, there is growing awareness of the limitations of the measurement as the sole predictor of fracture risk in metabolic bone diseases, especially limitations of the measurement as the sole predictor of fracture risk in metabolic bone diseases, especially osteoporosis. Other experimental methods in clinical trials that more directly evaluate the physical properties of bone, and do not require exposure to radiation, include ultrasound, acoustic emission, and low-frequency mechanical vibration. The last method can be considered a direct measure of the functional capacity of a long bone since it quantifies the mechanical response to a stimulus delivered directly to the bone. A low frequency vibration induces a response (impedance) curve with a minimum at the resonant frequency, that a few investigators use for the evaluation of the bone. An alternative approach, the method under consideration, is to use the response curve as the basis for determination of the bone bending stiffness EI (E is the intrinsic material property and I is the cross-sectional moment of inertia) and mass, fundamental mechanical properties of bone.

  2. Mechanical Loading Attenuates Radiation-Induced Bone Loss in Bone Marrow Transplanted Mice.

    PubMed

    Govey, Peter M; Zhang, Yue; Donahue, Henry J

    2016-01-01

    Exposure of bone to ionizing radiation, as occurs during radiotherapy for some localized malignancies and blood or bone marrow cancers, as well as during space travel, incites dose-dependent bone morbidity and increased fracture risk. Rapid trabecular and endosteal bone loss reflects acutely increased osteoclastic resorption as well as decreased bone formation due to depletion of osteoprogenitors. Because of this dysregulation of bone turnover, bone's capacity to respond to a mechanical loading stimulus in the aftermath of irradiation is unknown. We employed a mouse model of total body irradiation and bone marrow transplantation simulating treatment of hematologic cancers, hypothesizing that compression loading would attenuate bone loss. Furthermore, we hypothesized that loading would upregulate donor cell presence in loaded tibias due to increased engraftment and proliferation. We lethally irradiated 16 female C57Bl/6J mice at age 16 wks with 10.75 Gy, then IV-injected 20 million GFP(+) total bone marrow cells. That same day, we initiated 3 wks compression loading (1200 cycles 5x/wk, 10 N) in the right tibia of 10 of these mice while 6 mice were irradiated, non-mechanically-loaded controls. As anticipated, before-and-after microCT scans demonstrated loss of trabecular bone (-48.2% Tb.BV/TV) and cortical thickness (-8.3%) at 3 wks following irradiation. However, loaded bones lost 31% less Tb.BV/TV and 8% less cortical thickness (both p<0.001). Loaded bones also had significant increases in trabecular thickness and tissue mineral densities from baseline. Mechanical loading did not affect donor cell engraftment. Importantly, these results demonstrate that both cortical and trabecular bone exposed to high-dose therapeutic radiation remain capable of an anabolic response to mechanical loading. These findings inform our management of bone health in cases of radiation exposure.

  3. 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.

  4. Growth factors and cytokines in patients with long bone fractures and associated spinal cord injury.

    PubMed

    Khallaf, Fathy G; Kehinde, Elijah O; Mostafa, Ahmed

    2016-06-01

    The aim of the study was to test the effect of acute traumatic spinal cord injury of quadriplegia or paraplegia on bone healing in patients with associated long bone fractures and to investigate the molecular and cellular events of the underlying mechanism for a possible acceleration. Healing indicators of long bone fractures and growth factors, IGF-II, platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), Activin-A, and cytokine I-L-1, in the patients' blood were calculated and measured for 21 patients with spinal cord injuries and associated long bone fractures in prospective controlled study and compared to 20 patients with only spinal cord injuries, 30 patients with only long bone fractures, and 30 healthy volunteers. The study results showed that long bone fractures in patients with associated acute traumatic spinal cord injury of quadriplegia or paraplegia heal more expectedly, faster, and with exuberant florid union callus (P > 0.001) and show statistically significant higher levels of growth factors like PDGF, VEGF, Activin-A, and cytokine I-L-1, along the 3 weeks of follow-up (P > 0.005). I-IGF-II showed statistically significant subnormal level along the whole follow-up period in the same patients (P > 0.005). We concluded that long bone fractures in spinal cord injury patients heal more expectedly, faster, and with exuberant and florid callus formation; growth factors like IGF-II, PDGF, VEGF, Activin-A, and cytokine I-L-I have roles as mediators, in molecular events and as byproducts of the subtle mechanism of accelerated osteogenesis in these patients and may represent therapeutic potentials to serve as agents to enhance bone repair.

  5. In vivo loading increases mechanical properties of scaffold by affecting bone formation and bone resorption rates.

    PubMed

    Roshan-Ghias, Alireza; Lambers, Floor M; Gholam-Rezaee, Mehdi; Müller, Ralph; Pioletti, Dominique P

    2011-12-01

    A successful bone tissue engineering strategy entails producing bone-scaffold constructs with adequate mechanical properties. Apart from the mechanical properties of the scaffold itself, the forming bone inside the scaffold also adds to the strength of the construct. In this study, we investigated the role of in vivo cyclic loading on mechanical properties of a bone scaffold. We implanted PLA/β-TCP scaffolds in the distal femur of six rats, applied external cyclic loading on the right leg, and kept the left leg as a control. We monitored bone formation at 7 time points over 35 weeks using time-lapsed micro-computed tomography (CT) imaging. The images were then used to construct micro-finite element models of bone-scaffold constructs, with which we estimated the stiffness for each sample at all time points. We found that loading increased the stiffness by 60% at 35 weeks. The increase of stiffness was correlated to an increase in bone volume fraction of 18% in the loaded scaffold compared to control scaffold. These changes in volume fraction and related stiffness in the bone scaffold are regulated by two independent processes, bone formation and bone resorption. Using time-lapsed micro-CT imaging and a newly-developed longitudinal image registration technique, we observed that mechanical stimulation increases the bone formation rate during 4-10 weeks, and decreases the bone resorption rate during 9-18 weeks post-operatively. For the first time, we report that in vivo cyclic loading increases mechanical properties of the scaffold by increasing the bone formation rate and decreasing the bone resorption rate.

  6. Role of Osteocyte-derived Insulin-Like Growth Factor I in Developmental Growth, Modeling, Remodeling, and Regeneration of the Bone

    PubMed Central

    Sheng, Matilda H. C.; Lau, K. H. William

    2014-01-01

    The osteocyte has long been considered to be the primary mechanosensory cell in the bone. Recent evidence has emerged that the osteocyte is also a key regulator of various bone and mineral metabolism and that its regulatory effects are in part mediated through locally produced osteocyte-derived factors, such as sclerostin, receptor activator of nuclear factor-kappa B ligand (RANKL), and fibroblast growth factor (FGF)-23. Osteocytes secrete large amounts of insulin-like growth factor (IGF)-I in bone. Although IGF-I produced locally by other bone cells, such as osteoblasts and chondrocytes, has been shown to play important regulatory roles in bone turnover and developmental bone growth, the functional role of osteocyte-derived IGF-I in the bone and mineral metabolism has not been investigated and remains unclear. However, results of recent studies in osteocyte Igf1 conditional knockout transgenic mice have suggested potential regulatory roles of osteocyte-derived IGF-I in various aspects of bone and mineral metabolism. In this review, evidence supporting a regulatory role for osteocyte-derived IGF-I in the osteogenic response to mechanical loading, the developmental bone growth, the bone response to dietary calcium depletion and repletion, and in fracture repair is discussed. A potential coordinated regulatory relationship between the effect of osteocyte-derived IGF-I on bone size and the internal organ size is also proposed. PMID:24707466

  7. Role of Osteocyte-derived Insulin-Like Growth Factor I in Developmental Growth, Modeling, Remodeling, and Regeneration of the Bone.

    PubMed

    Sheng, Matilda H C; Lau, K H William; Baylink, David J

    2014-02-01

    The osteocyte has long been considered to be the primary mechanosensory cell in the bone. Recent evidence has emerged that the osteocyte is also a key regulator of various bone and mineral metabolism and that its regulatory effects are in part mediated through locally produced osteocyte-derived factors, such as sclerostin, receptor activator of nuclear factor-kappa B ligand (RANKL), and fibroblast growth factor (FGF)-23. Osteocytes secrete large amounts of insulin-like growth factor (IGF)-I in bone. Although IGF-I produced locally by other bone cells, such as osteoblasts and chondrocytes, has been shown to play important regulatory roles in bone turnover and developmental bone growth, the functional role of osteocyte-derived IGF-I in the bone and mineral metabolism has not been investigated and remains unclear. However, results of recent studies in osteocyte Igf1 conditional knockout transgenic mice have suggested potential regulatory roles of osteocyte-derived IGF-I in various aspects of bone and mineral metabolism. In this review, evidence supporting a regulatory role for osteocyte-derived IGF-I in the osteogenic response to mechanical loading, the developmental bone growth, the bone response to dietary calcium depletion and repletion, and in fracture repair is discussed. A potential coordinated regulatory relationship between the effect of osteocyte-derived IGF-I on bone size and the internal organ size is also proposed.

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

    PubMed

    Roselló-Díez, Alberto; Joyner, Alexandra L

    2015-12-01

    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.

  9. Human alveolar bone cell adhesion and growth on ion-implanted titanium.

    PubMed

    Nayab, S N; Jones, F H; Olsen, I

    2004-06-15

    Surface characteristics play a vital role in determining the biocompatibility of materials used as bone implants. Calcium ion implantation of titanium was previously reported to enhance osseointegration and bone formation in vivo, although the lack of consistent and reproducible effects highlight the need to understand the basic mechanisms involved in the response of target cells to such surfaces. The aim of this study was therefore to measure the precise effects of ion implantation of titanium on bone cells in vitro. Alveolar bone cells were seeded on the surface of polished titanium disks implanted with calcium, potassium, and argon ions. Using radioisotopically tagged bone cells, the results showed that although the calcium ion implanted surface reduced cell adhesion, it nevertheless significantly enhanced cell spreading and subsequent cell growth. In contrast, few differences in bone cell behavior were observed between the potassium- and argon-implanted titanium and the control nonimplanted titanium disks. These findings suggest the possibility that the calcium-implanted surface may significantly affect the biocompatibility of titanium implants by enhancing bone cell growth. Surface modification by ion implantation could thus prove to be a valuable tool for improving the clinical efficacy of titanium for bone repair and regeneration in vivo. Copyright 2004 Wiley Periodicals, Inc.

  10. Mechanical Loading Attenuates Radiation-Induced Bone Loss in Bone Marrow Transplanted Mice

    PubMed Central

    Govey, Peter M.; Zhang, Yue; Donahue, Henry J.

    2016-01-01

    Exposure of bone to ionizing radiation, as occurs during radiotherapy for some localized malignancies and blood or bone marrow cancers, as well as during space travel, incites dose-dependent bone morbidity and increased fracture risk. Rapid trabecular and endosteal bone loss reflects acutely increased osteoclastic resorption as well as decreased bone formation due to depletion of osteoprogenitors. Because of this dysregulation of bone turnover, bone’s capacity to respond to a mechanical loading stimulus in the aftermath of irradiation is unknown. We employed a mouse model of total body irradiation and bone marrow transplantation simulating treatment of hematologic cancers, hypothesizing that compression loading would attenuate bone loss. Furthermore, we hypothesized that loading would upregulate donor cell presence in loaded tibias due to increased engraftment and proliferation. We lethally irradiated 16 female C57Bl/6J mice at age 16 wks with 10.75 Gy, then IV-injected 20 million GFP(+) total bone marrow cells. That same day, we initiated 3 wks compression loading (1200 cycles 5x/wk, 10 N) in the right tibia of 10 of these mice while 6 mice were irradiated, non-mechanically-loaded controls. As anticipated, before-and-after microCT scans demonstrated loss of trabecular bone (-48.2% Tb.BV/TV) and cortical thickness (-8.3%) at 3 wks following irradiation. However, loaded bones lost 31% less Tb.BV/TV and 8% less cortical thickness (both p<0.001). Loaded bones also had significant increases in trabecular thickness and tissue mineral densities from baseline. Mechanical loading did not affect donor cell engraftment. Importantly, these results demonstrate that both cortical and trabecular bone exposed to high-dose therapeutic radiation remain capable of an anabolic response to mechanical loading. These findings inform our management of bone health in cases of radiation exposure. PMID:27936104

  11. 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.

  12. Central IL-1 receptor signaling regulates bone growth and mass

    PubMed Central

    Bajayo, Alon; Goshen, Inbal; Feldman, Sharon; Csernus, Valer; Iverfeldt, Kerstin; Shohami, Esther; Yirmiya, Raz; Bab, Itai

    2005-01-01

    The proinflammatory cytokine IL-1, acting via the hypothalamic IL-1 receptor type 1 (IL-1RI), activates pathways known to suppress bone formation such as the hypothalamo pituitary-adrenocortical axis and the sympathetic nervous system. In addition, peripheral IL-1 has been implicated as a mediator of the bone loss induced by sex hormone depletion and TNF. Here, we report an unexpected low bone mass (LBM) phenotype, including impairment of bone growth, in IL-1RI-deficient mice (IL-1rKO mice). Targeted overexpression of human IL-1 receptor antagonist to the central nervous system using the murine glial fibrillary acidic protein promoter (IL-1raTG mice) resulted in a similar phenotype, implying that central IL-1RI silencing is the causative process in the LBM induction. Analysis of bone remodeling indicates that the process leading to the LBM in both IL-1rKO and IL-1raTG is characterized mainly by doubling the osteoclast number. Either genetic modification does not decrease testosterone or increase corticosterone serum levels, suggesting that systems other than the gonads and hypothalamo pituitary-adrenocortical axis mediate the central IL-1RI effect on bone. We further demonstrate that WT mice express mouse IL-1ra in bone but not in the hypothalamus. Because low levels of IL-1 are present in both tissues, it is suggested that skeletal IL-1 activity is normally suppressed, whereas central IL-1 produces a constant physiologic stimulation of IL-1RI signaling. Although the pathway connecting the central IL-1RI signaling to bone remodeling remains unknown, the outburst of osteoclastogenesis in its absence suggests that normally it controls bone growth and mass by tonically restraining bone resorption. PMID:16126903

  13. The Local CNP/GC-B system in growth plate is responsible for physiological endochondral bone growth.

    PubMed

    Nakao, Kazumasa; Osawa, Kenji; Yasoda, Akihiro; Yamanaka, Shigeki; Fujii, Toshihito; Kondo, Eri; Koyama, Noriaki; Kanamoto, Naotetsu; Miura, Masako; Kuwahara, Koichiro; Akiyama, Haruhiko; Bessho, Kazuhisa; Nakao, Kazuwa

    2015-05-27

    Recent studies revealed C-type natriuretic peptide (CNP) and its receptor, guanylyl cyclase-B (GC-B) are potent stimulators of endochondral bone growth. As they exist ubiquitously in body, we investigated the physiological role of the local CNP/GC-B in the growth plate on bone growth using cartilage-specific knockout mice. Bones were severely shorter in cartilage-specific CNP or GC-B knockout mice and the extent was almost the same as that in respective systemic knockout mice. Cartilage-specific GC-B knockout mice were shorter than cartilage-specific CNP knockout mice. Hypertrophic chondrocyte layer of the growth plate was drastically reduced and proliferative chondrocyte layer, along with the proliferation of chondrocytes there, was moderately reduced in either cartilage-specific knockout mice. The survival rate of cartilage-specific CNP knockout mice was comparable to that of systemic CNP knockout mice. The local CNP/GC-B system in growth plate is responsible for physiological endochondral bone growth and might further affect mortality via unknown mechanisms.

  14. Evaluation of bone mass and growth in young diabetics.

    PubMed

    Wiske, P S; Wentworth, S M; Norton, J A; Epstein, S; Johnston, C C

    1982-08-01

    To determine the relationships among bone mass, bone growth and serum glucose control in young, insulin-dependent diabetics, we performed photon absorptiometry and radiogrammetry on a clinically well-characterized group of 78 diabetics (mean age 15.2 yr, mean duration of diabetes 6.7 yr). Total and ionized calcium (TCa, ICa), magnesium (Mg), immunoreactive parathyroid hormone (iPTH) and phosphorus (P) were measured in fasting serum. Bone age was calculated from hand x-rays; and bone measurements, heights, and weights were standardized against normal groups of corresponding age, sex, and race. Mean deviation of bone mass measurement score was 1.24 SD below the normal mean (p less than .001); mean cortical area score was .22 SD and percent cortical area .25 SD below the normal means (both p less than .05). Radical width and metacarpal width for the diabetics were not less than normal. Mean percentiles for height and weight were 52.3 and 57.1 respectively, the latter significantly elevated (p less than .02). Bone mass and cortical area were inversely related to duration of disease (r = -.228, p less than .05; r = -.216, p less than .05). They were not correlated with serum parameters of mineral metabolism or of glucose control. Bone age was not significantly different from chronological age in those who had not achieved maturity (14.4 versus 14.5 yr). Mean age of menarche was 12.9 yr. When compared to normals the diabetic sample had diminished serum ICa (p less than .001), and Mg (p less than .001), though P and iPTH were not significantly different. We have demonstrated: (1) bone mass in this sample of juvenile diabetics is depressed, without evidence of impaired overall growth or delayed maturation, (2) this reduced bone mass probably results from a failure to gain the normal component of endosteal bone expected at this age, (3) this abnormality in bone growth progresses with disease but does not appear to vary with serum glucose control, and (4) in this population

  15. Regional variability in secondary remodeling within long bone cortices of catarrhine primates: the influence of bone growth history

    PubMed Central

    McFarlin, Shannon C; Terranova, Carl J; Zihlman, Adrienne L; Enlow, Donald H; Bromage, Timothy G

    2008-01-01

    Secondary intracortical remodeling of bone varies considerably among and within vertebrate skeletons. Although prior research has shed important light on its biomechanical significance, factors accounting for this variability remain poorly understood. We examined regional patterning of secondary osteonal bone in an ontogenetic series of wild-collected primates, at the midshaft femur and humerus of Chlorocebus (Cercopithecus) aethiops (n = 32) and Hylobates lar (n = 28), and the midshaft femur of Pan troglodytes (n = 12). Our major objectives were: 1) to determine whether secondary osteonal bone exhibits significant regional patterning across inner, mid-cortical and outer circumferential cortical rings within cross-sections; and if so, 2) to consider the manner in which this regional patterning may reflect the influence of relative tissue age and other circumstances of bone growth. Using same field-of-view images of 100-µm-thick cross-sections acquired in brightfield and circularly polarized light microscopy, we quantified the percent area of secondary osteonal bone (%HAV) for whole cross-sections and across the three circumferential rings within cross-sections. We expected bone areas with inner and middle rings to exhibit higher %HAV than the outer cortical ring within cross-sections, the latter comprising tissues of more recent depositional history. Observations of primary bone microstructural development provided an additional context in which to evaluate regional patterning of intracortical remodeling. Results demonstrated significant regional variability in %HAV within all skeletal sites. As predicted,%HAV was usually lowest in the outer cortical ring within cross-sections. However, regional patterning across inner vs. mid-cortical rings showed a more variable pattern across taxa, age classes, and skeletal sites examined. Observations of primary bone microstructure revealed that the distribution of endosteally deposited bone had an important influence on the

  16. Regional variability in secondary remodeling within long bone cortices of catarrhine primates: the influence of bone growth history.

    PubMed

    McFarlin, Shannon C; Terranova, Carl J; Zihlman, Adrienne L; Enlow, Donald H; Bromage, Timothy G

    2008-09-01

    Secondary intracortical remodeling of bone varies considerably among and within vertebrate skeletons. Although prior research has shed important light on its biomechanical significance, factors accounting for this variability remain poorly understood. We examined regional patterning of secondary osteonal bone in an ontogenetic series of wild-collected primates, at the midshaft femur and humerus of Chlorocebus (Cercopithecus) aethiops (n = 32) and Hylobates lar (n = 28), and the midshaft femur of Pan troglodytes (n = 12). Our major objectives were: 1) to determine whether secondary osteonal bone exhibits significant regional patterning across inner, mid-cortical and outer circumferential cortical rings within cross-sections; and if so, 2) to consider the manner in which this regional patterning may reflect the influence of relative tissue age and other circumstances of bone growth. Using same field-of-view images of 100-microm-thick cross-sections acquired in brightfield and circularly polarized light microscopy, we quantified the percent area of secondary osteonal bone (%HAV) for whole cross-sections and across the three circumferential rings within cross-sections. We expected bone areas with inner and middle rings to exhibit higher %HAV than the outer cortical ring within cross-sections, the latter comprising tissues of more recent depositional history. Observations of primary bone microstructural development provided an additional context in which to evaluate regional patterning of intracortical remodeling. Results demonstrated significant regional variability in %HAV within all skeletal sites. As predicted,%HAV was usually lowest in the outer cortical ring within cross-sections. However, regional patterning across inner vs. mid-cortical rings showed a more variable pattern across taxa, age classes, and skeletal sites examined. Observations of primary bone microstructure revealed that the distribution of endosteally deposited bone had an important influence on

  17. Alteration in bone geometric and mechanical properties, histomorphometrical parameters of trabecular bone, articular cartilage, and growth plate in adolescent rats after chronic co-exposure to cadmium and lead in the case of supplementation with green, black, red and white tea.

    PubMed

    Tomaszewska, Ewa; Dobrowolski, Piotr; Winiarska-Mieczan, Anna; Kwiecień, Małgorzata; Tomczyk, Agnieszka; Muszyński, Siemowit; Radzki, Radosław

    2016-09-01

    Adolescent male Wistar rats were used to check whether regular consumption of black, red, white, or green tea would have a protective effect on femur development during 12-week exposure to Cd and Pb (7mg Cd and 50mg Pb in 1kg of the diet). The animals were randomly divided (n=12) into a positive control (without Cd, Pb and teas), a negative control group (Cd and Pb), and groups supplemented additionally with green (GT), black (BT), red (RT), and white tea (WT). Heavy metals reduced the geometric and densitometric parameters and the total thickness of articular cartilage irrespective of tea administration and influenced mechanical endurance, growth plate thickness, and trabecular histomorphometry depending on the tea type. It is difficult to indicate which tea has the best protective effects on bone and hyaline cartilage against heavy metal action.

  18. 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

  19. Mechanisms of PDGF siRNA-mediated inhibition of bone cancer pain in the spinal cord

    PubMed Central

    Xu, Yang; Liu, Jia; He, Mu; Liu, Ran; Belegu, Visar; Dai, Ping; Liu, Wei; Wang, Wei; Xia, Qing-Jie; Shang, Fei-Fei; Luo, Chao-Zhi; Zhou, Xue; Liu, Su; McDonald, JohnW.; Liu, Jin; Zuo, Yun-Xia; Liu, Fei; Wang, Ting-Hua

    2016-01-01

    Patients with tumors that metastasize to bone frequently suffer from debilitating pain, and effective therapies for treating bone cancer are lacking. This study employed a novel strategy in which herpes simplex virus (HSV) carrying a small interfering RNA (siRNA) targeting platelet-derived growth factor (PDGF) was used to alleviate bone cancer pain. HSV carrying PDGF siRNA was established and intrathecally injected into the cavum subarachnoidale of animals suffering from bone cancer pain and animals in the negative group. Sensory function was assessed by measuring thermal and mechanical hyperalgesia. The mechanism by which PDGF regulates pain was also investigated by comparing the differential expression of pPDGFRα/β and phosphorylated ERK and AKT. Thermal and mechanical hyperalgesia developed in the rats with bone cancer pain, and these effects were accompanied by bone destruction in the tibia. Intrathecal injection of PDGF siRNA and morphine reversed thermal and mechanical hyperalgesia in rats with bone cancer pain. In addition, we observed attenuated astrocyte hypertrophy, down-regulated pPDGFRα/β levels, reduced levels of the neurochemical SP, a reduction in CGRP fibers and changes in pERK/ERK and pAKT/AKT ratios. These results demonstrate that PDGF siRNA can effectively treat pain induced by bone cancer by blocking the AKT-ERK signaling pathway. PMID:27282805

  20. The acrophysis: a unifying concept for enchondral bone growth and its disorders. I. Normal growth.

    PubMed

    Oestreich, Alan E

    2003-03-01

    In order to discuss and illustrate the common effects on normal and abnormal enchondral bone at the physes and at all other growth plates of the developing child, the term "acrophysis" is proposed. Acrophyses include the growth plates of secondary growth centers including carpals and tarsals and apophyses, and the growth plates at the non-physeal ends of small tubular bones. The last layer of development of both physes and acrophysis is the cartilaginous zone of provisional calcification (ZPC). The enchondral bone abutting the ZPC shares similar properties at physes and acrophyses, including the relatively lucent metaphyseal bands of many normal infants at several weeks of age. The bone-in-bone pattern of the normal vertebral bodies and bands of demineralization of the tarsal bones just under the ZPC are the equivalent of those bands. The growth arrest/recovery lines of metaphyses similarly have equivalent lines in growth centers and other acrophyseal sites. Nearly the same effects can also be anticipated from the relatively similar growth plate at the cartilaginous cap of benign exostoses ("paraphysis"). The companion article will explore abnormalities at acrophyseal sites, including metabolic bone disease and dysplasias.

  1. The influence of follistatin on mechanical properties of bone tissue in growing mice with overexpression of follistatin.

    PubMed

    Gajos-Michniewicz, Anna; Pawlowska, Elzbieta; Ochedalski, Tomasz; Piastowska-Ciesielska, Agnieszka

    2012-07-01

    Mechanical competence of bones is mainly associated with tissue quality that depends on proper bone metabolism processes. An imbalance in the regulation of bone metabolism leads to pathological changes in bone tissue leading to susceptibility to bone fractures and bone deterioration processes. Bone metabolism is regulated to a large extent by the members of the transforming growth factor-β superfamily, i.e., activins and bone morphogenetic proteins. However, their function is regulated by a single-chain protein called follistatin (FS). The aim of this study was to test the hypothesis that overexpression of FS in growing mice results in impairments in bone morphology and mechanical properties. Moreover, we wanted to investigate how geometrical, structural and material properties of bone tissue change with age. The experiment was performed on growing C57BL/6 TgNK14-mFst/6J mice, overexpressing FS (F mice) versus C57BL/6J mice used as controls (C mice). To establish how overexpression of FS influences bone tissue quality, we studied mice femurs to determine geometrical, structural and material properties of the skeleton. To determine mechanical resistance of bone tissue, femurs were loaded to failure in a three-point bending test. Obtained results indicated that overexpression of FS negatively influences bone metabolism. It was found that mutation results with a significant decrease of all measured biomechanical strength variables in F mice in comparison to C mice. Overexpression of FS leads to decreased quality of skeleton, increasing susceptibility to bone fractures.

  2. Mechanisms of Bone Mineralization and Effects of Mechanical Loading

    NASA Technical Reports Server (NTRS)

    Babich, Michael

    1996-01-01

    The data suggest that PTH and PKC inhibit nodule formation, and that alternative energy sources are utilized by osteoblasts in the process of mineralization. The conditions and techniques to grow, fix, photograph, and measure bone mineralization in vitro were defined. The results are presently in preliminary form and require further assessment as follows; quantitate the surface area of nodules + treatments via computer-aided image analysis; use PTH + inhibitors of signaling pathways to determine the mechanism of nodule formation; determine how protein kinase C is involved as a promotor of nodule formation; cell proliferation vs. cell death affected by modulation of signal transduction (i.e., PTH, enzyme inhibitors and activators); identify mRNA induced or decreased in response to PTH and signaling modulators that encode proteins that regulate cell morphology, proliferation, and nodule formation. Therefore, several follow-up studies between the laboratories at NASA-Ames Research Center and my laboratory at the University of Illinois have been initiated.

  3. Mechanisms of Bone Mineralization and Effects of Mechanical Loading

    NASA Technical Reports Server (NTRS)

    Babich, Michael

    1996-01-01

    The data suggest that PTH and PKC inhibit nodule formation, and that alternative energy sources are utilized by osteoblasts in the process of mineralization. The conditions and techniques to grow, fix, photograph, and measure bone mineralization in vitro were defined. The results are presently in preliminary form and require further assessment as follows; quantitate the surface area of nodules + treatments via computer-aided image analysis; use PTH + inhibitors of signaling pathways to determine the mechanism of nodule formation; determine how protein kinase C is involved as a promotor of nodule formation; cell proliferation vs. cell death affected by modulation of signal transduction (i.e., PTH, enzyme inhibitors and activators); identify mRNA induced or decreased in response to PTH and signaling modulators that encode proteins that regulate cell morphology, proliferation, and nodule formation. Therefore, several follow-up studies between the laboratories at NASA-Ames Research Center and my laboratory at the University of Illinois have been initiated.

  4. 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.

  5. 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.

  6. Investigation on mechanical properties of contemporary metallic bone plates: towards the development of composite bone plates.

    PubMed

    Hoque, M E; Zainal, N H; Syarif, J

    2008-07-01

    This study aims at investigating the mechanical properties of the contemporary metallic bone plates determining the effect of their length, width and thickness on the properties and compares with the composite bone plates. Three-points bending test was performed over the stainless steel plates of different length, width and thickness. The test results showed that different plates had different mechanical properties. However, the properties are still much higher than that of particular bones intended to be treated. Therefore, the reported findings strongly encourage developing composite bone plates with biocompatible polymers/fibers that would have modulated properties according to the requirements.

  7. Comparative data on the differentiation and growth of bone ornamentation in gnathostomes (Chordata: Vertebrata).

    PubMed

    de Buffrénil, Vivian; Clarac, François; Canoville, Aurore; Laurin, Michel

    2016-05-01

    Bone ornamentation, in the form of rounded pits framed by a network of ridges, is a frequent feature among a great diversity of gnathostome taxa. However, the basic osteogenic processes controlling the differentiation and development of these reliefs remain controversial. The present study is a broad comparative survey of this question with the classical methods used in hard tissue histology and paleohistology. Distinct processes, unevenly distributed among taxa, are involved in the creation and growth of pits and ridges. The simplest one is mere differential growth between pit bottom (slow growth) and ridge top (faster growth). The involvement of several complex remodeling processes, with the local succession of resorption and reconstruction cycles, is frequent and occurs in all major gnathostome clades. Some broad, inclusive clades (e.g., Temnospondyli) display consistency in the mechanisms controlling ornamentation, whereas other clades (e.g., Actinopterygii) are characterized by the diversity of the mechanisms involved. If osteogenic mechanisms are taken into account, bone ornamentation should be considered as a character extremely prone to homoplasy. Maximum likelihood (ML) optimizations reveal that the plesiomorphic mechanism creating ornamentation is differential apposition rate over pits (slow growth) and ridges (faster growth). In some taxas e.g., temnospondyls vs lissamphibians or pseudosuchians, bone ornamentation is likely to be a homoplastic feature due to a convergence process driven by similar selective pressures. ML models of character evolution suggest that the presence of resorption in the development of ornamentation may be selectively advantageous, although support for this conclusion is only moderate.

  8. Radiation-induced craniofacial bone growth inhibition: acute and long-term effects on bone histopathology with and without cytoprotection.

    PubMed

    Oʼdonovan, David A; La Scala, Giorgio C; Leong, Iona; Mendes, Maria; Rogers, Marianne; Pritzker, Kenneth H; Yeung, Ivan; Pang, Cho Y; Neligan, Peter C; Forrest, Christopher R

    2012-04-01

    The authors previously established an animal model of radiation-induced craniofacial bone growth inhibition and demonstrated the effectiveness of cytoprotection in preserving growth using amifostine, but the mechanism is unclear. The objective of this study was to investigate the acute and long-term histopathologic effects of single-dose orthovoltage irradiation on craniofacial bone with and without cytoprotection. Sixty infant New Zealand White rabbits (7-week-old) were randomized into three groups (n = 20 per group): group 1, 0-Gy, sham irradiation; group 2, 35-Gy single-dose orthovoltage irradiation; and group 3, cytoprotection with amifostine before irradiation. Orbitozygomatic complex bone was harvested from animals 12 hours after irradiation and at skeletal maturity (21 weeks of age). Histologic parameters measured included native bone cell (osteoblast, osteoclast, and osteocyte) populations, periosteal proliferation indices (MIB-1 stains), bone turnover rates [triple fluorochromes: tetracycline administered at 7 weeks of age (before irradiation), alizarin complexone at 12 weeks, and calcein at 16 weeks of age], and endosteal space fibrosis levels. Orthovoltage irradiation significantly (p < 0.05) reduced osteoblast and osteoclast counts 12 hours after irradiation (age, 7 weeks) with or without pretreatment with amifostine but had no effect on osteocyte populations. Long-term analysis at age 21 weeks demonstrated significantly (p < 0.05) increased osteoblast counts, reduced endosteal space fibrosis, reduced periosteal proliferation indices, and improved bone turnover (fluorochrome stains) in amifostine-treated animals. This study suggests that amifostine cytoprotection is mediated through a combination of reduced cellular injury with enhanced promotion of cellular bone rebuilding potential.

  9. Tamoxifen induces permanent growth arrest through selective induction of apoptosis in growth plate chondrocytes in cultured rat metatarsal bones.

    PubMed

    Chagin, Andrei S; Karimian, Elham; Zaman, Farasat; Takigawa, Masaharu; Chrysis, Dionisios; Sävendahl, Lars

    2007-05-01

    Estrogen affects skeletal growth and promotes growth plate fusion in humans. High doses of estrogen have been used to limit growth in girls with predicted extreme tall stature; a treatment which has been associated with severe side effects. Selective estrogen receptor modulators (SERMs) could potentially be used as an alternative treatment. We chose to study the effects of Tamoxifen (Tam), a first generation SERM that has been used in the treatment of pubertal gynecomastia or McCune-Albright syndrome. Cultured fetal rat metatarsal bones were used to study the effects of Tam on longitudinal bone growth. In sectioned bones, chondrocyte apoptosis and proliferation were analyzed by TUNEL assay and BrdU incorporation, respectively. We also used a human chondrocytic cell line, HSC-2/8, to study the effects of Tam on apoptosis (FACS analysis and Cell Death detection ELISA) and caspase activation (caspase substrate cleavage and Western immunoblotting). Tam caused a dose-dependent growth retardation of cultured metatarsal bones. No catch-up growth was observed after Tam was removed from the culture medium. Detailed analysis of sectioned growth plate cartilage revealed increased apoptosis of chondrocytes within the resting and hypertrophic zones. HCS-2/8 cells also underwent apoptosis upon Tam treatment. Tam-induced apoptosis was caspase-dependent and completely abrogated by either caspase-8 or -9 inhibitors. A substrate assay revealed that caspase-8 is first activated followed by caspase-9 and -3. Finally, FasL secretion was stimulated by Tam and blocking of either FasL or Fas decreased Tam-induced apoptosis in chondrocytes. We here describe a novel mechanism of tamoxifen-induced apoptosis in chondrocytes, involving the activation of caspases and the FasL/Fas pathway, which diminishes the potential for bone growth.

  10. A review of the actual knowledge of the processes governing growth and development of long bones.

    PubMed

    Pazzaglia, Ugo Ernesto; Beluffi, Giampiero; Benetti, Anna; Bondioni, Maria Pia; Zarattini, Guido

    2011-01-01

    Autoptic samples of human bones (from 8 weeks of gestation to 12 years of age) and a second group of serial, skeletal x-rays (required for pathologies not related to bone dysplasia in children from 4 months to 17 years of age) provided the material for the analysis of the physes normal growth mechanism presented in this review. Before the appearance of the ossification centers epiphyseal growth rests exclusively on chondrocytes proliferation (interstitial growth), without any detectable differentiated cellular organization. When endochondral ossification starts a defined spatial disposition of chondrocytes and a corresponding organization of the intercellular matrix is set up, so that it is possible to identify a growth vector corresponding to the columns of piled chondrocytes with direction from hypertrophic toward the proliferative cell layers. The complexity of the tubular bones growth process is well represented by the spatial arrangement of the growth vectors. In the late epiphyseal growth another mechanism is active in addition to endochondral ossification, namely, articular cartilage interstitial growth and subchondral remodelling. The knowledge of the normal mode of organization of the physis and its temporal sequence can help to better understand of the deviaton from the normal development of metaphyseal and epiphyseal dysplasias.

  11. Osteoimmune Mechanisms of Segmental Bone Fracture Healing and Therapy

    DTIC Science & Technology

    2016-09-01

    it is essential to understand additional mechanisms that play a crucial role in bone healing through participation of cells other than osteoblasts...osteoclasts and their respective progenitors. Bone fractures heal with overlapping phases of inflammation, cell proliferation, and bone remodeling...fracture healing. During fracture repair, there is an abundant infiltration of immune cells at the fracture site that not only mediate the inflammatory

  12. Fibroblast growth factor-2 and vascular endothelial growth factor mediated augmentation of angiogenesis and bone formation in vascularized bone allotransplants.

    PubMed

    Larsen, Mikko; Willems, Wouter F; Pelzer, Michael; Friedrich, Patricia F; Dadsetan, Mahrokh; Bishop, Allen T

    2014-05-01

    We previously demonstrated recipient-derived neoangiogenesis to maintain viability of living bone allogeneic transplants without long-term immunosuppression. The effect of cytokine delivery to enhance this process is studied. Vascularized femur transplantation was performed from Dark Agouti to Piebald Virol Glaxo rats. Poly(d,l-lactide-co-glycolide) microspheres loaded with buffer (N = 11), basic fibroblast growth factor (FGF2) (N = 10), vascular endothelial growth factor (VEGF) (N = 11), or both (N = 11) were inserted intramedullarly alongside a recipient-derived arteriovenous bundle. FK-506 was administered for 2 weeks. At 18 weeks, bone blood flow, microangiography, histologic, histomorphometric, and alkaline phosphatase measurements were performed. Bone blood flow was greater in the combined group than control and VEGF groups (P = 0.04). Capillary density was greater in the FGF2 group than in the VEGF and combined groups (P < 0.05). Bone viability, growth, and alkaline phosphatase activity did not vary significantly between groups. Neoangiogenesis in vascularized bone allotransplants is enhanced by angiogenic cytokine delivery, with results using FGF2 that are comparable to isotransplant from previous studies. Further studies are needed to achieve bone formation similar to isotransplants. Copyright © 2013 Wiley Periodicals, Inc.

  13. Alveolar bone loss: mechanisms, potential therapeutic targets, and interventions.

    PubMed

    Intini, G; Katsuragi, Y; Kirkwood, K L; Yang, S

    2014-05-01

    This article reviews recent research into mechanisms underlying bone resorption and highlights avenues of investigation that may generate new therapies to combat alveolar bone loss in periodontitis. Several proteins, signaling pathways, stem cells, and dietary supplements are discussed as they relate to periodontal bone loss and regeneration. RGS12 is a crucial protein that mediates osteoclastogenesis and bone destruction, and a potential therapeutic target. RGS12 likely regulates osteoclast differentiation through regulating calcium influx to control the calcium oscillation-NFATc1 pathway. A working model for RGS10 and RGS12 in the regulation of Ca(2+) oscillations during osteoclast differentiation is proposed. Initiation of inflammation depends on host cell-microbe interactions, including the p38 mitogen-activated protein kinase (MAPK) signaling pathway. Oral p38 inhibitors reduced lipopolysaccharide (LPS)-induced bone destruction in a rat periodontitis model but showed unsatisfactory safety profiles. The p38 substrate MK2 is a more specific therapeutic target with potentially superior tolerability. Furthermore, MKP-1 shows anti-inflammatory activity, reducing inflammatory cytokine biosynthesis and bone resorption. Multipotent skeletal stem cell (SSC) populations exist within the bone marrow and periosteum of long bones. These bone-marrow-derived SSCs and periosteum-derived SSCs have shown therapeutic potential in several applications, including bone and periodontal regeneration. The existence of craniofacial bone-specific SSCs is suggested based on existing studies. The effects of calcium, vitamin D, and soy isoflavone supplementation on alveolar and skeletal bone loss in post-menopausal women were investigated. Supplementation resulted in stabilization of forearm bone mass density and a reduced rate of alveolar bone loss over 1 yr, compared with placebo. Periodontal attachment levels were also well-maintained and alveolar bone loss suppressed during 24 wk of

  14. Multi-axial mechanical properties of human trabecular bone.

    PubMed

    Rincón-Kohli, Liliana; Zysset, Philippe K

    2009-06-01

    In the context of osteoporosis, evaluation of bone fracture risk and improved design of epiphyseal bone implants rely on accurate knowledge of the mechanical properties of trabecular bone. A multi-axial loading chamber was designed, built and applied to explore the compressive multi-axial yield and strength properties of human trabecular bone from different anatomical locations. A thorough experimental protocol was elaborated for extraction of cylindrical bone samples, assessment of their morphology by micro-computed tomography and application of different mechanical tests: torsion, uni-axial traction, uni-axial compression and multi-axial compression. A total of 128 bone samples were processed through the protocol and subjected to one of the mechanical tests up to yield and failure. The elastic data were analyzed using a tensorial fabric-elasticity relationship, while the yield and strength data were analyzed with fabric-based, conewise generalized Hill criteria. For each loading mode and more importantly for the combined results, strong relationships were demonstrated between volume fraction, fabric and the elastic, yield and strength properties of human trabecular bone. Despite the reviewed limitations, the obtained results will help improve the simulation of the damage behavior of human bones and bone-implant systems using the finite element method.

  15. The importance of mechanical loading in bone biology and medicine.

    PubMed

    Martin, R B

    2007-01-01

    This paper discusses the premise that the skeleton is primarily a mechanical organ, and reviews the reasons that mechanical factors play a major role in bone biology. It begins by considering three basic observations: (1) Galileo's observation that bone proportions become more robust as the species' overall size increases; (2) da Vinci's observation that larger structures are inherently weaker than smaller structures subjected to the same stress; and (3) the general observation that each unit of bone mass provides structural support for about 15 units of soft tissue organ mass. Together, these observations lead to the concept that it can be advantageous to minimize bone mass, consistent with constraints on other factors. This premise is discussed here in relation to the phenomenon of bone remodeling, which is seen to serve two purposes: the adjustment of bone mass and geometry to maintain peak bone strains at their maximum tolerable values, and the continual removal of fatigue damage produced at those strain levels. Finally, it is observed that bone remodeling apparently originated approximately 250 million years ago when the first vertebrates of substantial size became weight-bearing on land, suggesting that mechanical forces associated with weight-bearing were instrumental in the evolution of bone remodeling.

  16. Investigation into mechanical properties of bone and its main constituents

    NASA Astrophysics Data System (ADS)

    Evdokimenko, Ekaterina

    Bone is a hierarchically structured natural composite material, consisting of organic phase (type-I collagen), inorganic phase (hydroxyapatite), and water. Studies of the two main bone constituents, utilizing controlled demineralization and deproteinization, can shed light on mineral-collagen interaction which makes bone such a unique biological material. This knowledge is necessary for computational analysis of bone structure to identify preferential sites in the collagen matrix and mineral network that degrade more easily. The main goal of this work is to develop a comprehensive picture of mechanical properties of bone and its main constituents. Following the Introduction, Chapter 2 presents an investigation of microstructure and compressive mechanical properties of bovine femur cortical bone carried out on completely demineralized, completely deproteinized, and untreated bone samples in three anatomical directions. Anisotropic nature of bone was clearly identified in all cases. Extra levels of porosity along with microstructural differences for the three directions were found to be the main sources of the anisotropy. In Chapter 3, a new theoretical model of cortical and trabecular bone as composite materials with hierarchical structure spanning from nanometer (collagen-mineral) level to millimeter (bone) level was developed. Compression testing was performed on untreated, demineralized, and deproteinized cortical and trabecular bovine femur bone samples to verify the model. The experimental data were compared with theoretical predictions; excellent agreement was found between the theory and experiments for all bone phases. Optical microscopy, scanning electron microscopy, and micro-computed tomography techniques were applied to characterize the structure of the samples at multiple length scales and provide further inputs for the modeling. Chapter 4 presents a comparative study of mechanical properties, microstructure, and porosity of mature and young bovine

  17. Growth in infancy and bone mass in later life

    PubMed Central

    Cooper, C.; Fall, C.; Egger, P.; Hobbs, R.; Eastell, R.; Barker, D.

    1997-01-01

    OBJECTIVE—To examine the association between weight in infancy and bone mass during the seventh decade of life in a population based cohort for which detailed birth and childhood records were preserved.
METHODS—189 women and 224 men who were aged 63-73 years and were born in East Hertfordshire underwent bone densitometry by dual energy x ray absorptiometry. Measurements were also made of serum osteocalcin and urinary excretion of type 1 collagen cross linked N-telopeptide.
RESULTS—There were statistically significant associations between weight at 1 year and bone mineral content (but not bone mineral density) at the spine (P < 0.02) and femoral neck (P < 0.01) among women, and spine (P < 0.03) among men. Although serum osteocalcin was negatively correlated with bone mineral density at both sites among men and women, infant weight was not significantly associated with either biochemical marker of bone turnover.
CONCLUSIONS—These data confirm our previous observations that growth in infancy is associated with skeletal size in adulthood, and suggest that skeletal growth may be programmed during intrauterine or early postnatal life.

 PMID:9059135

  18. From mechanical stimulus to bone formation: A review.

    PubMed

    Rosa, Natacha; Simoes, Ricardo; Magalhães, Fernão D; Marques, Antonio Torres

    2015-08-01

    Bone is a remarkable tissue that can respond to external stimuli. The importance of mechanical forces on the mass and structural development of bone has long been accepted. This adaptation behaviour is very complex and involves multidisciplinary concepts, and significant progress has recently been made in understanding this process. In this review, we describe the state of the art studies in this area and highlight current insights while simultaneously clarifying some basic yet essential topics related to the origin of mechanical stimulus in bone, the biomechanisms associated with mechanotransduction, the nature of physiological bone stimuli and the test systems most commonly used to study the mechanical stimulation of bone. Copyright © 2015 IPEM. Published by Elsevier Ltd. All rights reserved.

  19. Cranial Sutures and Bones: Growth and Fusion in Relation to Masticatory Strain

    PubMed Central

    SUN, ZONGYANG; LEE, EUGENIA; HERRING, SUSAN W.

    2010-01-01

    Cranial bones and sutures are mechanically loaded during mastication. Their response to masticatory strain, however, is largely unknown, especially in the context of age change. Using strain gages, this study investigated masticatory strain in the posterior interfrontal and the anterior interparietal sutures and their adjacent bones in 3- and 7-month-old miniature swine (Sus scrofa). Double-fluorochrome labeling of these animals and an additional 5-month group was used to reveal suture and bone growth as well as features of suture morphology and fusion. With increasing age, the posterior interfrontal suture strain decreased in magnitude and changed in pattern from pure compression to both compression and tension, whereas the interparietal suture remained in tension and the magnitude increased unless the suture was fused. Morphologically, the posterior interfrontal suture was highly interdigitated at 3 months and then lost interdigitation ectocranially in older pigs, whereas the anterior interparietal suture remained butt-ended. Mineralization apposition rate (MAR) decreased with age in both sutures and was unrelated to strain. Bone mineralization was most vigorous on the ectocranial surface of the frontal and the parietal bones. Unlike the sutures, with age bone strain remained constant while bone MARs significantly increased and were correlated with bone thickness. Fusion had occurred in the interparietal suture of some pigs. In all cases fusion was ectocranial rather than endocranial. Fusion appeared to be associated with increased suture strain and enhanced bone growth on the ectocranial surface. Collectively, these results indicate that age is an important factor for strain and growth of the cranium. PMID:14752854

  20. Bone histology. Evolution of growth pattern in birds.

    PubMed

    Chinsamy, A; Elzanowski, A

    2001-07-26

    Living (neornithine) birds grow up rapidly and without interruption, terminating their growth within one year and, with a few secondary exceptions, starting to fly only after or near the completion of growth. Bone histology has revealed that pre-avian theropods also grew fast for most of the postnatal period, but that this growth was usually intermittent and probably extended for more than one year. We have found surprising evidence for an early postnatal slowing-down of growth in two lineages of flying basal birds, which suggests that birds may have started their evolution as precocious fliers.

  1. [Effects of growth hormone replacement therapy on bone metabolism].

    PubMed

    Yamamoto, Masahiro; Sugimoto, Toshitsugu

    2014-06-01

    Growth hormone (GH) as well as insulin like growth factor-1 (IGF-1) are essential hormones to maintain homeostasis of bone turnover by activating osteoblastogenesis and osteoclastogenesis. Results from GH replacement therapy for primary osteoporosis and adult-onset GH deficiency (AGHD) suggest that one year or more treatment period by this agent is required to gain bone mineral density (BMD) over the basal level after compensating BMD loss caused by dominant increase in bone resorption which was observed at early phase of GH treatment. A recent meta-analysis demonstrates the efficacy of GH replacement therapy on increases in BMD in male patients with AGHD. Additional analyses are needed to draw firm conclusions in female patients with AGHD, because insufficient amounts of GH might be administrated to them without considerations of influence of estrogen replacement therapy on IGF-1 production. Further observational studies are needed to clarify whether GH replacement therapy prevent fracture risk in these patients.

  2. Focus on growth hormone deficiency and bone in adults.

    PubMed

    Tritos, Nicholas A

    2017-02-01

    Growth hormone (GH) exerts several effects on the skeleton, mediated either directly or indirectly, leading to increased bone formation and resorption rates. Patients with growth hormone deficiency (GHD) of adult onset have decreased bone mineral density (BMD) and increased fracture risk. Some, but not all, studies have found that adults with childhood onset GHD also have lower BMD than healthy controls. Adults with GHD of childhood onset have smaller bone dimensions, leading to possible underestimation of areal BMD (measured by dual energy X-ray absorptiometry), thus potentially confounding the interpretation of densitometric data. Available data suggest that patients with childhood onset GHD are at increased fracture risk. Prospective studies and some clinical trials found that GH replacement for at least 18-24 months leads to increased BMD. Retrospective and prospective data suggest that GH replacement is associated with decreased fracture risk in adults. However, data from randomized clinical trials are lacking. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Locally applied nerve growth factor enhances bone consolidation in a rabbit model of mandibular distraction osteogenesis.

    PubMed

    Wang, Lei; Zhou, Shuxia; Liu, Baolin; Lei, Delin; Zhao, Yinghua; Lu, Chao; Tan, Aixing

    2006-12-01

    Distraction osteogenesis is widely used in treating deformities, defects, and fractures of both long bones and craniofacial bones. Demands for acceleration of bone consolidation are increased in distraction osteogenesis. Nerve growth factor (NGF) can enhance innervation and bone regeneration in a fracture model and stimulate differentiation of osteoblastic cells. In this study, we tested the ability of locally applied NGF to enhance bone regeneration in a rabbit model of mandibular distraction osteogenesis. Twenty rabbits underwent bilateral distraction osteogenesis with a rate of 0.5 mm per 12 h. Two times 0.04 mg human NGFbeta (hNGFbeta) in buffer was injected into the callus after distraction. The contralateral side received placebo injections. Rabbits were euthanized at consolidation times of 14 and 28 days. Specimens were subjected to radiography, callus dimensions measurement, mechanical testing, and bone histological and histomorphometric analysis. The maximum load, bone volume/total volume, mineral apposition rate of the 1st to 11th day, and mineralized bone percentage were significantly higher in the hNGFbeta side at 14 and 28 days (p<0.05). The data indicate that locally applied hNGFbeta can accelerate callus maturation and may be an option to shorten the consolidation period in distraction osteogenesis.

  4. Estrogen regulates the rate of bone turnover but bone balance in ovariectomized rats is modulated by prevailing mechanical strain

    NASA Technical Reports Server (NTRS)

    Westerlind, K. C.; Wronski, T. J.; Ritman, E. L.; Luo, Z. P.; An, K. N.; Bell, N. H.; Turner, R. T.

    1997-01-01

    Estrogen deficiency induced bone loss is associated with increased bone turnover in rats and humans. The respective roles of increased bone turnover and altered balance between bone formation and bone resorption in mediating estrogen deficiency-induced cancellous bone loss was investigated in ovariectomized rats. Ovariectomy resulted in increased bone turnover in the distal femur. However, cancellous bone was preferentially lost in the metaphysis, a site that normally experiences low strain energy. No bone loss was observed in the epiphysis, a site experiencing higher strain energy. The role of mechanical strain in maintaining bone balance was investigated by altering the strain history. Mechanical strain was increased and decreased in long bones of ovariectomized rats by treadmill exercise and functional unloading, respectively. Functional unloading was achieved during orbital spaceflight and following unilateral sciatic neurotomy. Increasing mechanical loading reduced bone loss in the metaphysis. In contrast, decreasing loading accentuated bone loss in the metaphysis and resulted in bone loss in the epiphysis. Finally, administration of estrogen to ovariectomized rats reduced bone loss in the unloaded and prevented loss in the loaded limb following unilateral sciatic neurotomy in part by reducing indices of bone turnover. These results suggest that estrogen regulates the rate of bone turnover, but the overall balance between bone formation and bone resorption is influenced by prevailing levels of mechanical strain.

  5. Advances in the understanding of myeloma bone disease and tumour growth

    PubMed Central

    Yaccoby, Shmuel

    2010-01-01

    Summary Advances in multiple myeloma support the notion that the associated bone disease, characterized by increased osteoclastogenesis and suppressed osteoblastogenesis, is both a consequence and necessity of tumour progression. Osteoblastogenesis is suppressed by secreted inhibitors and dysregulation of cell-surface “coupling” factors on osteogenic cells. Osteoclastogenesis is increased as a consequence of osteoblast deactivation and of production of osteoclast-activating factors. Osteoclasts express soluble and cell-surface factors that stimulate myeloma growth, while osteoblasts produce bone-building factors that restrain growth of myeloma cells that are dependent on the microenvironment; detailed molecular mechanisms are discussed. Experimental and clinical findings indicate that pharmacological and experimental osteoblast-activating agents that effectively promote bone formation also reduce growth of myeloma cells within bone, seemingly by simultaneously stimulating osteoblastogenesis and restraining osteoclastogenesis. Unravelling mechanisms of myeloma bone disease expands horizons for developing novel interventions and also facilitates better understanding of the association between induction of osteolysis and disease progression. PMID:20230410

  6. The aging of Wolff's "law": ontogeny and responses to mechanical loading in cortical bone.

    PubMed

    Pearson, Osbjorn M; Lieberman, Daniel E

    2004-01-01

    The premise that bones grow and remodel throughout life to adapt to their mechanical environment is often called Wolff's law. Wolff's law, however, is not always true, and in fact comprises a variety of different processes that are best considered separately. Here we review the molecular and physiological mechanisms by which bone senses, transduces, and responds to mechanical loads, and the effects of aging processes on the relationship (if any) between cortical bone form and mechanical function. Experimental and comparative evidence suggests that cortical bone is primarily responsive to strain prior to sexual maturity, both in terms of the rate of new bone growth (modeling) as well as rates of turnover (Haversian remodeling). Rates of modeling and Haversian remodeling, however, vary greatly at different skeletal sites. In addition, there is no simple relationship between the orientation of loads in long bone diaphyses and their cross-sectional geometry. In combination, these data caution against assuming without testing adaptationist views about form-function relationships in order to infer adult activity patterns from skeletal features such as cross-sectional geometry, cortical bones density, and musculo-skeletal stress markers. Efforts to infer function from shape in the human skeleton should be based on biomechanical and developmental models that are experimentally tested and validated.

  7. A reaction-diffusion model for long bones growth.

    PubMed

    Garzón-Alvarado, D A; García-Aznar, J M; Doblaré, M

    2009-10-01

    Bone development is characterized by differentiation and growth of chondrocytes from the proliferation zone to the hypertrophying one. These two cellular processes are controlled by a complex signalling regulatory loop between different biochemical signals, whose production depends on the current cell density, constituting a coupled cell-chemical system. In this work, a mathematical model of the process of early bone growth is presented, extending and generalizing other earlier approaches on the same topic. A reaction-diffusion regulatory loop between two chemical factors: parathyroid hormone-related peptide (PTHrP) and Indian hedgehog (Ihh) is hypothesized, where PTHrP is activated by Ihh and inhibits Ihh production. Chondrocytes proliferation and hypertrophy are described by means of population equations being both regulated by the PTHrP and Ihh concentrations. In the initial stage of bone growth, these two cellular proceses are considered to be directionally dependent, modelling the well known column cell formation, characteristic of endochondral ossification. This coupled set of equations is solved within a finite element framework, getting an estimation of the chondrocytes spatial distribution, growth of the diaphysis and formation of the epiphysis of a long bone. The results obtained are qualitatively similar to the actual physiological ones and quantitatively close to some available experimental data. Finally, this extended approach allows finding important relations between the model parameters to get stability of the physiological process and getting additional insight on the spatial and directional distribution of cells and paracrine factors.

  8. Osteogenesis mechanism of chitosan-coated calcium sulfate pellets on the restoration of segmental bone defects.

    PubMed

    Cui, Xu; Zhao, Dewei; Zhang, Boxun; Gao, Yongliang

    2009-09-01

    A radial segmental defect model of a rabbit was used to study the restoration effect on defects treated with chitosan-coated pressed calcium sulfate pellets combined with recombinant human bone morphogenetic protein-2 (rhBMP-2), coated pressed calcium sulfate pellets, and uncoated pressed calcium sulfate pellets. Nothing was implanted in the control group. After 4, 8, and 12 weeks, the results indicated that coated pressed calcium sulfate pellets combined with rhBMP-2 and coated pressed calcium sulfate pellets facilitated new bone formation on defected bones and that, particularly, the coated pressed calcium sulfate pellets combined with rhBMP-2 was more effective than the coated pressed calcium sulfate pellet. Histologic and tetracycline fluorimetric findings showed that the osteogenesis mechanism of chitosan-coated pressed calcium sulfate pellets is membrane bone formation, and the pellets showed slightly slower resorption that closely coincides with the growth rate of new bone.

  9. Non-linear pattern formation in bone growth and architecture.

    PubMed

    Salmon, Phil

    2014-01-01

    The three-dimensional morphology of bone arises through adaptation to its required engineering performance. Genetically and adaptively bone travels along a complex spatiotemporal trajectory to acquire optimal architecture. On a cellular, micro-anatomical scale, what mechanisms coordinate the activity of osteoblasts and osteoclasts to produce complex and efficient bone architectures? One mechanism is examined here - chaotic non-linear pattern formation (NPF) - which underlies in a unifying way natural structures as disparate as trabecular bone, swarms of birds flying, island formation, fluid turbulence, and others. At the heart of NPF is the fact that simple rules operating between interacting elements, and Turing-like interaction between global and local signals, lead to complex and structured patterns. The study of "group intelligence" exhibited by swarming birds or shoaling fish has led to an embodiment of NPF called "particle swarm optimization" (PSO). This theoretical model could be applicable to the behavior of osteoblasts, osteoclasts, and osteocytes, seeing them operating "socially" in response simultaneously to both global and local signals (endocrine, cytokine, mechanical), resulting in their clustered activity at formation and resorption sites. This represents problem-solving by social intelligence, and could potentially add further realism to in silico computer simulation of bone modeling. What insights has NPF provided to bone biology? One example concerns the genetic disorder juvenile Pagets disease or idiopathic hyperphosphatasia, where the anomalous parallel trabecular architecture characteristic of this pathology is consistent with an NPF paradigm by analogy with known experimental NPF systems. Here, coupling or "feedback" between osteoblasts and osteoclasts is the critical element. This NPF paradigm implies a profound link between bone regulation and its architecture: in bone the architecture is the regulation. The former is the emergent

  10. Non-Linear Pattern Formation in Bone Growth and Architecture

    PubMed Central

    Salmon, Phil

    2014-01-01

    The three-dimensional morphology of bone arises through adaptation to its required engineering performance. Genetically and adaptively bone travels along a complex spatiotemporal trajectory to acquire optimal architecture. On a cellular, micro-anatomical scale, what mechanisms coordinate the activity of osteoblasts and osteoclasts to produce complex and efficient bone architectures? One mechanism is examined here – chaotic non-linear pattern formation (NPF) – which underlies in a unifying way natural structures as disparate as trabecular bone, swarms of birds flying, island formation, fluid turbulence, and others. At the heart of NPF is the fact that simple rules operating between interacting elements, and Turing-like interaction between global and local signals, lead to complex and structured patterns. The study of “group intelligence” exhibited by swarming birds or shoaling fish has led to an embodiment of NPF called “particle swarm optimization” (PSO). This theoretical model could be applicable to the behavior of osteoblasts, osteoclasts, and osteocytes, seeing them operating “socially” in response simultaneously to both global and local signals (endocrine, cytokine, mechanical), resulting in their clustered activity at formation and resorption sites. This represents problem-solving by social intelligence, and could potentially add further realism to in silico computer simulation of bone modeling. What insights has NPF provided to bone biology? One example concerns the genetic disorder juvenile Pagets disease or idiopathic hyperphosphatasia, where the anomalous parallel trabecular architecture characteristic of this pathology is consistent with an NPF paradigm by analogy with known experimental NPF systems. Here, coupling or “feedback” between osteoblasts and osteoclasts is the critical element. This NPF paradigm implies a profound link between bone regulation and its architecture: in bone the architecture is the regulation. The former is the

  11. Effects of growth hormone (GH) transgene and nutrition on growth and bone development in common carp.

    PubMed

    Zhu, Tingbing; Zhang, Tanglin; Wang, Yaping; Chen, Yushun; Hu, Wei; Zhu, Zuoyan

    2013-10-01

    Limited information is available on effects of growth hormone transgene and nutrition on growth and development of aquatic animals. Here, we present a study to test these effects with growth-enhanced transgenic common carp under two nutritional conditions or feeding rations (i.e., 5% and 10% of fish body weight per day). Compared with the nontransgenic fish, the growth rates of the transgenic fish increased significantly in both feeding rations. The shape of the pharyngeal bone was similar among treatments, but the transgenic fish had relatively smaller and lighter pharyngeal bone compared with the nontransgenic fish. Calcium content of the pharyngeal bone of the transgenic fish was significantly lower than that of the nontransgenic fish. Feeding ration also affected growth rate but less of an effect on bone development. By manipulating intrinsic growth and controlling for both environment (e.g., feeding ration) and genetic background or genotype (e.g., transgenic or not), this study provides empirical evidence that the genotype has a stronger effect than the environment on pharyngeal bone development. The pharyngeal bone strength could be reduced by decreased calcium content and calcification in the transgenic carp.

  12. Mechanical properties of human trabecular bone lamellae quantified by nanoindentation.

    PubMed

    Zysset, P K; Guo, X E; Hoffler, C E; Moore, K E; Goldstein, S A

    1998-12-01

    Improved preventive and therapeutic strategies for skeletal diseases such as osteoporosis rely on a better understanding of the mechanical properties of trabecular bone and their influence on cell mediated adaptation processes. The mechanical properties of trabecular bone are determined by composition as well as structural (trabecular architecture), microstructural (trabecular packets) and nanostructural (lamellae) organization. Density is the major predictor of the mechanical properties of trabecular structures and has been extended to the concept of fabric to include architectural anisotropy and improve even further the power of prediction. Recent advances in QCT and MRI technologies allow for precise assessment of 3D trabecular architecture and the mechanical consequences of structural changes can be increasingly well quantified by the means of computational methods. While single trabeculae have been tested using various techniques with contrasting results, little is known about the intrinsic mechanical properties of trabecular bone lamellae on which these computational methods rely. For instance, water and mineral content have a significant effect on the elastic, viscous, yield and postyield properties of bone tissue. In addition, collagen fiber orientation affects the mechanics of single remodeling units. Variations in composition and organization determined by age, accumulated damage or disease may therefore reduce the mechanical integrity of trabecular bone and deserve more attention. The aim of this work was to utilize a nanoindentation technique to quantify elastic modulus and hardness of human trabecular bone lamellae.

  13. Inhaled corticosteroids: Effects on growth and bone health.

    PubMed

    Skoner, David P

    2016-12-01

    Both slowed growth in children and reduced bone mineral density (BMD) are systemic effects of corticosteroids, and there is concern about the degree to which these systemic effects affect growth and BMD. To engage in a data-driven discussion of the effects of inhaled corticosteroids (ICSs) on growth in children and BMD. Articles were selected based on their relevance to this review. Studies of ICSs in children in which growth was a secondary outcome have revealed slowed growth associated with low doses of budesonide, fluticasone propionate, and beclomethasone dipropionate. In the study of budesonide, the effect was permanent, and in the study of fluticasone propionate, the effect was long-lasting, but it is unclear whether the effect was permanent. However, the results of studies in which growth was the primary outcome were mixed. Slowed growth was detected in a study of beclomethasone dipropionate; however, slowed growth was not detected in a study of ciclesonide or flunisolide. A decrease in BMD acquisition in children was associated with high doses but not low to medium doses of ICSs. In adults, there was a dose-related effect of ICSs on BMD. Both higher daily dose and larger cumulative dose were associated with increased bone density loss. Because of the systemic effects on growth and bone health, children should be monitored for growth using stadiometry every 3 to 6 months and BMD should be monitored yearly in patients being treated with high doses of ICSs. Copyright © 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  14. 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.

  15. Advances in the fracture mechanics of cortical bone.

    PubMed

    Bonfield, W

    1987-01-01

    As cortical bone is a semi-brittle solid, its fracture is dependent not only on the magnitude of the applied stress, but also on the nature of any intrinsic or introduced cracks. Consequently a variety of fracture mechanics techniques have been utilised to evaluate the fracture toughness of cortical bone, including the single edge notched, centre notched cylindrical and compact tension methods, and values have been established for the critical stress intensity factor (Kc) and the critical strain energy release rate (Gc). The Kc and Gc values obtained depend on the orientation of the cortical bone, as well as on bone density, the velocity of crack propagation and specimen geometry. The significance of these fracture mechanics parameters for cortical bone is critically reviewed.

  16. 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

  17. Growth-related structural, biochemical, and mechanical properties of the functional bone–cartilage unit

    PubMed Central

    Hamann, Nina; Zaucke, Frank; Dayakli, Münire; Brüggemann, Gert-Peter; Niehoff, Anja

    2013-01-01

    Articular cartilage and subchondral bone act together, forming a unit as a weight-bearing loading-transmitting surface. A close interaction between both structures has been implicated during joint cartilage degeneration, but their coupling during normal growth and development is insufficiently understood. The purpose of the present study was to examine growth-related changes of cartilage mechanical properties and to relate these changes to alterations in cartilage biochemical composition and subchondral bone structure. Tibiae and femora of both hindlimbs from 7- and 13-week-old (each n = 12) female Sprague-Dawley rats were harvested. Samples were processed for structural, biochemical and mechanical analyses. Immunohistochemical staining and protein expression analyses of collagen II, collagen IX, COMP and matrilin-3, histomorphometry of cartilage thickness and COMP staining height were performed. Furthermore, mechanical testing of articular cartilage and micro-CT analysis of subchondral bone was conducted. Growth decreased cartilage thickness, paralleled by a functional condensation of the underlying subchondral bone due to enchondral ossification. Cartilage mechanical properties seem to be rather influenced by growth-related changes in the assembly of major ECM proteins such as collagen II, collagen IX and matrilin-3 than by growth-related alterations in its underlying subchondral bone structure. Importantly, the present study provides a first insight into the growth-related structural, biochemical and mechanical interaction of articular cartilage and subchondral bone. Finally, these data contribute to the general knowledge about the cooperation between the articular cartilage and subchondral bone. PMID:23083449

  18. Physiological mechanisms and therapeutic potential of bone mechanosensing

    PubMed Central

    Xiao, Zhousheng

    2016-01-01

    Skeletal loading is an important physiological regulator of bone mass. Theoretically, mechanical forces or administration of drugs that activate bone mechanosensors would be a novel treatment for osteoporotic disorders, particularly age-related osteoporosis and other bone loss caused by skeletal unloading. Uncertainty regarding the identity of the molecular targets that sense and transduce mechanical forces in bone, however, has limited the therapeutic exploitation of mechanosesning pathways to control bone mass. Recently, two evolutionally conserved mechanosensing pathways have been shown to function as “physical environment” sensors in cells of the osteoblasts lineage. Indeed, polycystin–1 (Pkd1, or PC1) and polycystin–2 (Pkd2, or PC2, or TRPP2), which form a flow sensing receptor channel complex, and TAZ (transcriptional coactivator with PDZ-binding motif, or WWTR1), which responds to the extracellular matrix microenvironment act in concert to reciprocally regulate osteoblastogenesis and adipogenesis through co-activating Runx2 and a co-repressing PPARγ activities. Interactions of polycystins and TAZ with other putative mechanosensing mechanism, such as primary cilia, integrins and hemichannels, may create multifaceted mechanosensing networks in bone. Moreover, modulation of polycystins and TAZ interactions identify novel molecular targets to develop small molecules that mimic the effects of mechanical loading on bone. PMID:26038304

  19. Growth in bone strength, body size, and muscle size in a juvenile longitudinal sample.

    PubMed

    Ruff, Christopher

    2003-09-01

    A longitudinal sample of 20 subjects, measured an average of 34 to 35 times each at approximately 6-month intervals from near birth through late adolescence, was used to investigate relationships between body size, muscle size, and bone structural development. The section modulus, an index of bone strength, was calculated from humeral and femoral diaphyseal breadth measurements obtained from serial radiographs. Muscle breadths of the forearm and thigh, also measured radiographically, were used to estimate muscle cross-sectional areas. Body size was assessed as the product of body weight and bone length (humeral or femoral). Stature was also investigated as a surrogate body size measure. Growth velocity in femoral strength was strongly correlated with growth velocity in body weight. femoral length (r2=0.65-0.80), very poorly correlated with growth velocity in stature (r2<0.06), and weakly but significantly correlated with growth velocity in thigh muscle size (r2=0.10-.25). Growth velocity in humeral strength was moderately correlated with that for body weight x humeral length (r2=0.40-0.73), very poorly correlated with that for stature (r2<0.05), and showed a marked sex difference with forearm muscle area velocity, with males having a stronger correlation (r2 approximately 0.65) and females a much weaker correlation (r2 approximately 0.15). Ages at peak adolescent growth velocity were nonsignificantly different between bone strength, body weight x bone length, and muscle area, but significantly earlier for stature. Thus, while there was an early adolescent "lag" between stature and bone strength, there was no such "lag" between a more mechanically appropriate measure of body size and bone strength. "Infancy peaks" in bone strength velocities, earlier in the humerus than in the femur and not paralleled by similar changes in body size, may be the result of the initiation of walking, when mechanical loads relative to body size are changing in both the upper and lower

  20. Bone Blood Flow During Simulated Microgravity: Physiological and Molecular Mechanisms

    NASA Technical Reports Server (NTRS)

    Bloomfield, Susan A.

    1999-01-01

    Blood flow to bone has been shown to affect bone mass and presumably bone strength. Preliminary data indicate that blood flow to the rat femur decreases after 14 days of simulated microgravity, using hindlimb suspension (HLS). If adult rats subjected to HLS are given dobutamine, a synthetic catecholamine which can cause peripheral vasodilation and increased blood flow, the loss of cortical bone area usually observed is prevented. Further, mechanisms exist at the molecular level to link changes in bone blood flow to changes in bone cell activity, particularly for vasoactive agents like nitric oxide (NO). The decreases in fluid shear stress created by fluid flow associated with the shifts of plasma volume during microgravity may result in alterations in expression of vasoactive agents such as NO, producing important functional effects on bone cells. The primary aim of this project is to characterize changes in 1) bone blood flow, 2) indices of bone mass, geometry, and strength, and 3) changes in gene expression for modulators of nitric oxide activity (e.g., nitric oxide synthase) and other candidate genes involved in signal transduction of mechanical loading after 3, 7, 14, 21, and 28 days of HLS in the adult rat. Using a rat of at least 5 months of age avoids inadvertently studying effects of simulated microgravity on growing, rather than adult, bone. Utilizing the results of these studies, we will then define how altered blood flow contributes to changes in bone with simulated microgravity by administering a vasodilatory agent (which increases blood flow to tissues) during hindlimb suspension. In all studies, responses in the unloaded hindlimb bones (tibial shaft, femoral neck) will be compared with those in the weightbearing humeral shaft and the non-weightbearing calvarium (skull) from the same animal. Bone volumetric mineral density and geometry will be quantified by peripheral quantitative CT; structural and material properties of the long bones will be

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

    SciTech Connect

    Ikeda, Kazuhiro; Tsukui, Tohru; Imazawa, Yukiko; Horie-Inoue, Kuniko; Inoue, Satoshi

    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 active 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.

  2. Bariatric surgery, bone loss, obesity and possible mechanisms.

    PubMed

    Brzozowska, M M; Sainsbury, A; Eisman, J A; Baldock, P A; Center, J R

    2013-01-01

    Bariatric surgery remains the most effective treatment for severely obese patients. However, the potential long-term effects of bariatric surgical procedures on health, including bone health, are only partially understood. The goal of this review was to present data on the impact of bariatric surgery on bone metabolism and to analyse possible reasons for the loss of bone mass that frequently occurs after bariatric surgery. Such factors include nutritional deficiencies, rapid weight loss per se, effects of fat-derived adipokines and gut-derived appetite-regulatory hormones. However, the relative roles of these factors in skeletal regulation and the mechanisms by which they work are not yet fully defined. Our review was focussed on the complex relationship between body weight, fat mass and bone mass, as well as peripheral and central mediators potentially involved in the dual regulation of both energy and bone homeostasis. We also review the data on the inverse relationship between central obesity, bone marrow fat and osteoporosis. As the number of bariatric operations increases, it is imperative to recognize mechanisms responsible for bariatric surgery-induced bone loss, with careful monitoring of bone health including long-term fracture incidence in patients undergoing these procedures.

  3. Crack growth resistance in cortical bone: concept of microcrack toughening.

    PubMed

    Vashishth, D; Behiri, J C; Bonfield, W

    1997-08-01

    The role of microcracking in cortical bone as a toughening mechanism has been investigated in conjunction with the variation in fracture toughness with crack length. Fracture toughness tests were conducted on miniaturised compact tension specimens made from human and bovine cortical bone and the resultant microstructural damage, present in the form of microcracking on the surface, was analysed around the main propagating crack. It was found that the fracture toughness (Kc) and the cumulative number of microcracks increased linearly with crack extension in human and bovine cortical bone, although both Kc and number of microcracks were considerably higher in the latter case. Based on these results, a mechanism, derived from the resistance (R) curve concept developed for microcracking brittle solids, is proposed to explain the fracture of cortical bone, with microcracking distributed between a frontal process zone and a significant process zone wake. Evidence to support this mechanism is given from the existing bone literature, detailed scanning electron microscopical observations and the distribution of microcracks in the process zone wake.

  4. The chondrocytic journey in endochondral bone growth and skeletal dysplasia.

    PubMed

    Yeung Tsang, Kwok; Wa Tsang, Shun; Chan, Danny; Cheah, Kathryn S E

    2014-03-01

    The endochondral bones of the skeleton develop from a cartilage template and grow via a process involving a cascade of chondrocyte differentiation steps culminating in formation of a growth plate and the replacement of cartilage by bone. This process of endochondral ossification, driven by the generation of chondrocytes and their subsequent proliferation, differentiation, and production of extracellular matrix constitute a journey, deviation from which inevitably disrupts bone growth and development, and is the basis of human skeletal dysplasias with a wide range of phenotypic severity, from perinatal lethality to progressively deforming. This highly coordinated journey of chondrocyte specification and fate determination is controlled by a myriad of intrinsic and extrinsic factors. SOX9 is the master transcription factor that, in concert with varying partners along the way, directs the different phases of the journey from mesenchymal condensation, chondrogenesis, differentiation, proliferation, and maturation. Extracellular signals, including bone morphogenetic proteins, wingless-related MMTV integration site (WNT), fibroblast growth factor, Indian hedgehog, and parathyroid hormone-related peptide, are all indispensable for growth plate chondrocytes to align and organize into the appropriate columnar architecture and controls their maturation and transition to hypertrophy. Chondrocyte hypertrophy, marked by dramatic volume increase in phases, is controlled by transcription factors SOX9, Runt-related transcription factor, and FOXA2. Hypertrophic chondrocytes mediate the cartilage to bone transition and concomitantly face a live-or-die situation, a subject of much debate. We review recent insights into the coordination of the phases of the chondrocyte journey, and highlight the need for a systems level understanding of the regulatory networks that will facilitate the development of therapeutic approaches for skeletal dysplasia.

  5. Modern analysis of bone loss mechanisms in microgravity.

    PubMed

    Oganov, V S

    2004-07-01

    A summary of results of investigations by the author and a brief review of some literature data on human bone tissue deprived of mechanical loading (spaceflight, hypokinesia) is given. The direction and markedness of changes in bone mass--the bone mineral density and the bone mineral content--in different skeletal segments depend on their position relative to the gravity vector. A theoretically expected bone mass reduction was revealed in the trabecular structures of the bones of the lower part of the skeleton (local osteopenia). In the upper part of the skeleton, an increase in the bone mineral content is observed, which is considered as a secondary response and is due to redistribution of body fluids cephalad. The main cause of osteopenia is mechanical unloading. Arguments are presented that osteocyte osteolysis, delayed osteoblast histogenesis, and osteoclast resorption provoked by rearrangement in the hierarchy of the systems of fluid volume and ion regulation, and the endocrine control of calcium homeostasis are the main mechanisms of osteopenia.

  6. Spinal nociceptive transmission by mechanical stimulation of bone marrow

    PubMed Central

    Tanaka, Satoshi; Sekiguchi, Takemi; Sugiyama, Daisuke; Kawamata, Mikito

    2016-01-01

    Background Since bone marrow receives innervation from A-delta and C-fibers and since an increase in intramedullary pressure in bone marrow may induce acute pain in orthopedic patients during surgery and chronic pain in patients with bone marrow edema, skeletal pain may partly originate from bone marrow. Intraosseous lesions, such as osteomyelitis and bone cancer, are also known to produce cutaneous hypersensitivity, which might be referred pain from bone. However, little is known about pain perception in bone marrow and referred pain induced by bone disease. Thus, we carried out an in vivo electrophysiological study and behavioral study to determine whether increased intraosseous pressure of the femur induces acute pain and whether increased intraosseous pressure induces referred pain in the corresponding receptive fields of the skin. Results Intraosseous balloon inflation caused spontaneous pain-related behavior and mechanical hyperalgesia and allodynia in the lumbosacral region. Single neuronal activities of spinal dorsal horn neurons were extracellularly isolated, and then evoked responses to non-noxious and noxious cutaneous stimuli and intraosseous balloon inflation were recorded. Ninety-four spinal dorsal horn neurons, which had somatic receptive fields at the lower back and thigh, were obtained. Sixty-two percent of the wide-dynamic-range neurons (24/39) and 86% of the high-threshold neurons (12/14) responded to intraosseous balloon inflation, while none of the low-threshold neurons (0/41) responded to intraosseous balloon inflation. Spinally administered morphine (1 µg) abolished balloon inflation-induced spontaneous pain-related behavior and mechanical hyperalgesia in awake rats and also suppressed evoked activities of wide-dynamic-range neurons to noxious cutaneous stimulation and intraosseous balloon inflation. Conclusions The results suggest that mechanical stimulation to bone marrow produces nociception, concomitantly producing its referred pain

  7. Elastic-plastic fracture mechanics of compact bone

    NASA Astrophysics Data System (ADS)

    Yan, Jiahau

    Bone is a composite composed mainly of organics, minerals and water. Most studies on the fracture toughness of bone have been conducted at room temperature. Considering that the body temperature of animals is higher than room temperature, and that bone has a high volumetric percentage of organics (generally, 35--50%), the effect of temperature on fracture toughness of bone should be studied. Single-edged V-shaped notched (SEVN) specimens were prepared to measure the fracture toughness of bovine femur and manatee rib in water at 0, 10, 23, 37 and 50°C. The fracture toughness of bovine femur and manatee rib were found to decrease from 7.0 to 4.3 MPa·m1/2 and from 5.5 to 4.1 MPa·m1/2, respectively, over a temperature range of 50°C. The decreases were attributed to inability of the organics to sustain greater stresses at higher temperatures. We studied the effects of water and organics on fracture toughness of bone using water-free and organics-free SEVN specimens at 23°C. Water-free and organics-free specimens were obtained by placing fresh bone specimen in a furnace at different temperatures. Water and organics significantly affected the fracture toughness of bone. Fracture toughness of the water-free specimens was 44.7% (bovine femur) and 32.4% (manatee rib) less than that of fresh-bone specimens. Fracture toughness of the organics-free specimens was 92.7% (bovine femur) and 91.5% (manatee rib) less than that of fresh bone specimens. Linear Elastic Fracture Mechanics (LEFM) is widely used to study bone. However, bone often has small to moderate scale yielding during testing. We used J integral, an elastic-plastic fracture-mechanics parameter, to study the fracture process of bone. The J integral of bovine femur increased from 6.3 KJ/mm2 at 23°C to 6.7 KJ/mm2 at 37°C. Although the fracture toughness of bovine bone decreases as the temperature increases, the J integral results show a contrary trend. The energy spent in advancing the crack beyond the linear

  8. Effect of trehalose coating on basic fibroblast growth factor release from tailor-made bone implants.

    PubMed

    Choi, Sungjin; Lee, Jongil; Igawa, Kazuyo; Suzuki, Shigeki; Mochizuki, Manabu; Nishimura, Ryohei; Chung, Ung-il; Sasaki, Nobuo

    2011-12-01

    Artificial bone implants are often incorporated with osteoinductive factors to facilitate early bone regeneration. Calcium phosphate, the main component in artificial bone implants, strongly binds these factors, and in a few cases, the incorporated proteins are not released from the implant under conditions of physiological pH, thereby leading to reduction in their osteoinductivity. In this study, we coated tailor-made bone implants with trehalose to facilitate the release of basic fibroblast growth factor (bFGF). In an in vitro study, mouse osteoblastic cells were separately cultured for 48 hr in a medium with a untreated implant (T-), trehalose-coated implant (T+), bFGF-incorporated implant (FT-), and bFGF-incorporated implant with trehalose coating (FT+). In the FT+ group, cell viability was significantly higher than that in the other groups (P<0.05). Scanning electron microscopy (SEM) and X-ray diffraction (XRD) revealed that trehalose effectively covered the surface of the artificial bone implant without affecting the crystallinity or the mechanical strength of the artificial bone implant. These results suggest that coating artificial bone implants with trehalose could limit the binding of bFGF to calcium phosphate.

  9. mTORC2 signaling promotes skeletal growth and bone formation in mice.

    PubMed

    Chen, Jianquan; Holguin, Nilsson; Shi, Yu; Silva, Matthew J; Long, Fanxin

    2015-02-01

    Mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase controlling many physiological processes in mammals. mTOR functions in two distinct protein complexes, namely mTORC1 and mTORC2. Compared to mTORC1, the specific roles of mTORC2 are less well understood. To investigate the potential contribution of mTORC2 to skeletal development and homeostasis, we have genetically deleted Rictor, an essential component of mTORC2, in the limb skeletogenic mesenchyme of the mouse embryo. Loss of Rictor leads to shorter and narrower skeletal elements in both embryos and postnatal mice. In the embryo, Rictor deletion reduces the width but not the length of the initial cartilage anlage. Subsequently, the embryonic skeletal elements are shortened due to a delay in chondrocyte hypertrophy, with no change in proliferation, apoptosis, cell size, or matrix production. Postnatally, Rictor-deficient mice exhibit impaired bone formation, resulting in thinner cortical bone, but the trabecular bone mass is relatively normal thanks to a concurrent decrease in bone resorption. Moreover, Rictor-deficient bones exhibit a lesser anabolic response to mechanical loading. Thus, mTORC2 signaling is necessary for optimal skeletal growth and bone anabolism. © 2014 American Society for Bone and Mineral Research.

  10. The Mechanics of Long Bone Fractures.

    DTIC Science & Technology

    1981-01-31

    frequently at the rapid loading rates, indi- cating the relationship of fracture to energy dissipation, since crack formation is an energy...plotted in Figure 15. It can be seen that for angles as large as 100 the error is small. ERROR DUE TC fNCUNATfON OF SCANN NO PLANE TO :_ONGOTUD!NA!_ BONE...aspects. Flying Personnel Research Committee, FPRC/1166, 1961. 10. Lovejoy, C.O., and Barton, T.J.: A simple, rapid method of obtaining geometrical

  11. Structural and functional maturation of distal femoral cartilage and bone during postnatal development and growth in humans and mice.

    PubMed

    Chan, Elaine F; Harjanto, Ricky; Asahara, Hiroshi; Inoue, Nozomu; Masuda, Koichi; Bugbee, William D; Firestein, Gary S; Hosalkar, Harish S; Lotz, Martin K; Sah, Robert L

    2012-04-01

    The size and shape of joints markedly affect their biomechanical properties, but the macroscopic 3-dimensional (3-D) mechanism and extent of cartilage and joint maturation during normal growth are largely unknown. This study qualitatively illustrates the development of the bone-cartilage interface in the knee during postnatal growth in humans and C57BL/6 wild-type mice, quantitatively defines the 3-D shape using statistical shape modeling, and assesses growth strain rates in the mouse distal femur. Accurate quantification of the cartilage-bone interface geometry is imperative for furthering the understanding of the macroscopic mechanisms of cartilage maturation and overall joint development.

  12. Effects of spaceflight and simulated weightlessness on longitudinal bone growth

    NASA Technical Reports Server (NTRS)

    Sibonga, J. D.; Zhang, M.; Evans, G. L.; Westerlind, K. C.; Cavolina, J. M.; Morey-Holton, E.; Turner, R. T.

    2000-01-01

    Indirect measurements have suggested that spaceflight impairs bone elongation in rats. To test this possibility, our laboratory measured, by the fluorochrome labeling technique, bone elongation that occurred during a spaceflight experiment. The longitudinal growth rate (LGR) in the tibia of rats in spaceflight experiments (Physiological Space Experiments 1, 3, and 4 and Physiological-Anatomical Rodent Experiment 3) and in two models of skeletal unloading (hind-limb elevation and unilateral sciatic neurotomy) were calculated. The effects of an 11 day spaceflight on gene expression of cartilage matrix proteins in rat growth plates were also determined by northern analysis and are reported for the first time in this study. Measurements of longitudinal growth indicate that skeletal unloading generally did not affect LGR, regardless of age, strain, gender, duration of unloading, or method of unloading. There was, however, one exception with 34% suppression in LGR detected in slow-growing, ovariectomized rats skeletally unloaded for 8 days by hind-limb elevation. This detection of reduced LGR by hind-limb elevation is consistent with changes in steady-state mRNA levels for type II collagen (-33%) and for aggrecan (-53%) that were detected in rats unloaded by an 11 day spaceflight. The changes detected in gene expression raise concern that spaceflight may result in changes in the composition of extracellular matrix, which could have a negative impact on conversion of growth-plate cartilage into normal cancellous bone by endochondral ossification.

  13. Effects of spaceflight and simulated weightlessness on longitudinal bone growth

    NASA Technical Reports Server (NTRS)

    Sibonga, J. D.; Zhang, M.; Evans, G. L.; Westerlind, K. C.; Cavolina, J. M.; Morey-Holton, E.; Turner, R. T.

    2000-01-01

    Indirect measurements have suggested that spaceflight impairs bone elongation in rats. To test this possibility, our laboratory measured, by the fluorochrome labeling technique, bone elongation that occurred during a spaceflight experiment. The longitudinal growth rate (LGR) in the tibia of rats in spaceflight experiments (Physiological Space Experiments 1, 3, and 4 and Physiological-Anatomical Rodent Experiment 3) and in two models of skeletal unloading (hind-limb elevation and unilateral sciatic neurotomy) were calculated. The effects of an 11 day spaceflight on gene expression of cartilage matrix proteins in rat growth plates were also determined by northern analysis and are reported for the first time in this study. Measurements of longitudinal growth indicate that skeletal unloading generally did not affect LGR, regardless of age, strain, gender, duration of unloading, or method of unloading. There was, however, one exception with 34% suppression in LGR detected in slow-growing, ovariectomized rats skeletally unloaded for 8 days by hind-limb elevation. This detection of reduced LGR by hind-limb elevation is consistent with changes in steady-state mRNA levels for type II collagen (-33%) and for aggrecan (-53%) that were detected in rats unloaded by an 11 day spaceflight. The changes detected in gene expression raise concern that spaceflight may result in changes in the composition of extracellular matrix, which could have a negative impact on conversion of growth-plate cartilage into normal cancellous bone by endochondral ossification.

  14. [Mechanism of bone destruction and the contribution of T lymphocytes].

    PubMed

    Komatsu, Noriko

    2016-06-01

    Rheumatoid arthritis (RA), one of the most common autoimmune diseases, is characterized by inflammation and bone destruction in the joints. Abnormal activation of the immune system leads to RANKL-dependent osteoclast differentiation, which ultimately results in bone destruction in RA. A newly identified Th17 subset induces osteoclastogenesis potently by upregulating RANKL on synovial fibroblasts, indicating a synergy between T-synovial fibroblast plays a primary role in the bone destruction. Immune-regulating factors, such as CTLA-4 highly expressed on regulatory T cells, are identified as new bone-regulating factors and can be attractive therapeutic targets for bone destruction in RA. The mechanism by which T cells contribute to the RA pathogenesis will help understand the etiology of RA and develop therapeutic approach against it.

  15. Evaluation of the mechanical and architectural properties of glenoid bone.

    PubMed

    Mimar, Raghad; Limb, David; Hall, Richard M

    2008-01-01

    Successful glenoid fixation in shoulder arthroplasty is partly dependent on the properties of the underlying bone. Therefore, mapping of the glenoid surface and locating the bone with the highest quality, in terms of mechanical properties and morphology, is a key requirement in ensuring effective fixation. To this end, an investigation was undertaken to study the relationship between indentation behavior and the quality of the glenoid bone. Nineteen embalmed glenoids were obtained from human cadavers (mean age at death, 82 years). Each specimen was tested using a cylindrical indentor at 11 predetermined points to investigate load-displacement behavior. Microcomputed tomography analysis was performed to ascertain the bone volume (BV)/total volume (TV) fraction of the trabecular bone and the subchondral thickness. Statistical analysis showed that both strength and modulus varied with indentation position. Significant relationships were found between either strength or modulus and BV/TV or subchondral thickness, although the explained variance was relatively low.

  16. Mechanical properties of nacre and highly mineralized bone.

    PubMed

    Currey, J D; Zioupos, P; Davies, P; Casino, A

    2001-01-07

    We compared the mechanical properties of 'ordinary' bovine bone, the highly mineralized bone of the rostrum of the whale Mesoplodon densirostris, and mother of pearl (nacre) of the pearl oyster Pinctada margaritifera. The rostrum and the nacre are similar in having very little organic material. However, the rostral bone is much weaker and more brittle than nacre, which in these properties is close to ordinary bone. The ability of nacre to outperform rostral bone is the result of its extremely well-ordered microstructure, with organic material forming a nearly continuous jacket round all the tiny aragonite plates, a design well adapted to produce toughness. In contrast, in the rostrum the organic material, mainly collagen, is poorly organized and discontinuous, allowing the mineral to join up to form, in effect, a brittle stony material.

  17. Mechanical properties of nacre and highly mineralized bone.

    PubMed Central

    Currey, J D; Zioupos, P; Davies, P; Casino, A

    2001-01-01

    We compared the mechanical properties of 'ordinary' bovine bone, the highly mineralized bone of the rostrum of the whale Mesoplodon densirostris, and mother of pearl (nacre) of the pearl oyster Pinctada margaritifera. The rostrum and the nacre are similar in having very little organic material. However, the rostral bone is much weaker and more brittle than nacre, which in these properties is close to ordinary bone. The ability of nacre to outperform rostral bone is the result of its extremely well-ordered microstructure, with organic material forming a nearly continuous jacket round all the tiny aragonite plates, a design well adapted to produce toughness. In contrast, in the rostrum the organic material, mainly collagen, is poorly organized and discontinuous, allowing the mineral to join up to form, in effect, a brittle stony material. PMID:12123292

  18. Mechanical Forces and Growth in Animal Tissues.

    PubMed

    LeGoff, Loïc; Lecuit, Thomas

    2015-08-10

    Mechanical forces shape biological tissues. They are the effectors of the developmental programs that orchestrate morphogenesis. A lot of effort has been devoted to understanding morphogenetic processes in mechanical terms. In this review, we focus on the interplay between tissue mechanics and growth. We first describe how tissue mechanics affects growth, by influencing the orientation of cell divisions and the signaling pathways that control the rate of volume increase and proliferation. We then address how the mechanical state of a tissue is affected by the patterns of growth. The forward and reverse interactions between growth and mechanics must be investigated in an integrative way if we want to understand how tissues grow and shape themselves. To illustrate this point, we describe examples in which growth homeostasis is achieved by feedback mechanisms that use mechanical forces. Copyright © 2016 Cold Spring Harbor Laboratory Press; all rights reserved.

  19. Parathyroid hormone mediates bone growth through the regulation of osteoblast proliferation and differentiation.

    PubMed

    Pettway, Glenda J; Meganck, Jeffrey A; Koh, Amy J; Keller, Evan T; Goldstein, Steven A; McCauley, Laurie K

    2008-04-01

    PTH (1-34) is the only FDA-approved anabolic agent for osteoporosis treatment in the U.S., but its mechanisms are not completely understood. This study investigated PTH effects on osteogenic cells at various stages of differentiation and proliferation using an engineered bone growth model in vivo. Ossicles were generated from bone marrow stromal cells (BMSCs) implanted in immunocompromised mice. Three weeks of PTH (40 microg/kg/day) or vehicle treatment initiated 1 day, 1, 2, or 3 weeks after BMSC implantation resulted in an anabolic response in PTH-treated implants (via histomorphometry and muCT) in all treatment groups. A novel in vivo tracking strategy with luciferase tagged BMSCs and weekly bioluminescent imaging of ossicles revealed increased donor cell proliferation in PTH-treated ossicles. The greatest increase occurred during the first week, and the activity remained elevated in PTH-treated implants over time. Zoledronic acid (ZA) was combined with PTH to delineate interactive mechanisms of these bone active agents. Combining ZA with PTH treatment reduced the PTH-mediated increase in luciferase BMSC activity, serum osteocalcin, and serum tartrate resistant acid phosphotase-5b (TRAP-5b) but ZA did not reduce the PTH-induced increase in total bone. Since zoledronic acid reduced PTH-induced proliferation without reducing bone volume, these data suggest that combining PTH and bisphosphonate therapy warrants further investigation in the treatment of bone disorders.

  20. Mechanical design optimization of bioabsorbable fixation devices for bone fractures.

    PubMed

    Lovald, Scott T; Khraishi, Tariq; Wagner, Jon; Baack, Bret

    2009-03-01

    Bioabsorbable bone plates can eliminate the necessity for a permanent implant when used to fixate fractures of the human mandible. They are currently not in widespread use because of the low strength of the materials and the requisite large volume of the resulting bone plate. The aim of the current study was to discover a minimally invasive bioabsorbable bone plate design that can provide the same mechanical stability as a standard titanium bone plate. A finite element model of a mandible with a fracture in the body region is subjected to bite loads that are common to patients postsurgery. The model is used first to determine benchmark stress and strain values for a titanium plate. These values are then set as the limits within which the bioabsorbable bone plate must comply. The model is then modified to consider a bone plate made of the polymer poly-L/DL-lactide 70/30. An optimization routine is run to determine the smallest volume of bioabsorbable bone plate that can perform and a titanium bone plate when fixating fractures of this considered type. Two design parameters are varied for the bone plate design during the optimization analysis. The analysis determined that a strut style poly-L-lactide-co-DL-lactide plate of 690 mm2 can provide as much mechanical stability as a similar titanium design structure of 172 mm2. The model has determined a bioabsorbable bone plate design that is as strong as a titanium plate when fixating fractures of the load-bearing mandible. This is an intriguing outcome, considering that the polymer material has only 6% of the stiffness of titanium.

  1. Deformation and Fracture Mechanisms of Bone and Nacre

    NASA Astrophysics Data System (ADS)

    Wang, Rizhi; Gupta, Himadri S.

    2011-08-01

    Bone and nacre are the most-known biological hard tissues to materials researchers. Although highly mineralized, both bone and nacre are amazingly tough and exhibit remarkable inelasticity, properties that are still beyond the reach of many modern ceramic materials. Very interestingly, the two hard tissues seem to have adopted totally different structural strategies for achieving mechanical robustness. Starting from a true nanocomposite of the mineralized collagen fibril and following up to seven levels of hierarchical organization, bone is built on a structure with extreme complexity. In contrast, nacre possesses a structure of surprising simplicity. Polygonal mineral tablets of micrometer size are carefully cemented together into a macroscopic wonder. A comparative analysis of the structure-property relations in bone and nacre helps us to unveil the underlying mechanisms of this puzzling phenomenon. In this review, we critically compare the various levels of structures and their mechanical contributions between bone and nacre, with a focus on inelasticity and the toughening process. We demonstrate that, although nacre and bone differ from each other in many aspects, they have adopted very similar deformation and toughening mechanisms.

  2. Growth plate closure: Apex view on bone scan

    SciTech Connect

    Giles, P.H.; Trochei, M.; Yeates, K.

    1984-01-01

    Angular deformities of the extremities in children following premature closure of the growth plate are well known. The deformities depend on the position of an osseus bridge which forms between the epiphysis and metaphysis. Several surgical procedures including resection of the osseus bridge have been described, however, delineation of the site of fusion is difficult to define. The commonest site of growth plate arrest is the distal femoral or proximal tibial growth plate. A new technique using the bone scan has been developed which accurately defines the area and position of these osseus bridges. Two hours after injection of technetium 99m methylene diphosphonate apex views of the affected distal femoral growth plate were performed. The knee was flexed into its smallest angle. Using a pinhole collimator the gamma camera was angled to face the affected growth plate end on. The image was collected onto computer and analysed by: (I) regions of interest over segments of the growth plate to calculate the relative area of total growth plate affected: (II) generating histograms: (III) thresholding or performing isocontours to accentuate abnormal areas. The growth plate is normally uniformly increased when compared to the normal shaft of the bone. Fusion across the plate appears as an area of diminished uptake. The apex view gives a unique functional map of the growth plate such that abnormal areas are displayed, and the site, size and position of osseus fusion obtained. The technique has the potential for determining the metabolic activity of the growth plate before and after surgery. Serial studies will allow assessment of regneration of the plate and reformation of new osseus bridges.

  3. Osteonectin promotes prostate cancer cell migration and invasion: a possible mechanism for metastasis to bone.

    PubMed

    Jacob, K; Webber, M; Benayahu, D; Kleinman, H K

    1999-09-01

    The mechanism underlying the "organ-specific" metastasis of prostate cancer cells to the bone is still poorly understood. It is not clear whether the cells only invade the bone and proliferate there or whether they invade many tissues but survive mainly in the bone ("seed and soil"). Extracts from various organs were used as chemoattractants in the in vitro chemotaxis and invasion assays. Results show that, in comparison with extracts of other tissues, bone extracts promote a 2- to 4-fold increase in chemotaxis by human prostate epithelial cells and a 4-fold increase in the invasive ability of human prostate carcinoma cells. The purified active factor from bone and from marrow stromal-cell-conditioned medium is a low glycosylated osteonectin that specifically promotes the invasive ability of bone-metastasizing prostate (and breast) cancer cells but not that of non-bone-metastasizing tumor cells. It does not stimulate the growth of prostate cancer cells in vitro or in vivo. Because osteonectin specifically enhances matrix metalloprotease activity in prostate and breast cancer cells (and not in other tumor cell types), we conclude that prostate cancer cell metastasis to the bone is, in part, mediated by the ability of osteonectin to promote migration, protease activity, and invasion.

  4. Modulation of bone remodeling via mechanically activated ion channels

    NASA Technical Reports Server (NTRS)

    Duncan, Randall L. (Principal Investigator)

    1996-01-01

    A critical factor in the maintenance of bone mass is the physical forces imposed upon the skeleton. Removal of these forces, such as in a weightless environment, results in a rapid loss of bone, whereas application of exogenous mechanical strain has been shown to increase bone formation. Numerous flight and ground-based experiments indicate that the osteoblast is the key bone cell influenced by mechanical stimulation. Aside from early transient fluctuations in response to unloading, osteoclast number and activity seem unaffected by removal of strain. However, bone formation is drastically reduced in weightlessness and osteoblasts respond to mechanical strain with an increase in the activity of a number of second messenger pathways resulting in increased anabolic activity. Unfortunately, the mechanism by which the osteoblast converts physical stimuli into a biochemical message, a process we have termed biochemical coupling, remains elusive. Prior to the application of this grant, we had characterized a mechanosensitive, cation nonselective channel (SA-cat) in osteoblast-like osteosarcoma cells that we proposed is the initial signalling mechanism for mechanotransduction. During the execution of this grant, we have made considerable progress to further characterize this channel as well as to determine its role in the osteoblastic response to mechanical strain. To achieve these goals, we combined electrophysiologic techniques with cellular and molecular biology methods to examine the role of these channels in the normal function of the osteoblast in vitro.

  5. Cell Mechanisms of Bone Tissue Loss Under Space Flight Conditions

    NASA Astrophysics Data System (ADS)

    Rodionova, Natalia

    Investigations on the space biosatellites has shown that the bone skeleton is one of the most im-portant targets of the effect space flight factors on the organism. Bone tissue cells were studied by electron microscopy in biosamples of rats' long bones flown on the board american station "SLS-2" and in experiments with modelling of microgravity ("tail suspension" method) with using autoradiography. The analysis of data permits to suppose that the processes of remod-eling in bone tissue at microgravity include the following succession of cell-to-cell interactions. Osteocytes as mechanosensory cells are first who respond to a changing "mechanical field". The next stage is intensification of osteolytic processes in osteocytes, leading to a volume en-largement of the osteocytic lacunae and removal of the "excess bone". Then mechanical signals have been transmitted through a system of canals and processes of the osteocytic syncitium to certain superficial bone zones and are perceived by osteoblasts and bone-lining cells (superficial osteocytes), as well as by the bone-marrow stromal cells. The sensitivity of stromal cells, pre-osteoblasts and osteoblasts, under microgravity was shown in a number of works. As a response to microgravity, the system of stromal cells -preosteoblasts -osteoblasts displays retardation of proliferation, differentiation and specific functions of osteogenetic cells. This is supported by the 3H-thymidine studies of the dynamics of differentiation of osteogenetic cells in remodeling zones. But unloading is not adequate and in part of the osteocytes are apoptotic changes as shown by our electron microscopic investigations. An osteocytic apoptosis can play the role in attraction the osteoclasts and in regulation of bone remodeling. The apoptotic bodies with a liquid flow through a system of canals are transferred to the bone surface, where they fulfil the role of haemoattractants for monocytes come here and form osteoclasts. The osteoclasts destroy

  6. Bone marrow mesenchymal stem cells repair spinal cord ischemia/reperfusion injury by promoting axonal growth and anti-autophagy.

    PubMed

    Yin, Fei; Meng, Chunyang; Lu, Rifeng; Li, Lei; Zhang, Ying; Chen, Hao; Qin, Yonggang; Guo, Li

    2014-09-15

    Bone marrow mesenchymal stem cells can differentiate into neurons and astrocytes after transplantation in the spinal cord of rats with ischemia/reperfusion injury. Although bone marrow mesenchymal stem cells are known to protect against spinal cord ischemia/reperfusion injury through anti-apoptotic effects, the precise mechanisms remain unclear. In the present study, bone marrow mesenchymal stem cells were cultured and proliferated, then transplanted into rats with ischemia/reperfusion injury via retro-orbital injection. Immunohistochemistry and immunofluorescence with subsequent quantification revealed that the expression of the axonal regeneration marker, growth associated protein-43, and the neuronal marker, microtubule-associated protein 2, significantly increased in rats with bone marrow mesenchymal stem cell transplantation compared with those in rats with spinal cord ischemia/reperfusion injury. Furthermore, the expression of the autophagy marker, microtubule-associated protein light chain 3B, and Beclin 1, was significantly reduced in rats with the bone marrow mesenchymal stem cell transplantation compared with those in rats with spinal cord ischemia/reperfusion injury. Western blot analysis showed that the expression of growth associated protein-43 and neurofilament-H increased but light chain 3B and Beclin 1 decreased in rats with the bone marrow mesenchymal stem cell transplantation. Our results therefore suggest that bone marrow mesenchymal stem cell transplantation promotes neurite growth and regeneration and prevents autophagy. These responses may likely be mechanisms underlying the protective effect of bone marrow mesenchymal stem cells against spinal cord ischemia/reperfusion injury.

  7. Molecular Genetic Studies of Bone Mechanical Strain and of Pedigrees with Very High Bone Density

    DTIC Science & Technology

    2009-11-01

    phenotype, we have used 2 approaches; single nucleotide polymorphism (SNP) analyses and gene expression changes. These 2 strategies have been...32 Dr. Subburaman Mohan 5 Molecular Genetic Studies of Bone Mechanical Strain Osteoporosis is a disease that is characterized by low bone...annual economic burden of osteoporosis is $20 billion and is expected to reach $62 billion by the year 2020 (1). These numbers exceed the cost of

  8. Bioactive nanoparticle-gelatin composite scaffold with mechanical performance comparable to cancellous bones.

    PubMed

    Wang, Chen; Shen, Hong; Tian, Ye; Xie, Yue; Li, Ailing; Ji, Lijun; Niu, Zhongwei; Wu, Decheng; Qiu, Dong

    2014-08-13

    Mechanical properties are among the most concerned issues for artificial bone grafting materials. The scaffolds used for bone grafts are either too brittle (glass) or too weak (polymer), and therefore composite scaffolds are naturally expected as the solution. However, despite the intensive studies on composite bone grafting materials, there still lacks a material that could be matched to the natural cancellous bones. In this study, nanosized bioactive particles (BP) with controllable size and good colloidal stability were used to composite with gelatin, forming macroporous scaffolds. It was found that the mechanical properties of obtained composite scaffolds, in terms of elastic modulus, compressive strength, and strain at failure, could match to that of natural cancellous bones. This is ascribed to the good distribution of particle in matrix and strong interaction between particle and gelatin. Furthermore, the incorporation of BPs endues the composite scaffolds with bioactivity, forming HA upon reacting with simulated body fluid (SBF) within days, thus stimulating preosteoblasts attachment, growth, and proliferation in these scaffolds. Together with their good mechanical properties, these composite scaffolds are promising artificial bone grating materials.

  9. How tough is bone? Application of elastic-plastic fracture mechanics to bone.

    PubMed

    Yan, Jiahau; Mecholsky, John J; Clifton, Kari B

    2007-02-01

    Bone, with a hierarchical structure that spans from the nano-scale to the macro-scale and a composite design composed of nano-sized mineral crystals embedded in an organic matrix, has been shown to have several toughening mechanisms that increases its toughness. These mechanisms can stop, slow, or deflect crack propagation and cause bone to have a moderate amount of apparent plastic deformation before fracture. In addition, bone contains a high volumetric percentage of organics and water that makes it behave nonlinearly before fracture. Many researchers used strength or critical stress intensity factor (fracture toughness) to characterize the mechanical property of bone. However, these parameters do not account for the energy spent in plastic deformation before bone fracture. To accurately describe the mechanical characteristics of bone, we applied elastic-plastic fracture mechanics to study bone's fracture toughness. The J integral, a parameter that estimates both the energies consumed in the elastic and plastic deformations, was used to quantify the total energy spent before bone fracture. Twenty cortical bone specimens were cut from the mid-diaphysis of bovine femurs. Ten of them were prepared to undergo transverse fracture and the other 10 were prepared to undergo longitudinal fracture. The specimens were prepared following the apparatus suggested in ASTM E1820 and tested in distilled water at 37 degrees C. The average J integral of the transverse-fractured specimens was found to be 6.6 kPa m, which is 187% greater than that of longitudinal-fractured specimens (2.3 kPa m). The energy spent in the plastic deformation of the longitudinal-fractured and transverse-fractured bovine specimens was found to be 3.6-4.1 times the energy spent in the elastic deformation. This study shows that the toughness of bone estimated using the J integral is much greater than the toughness measured using the critical stress intensity factor. We suggest that the J integral method is

  10. Mechanical Loading Synergistically Increases Trabecular Bone Volume and Improves Mechanical Properties in the Mouse when BMP Signaling Is Specifically Ablated in Osteoblasts

    PubMed Central

    Iura, Ayaka; McNerny, Erin Gatenby; Zhang, Yanshuai; Kamiya, Nobuhiro; Tantillo, Margaret; Lynch, Michelle; Kohn, David H.; Mishina, Yuji

    2015-01-01

    Bone homeostasis is affected by several factors, particularly mechanical loading and growth factor signaling pathways. There is overwhelming evidence to validate the importance of these signaling pathways, however, whether these signals work synergistically or independently to contribute to proper bone maintenance is poorly understood. Weight-bearing exercise increases mechanical load on the skeletal system and can improves bone quality. We previously reported that conditional knockout (cKO) of Bmpr1a, which encodes one of the type 1 receptors for Bone Morphogenetic Proteins (BMPs), in an osteoblast-specific manner increased trabecular bone mass by suppressing osteoclastogenesis. The cKO bones also showed increased cortical porosity, which is expected to impair bone mechanical properties. Here, we evaluated the impact of weight-bearing exercise on the cKO bone phenotype to understand interactions between mechanical loading and BMP signaling through BMPR1A. Male mice with disruption of Bmpr1a induced at 9 weeks of age, exercised 5 days per week on a motor-driven treadmill from 11 to 16 weeks of age. Trabecular bone volume in cKO tibia was further increased by exercise, whereas exercise did not affect the trabecular bone in the control genotype group. This finding was supported by decreased levels of osteoclasts in the cKO tibiae. The cortical porosity in the cKO bones showed a marginally significant decrease with exercise and approached normal levels. Exercise increased ductility and toughness in the cKO bones. Taken together, reduction in BMPR1A signaling may sensitize osteoblasts for mechanical loading to improve bone mechanical properties. PMID:26489086

  11. Reference-point indentation correlates with bone toughness assessed using whole-bone traditional mechanical testing.

    PubMed

    Gallant, Maxime A; Brown, Drew M; Organ, Jason M; Allen, Matthew R; Burr, David B

    2013-03-01

    Traditional bone mechanical testing techniques require excised bone and destructive sample preparation. Recently, a cyclic-microindentation technique, reference-point indentation (RPI), was described that allows bone to be tested in a clinical setting, permitting the analysis of changes to bone material properties over time. Because this is a new technique, it has not been clear how the measurements generated by RPI are related to the material properties of bone measured by standard techniques. In this paper, we describe our experience with the RPI technique, and correlate the results obtained by RPI with those of traditional mechanical testing, namely 3-point bending and axial compression. Using different animal models, we report that apparent bone material toughness obtained from 3-point bending and axial compression is inversely correlated with the indentation distance increase (IDI) obtained from RPI with r(2) values ranging from 0.50 to 0.57. We also show that conditions or treatments previously shown to cause differences in toughness, including diabetes and bisphosphonate treatment, had significantly different IDI values compared to controls. Collectively these results provide a starting point for understanding how RPI relates to traditional mechanical testing results.

  12. Effect of thermodisinfection on mechanic parameters of cancellous bone.

    PubMed

    Fölsch, Christian; Kellotat, Andreas; Rickert, Markus; Ishaque, Bernd; Ahmed, Gafar; Pruss, Axel; Jahnke, Alexander

    2016-09-01

    Revision surgery of joint replacements is increasing and raises the demand for allograft bone since restoration of bone stock is crucial for longevity of implants. Proceedings of bone grafts influence the biological and mechanic properties differently. This study examines the effect of thermodisinfection on mechanic properties of cancellous bone. Bone cylinders from both femoral heads with length 45 mm were taken from twenty-three 6-8 months-old piglets, thermodisinfected at 82.5 °C according to bone bank guidelines and control remained native. The specimens were stored at -20 °C immediately and were put into 21 °C Ringer's solution for 3 h before testing. Shear and pressure modulus were tested since three point bending force was examined until destruction. Statistical analysis was done with non-parametric Wilcoxon, t test and SPSS since p < 0.05 was significant. Shear modulus was significantly reduced by thermodisinfection to 1.02 ± 0.31 GPa from 1.28 ± 0.68 GPa for unprocessed cancellous bone (p = 0.029) since thermodisinfection reduced pressure modulus not significantly from 6.30 ± 4.72 GPa for native specimens to 4.97 ± 2.23 GPa and maximum bending force was 270.03 ± 116.68 N for native and 228.80 ± 70.49 N for thermodisinfected cancellous bone. Shear and pressure modulus were reduced by thermodisinfection around 20 % and maximum bending force was impaired by about 15 % compared with native cancellous bone since only the reduction of shear modulus reached significance. The results suggest that thermodisinfection similarly affects different mechanic properties of cancellous bone and the reduction of mechanic properties should not relevantly impair clinical use of thermodisinfected cancellous bone.

  13. Molecular mechanics of mineralized collagen fibrils in bone

    NASA Astrophysics Data System (ADS)

    Nair, Arun K.; Gautieri, Alfonso; Chang, Shu-Wei; Buehler, Markus J.

    2013-04-01

    Bone is a natural composite of collagen protein and the mineral hydroxyapatite. The structure of bone is known to be important to its load-bearing characteristics, but relatively little is known about this structure or the mechanism that govern deformation at the molecular scale. Here we perform full-atomistic calculations of the three-dimensional molecular structure of a mineralized collagen protein matrix to try to better understand its mechanical characteristics under tensile loading at various mineral densities. We find that as the mineral density increases, the tensile modulus of the network increases monotonically and well beyond that of pure collagen fibrils. Our results suggest that the mineral crystals within this network bears up to four times the stress of the collagen fibrils, whereas the collagen is predominantly responsible for the material’s deformation response. These findings reveal the mechanism by which bone is able to achieve superior energy dissipation and fracture resistance characteristics beyond its individual constituents.

  14. Molecular mechanics of mineralized collagen fibrils in bone

    PubMed Central

    Nair, Arun K.; Gautieri, Alfonso; Chang, Shu-Wei; Buehler, Markus J.

    2013-01-01

    Bone is a natural composite of collagen protein and the mineral hydroxyapatite. The structure of bone is known to be important to its load-bearing characteristics, but relatively little is known about this structure or the mechanism that govern deformation at the molecular scale. Here we perform full-atomistic calculations of the three-dimensional molecular structure of a mineralized collagen protein matrix to try to better understand its mechanical characteristics under tensile loading at various mineral densities. We find that as the mineral density increases, the tensile modulus of the network increases monotonically and well beyond that of pure collagen fibrils. Our results suggest that the mineral crystals within this network bears up to four times the stress of the collagen fibrils, whereas the collagen is predominantly responsible for the material’s deformation response. These findings reveal the mechanism by which bone is able to achieve superior energy dissipation and fracture resistance characteristics beyond its individual constituents. PMID:23591891

  15. Mechanical Vibration Mitigates the Decrease of Bone Quantity and Bone Quality of Leptin Receptor-Deficient Db/Db Mice by Promoting Bone Formation and Inhibiting Bone Resorption.

    PubMed

    Jing, Da; Luo, Erping; Cai, Jing; Tong, Shichao; Zhai, Mingming; Shen, Guanghao; Wang, Xin; Luo, Zhuojing

    2016-09-01

    Leptin, a major hormonal product of adipocytes, is involved in regulating appetite and energy metabolism. Substantial studies have revealed the anabolic actions of leptin on skeletons and bone cells both in vivo and in vitro. Growing evidence has substantiated that leptin receptor-deficient db/db mice exhibit decreased bone mass and impaired bone microstructure despite several conflicting results previously reported. We herein systematically investigated bone microarchitecture, mechanical strength, bone turnover and its potential molecular mechanisms in db/db mice. More importantly, we also explored an effective approach for increasing bone mass in leptin receptor-deficient animals in an easy and noninvasive manner. Our results show that deterioration of trabecular and cortical bone microarchitecture and decreases of skeletal mechanical strength-including maximum load, yield load, stiffness, energy, tissue-level modulus and hardness-in db/db mice were significantly ameliorated by 12-week, whole-body vibration (WBV) with 0.5 g, 45 Hz via micro-computed tomography (μCT), three-point bending, and nanoindentation examinations. Serum biochemical analysis shows that WBV significantly decreased serum tartrate-resistant acid phosphatase 5b (TRACP5b) and CTx-1 levels and also mitigated the reduction of serum osteocalcin (OCN) in db/db mice. Bone histomorphometric analysis confirmed that decreased bone formation-lower mineral apposition rate, bone formation rate, and osteoblast numbers in cancellous bone-in db/db mice were suppressed by WBV. Real-time PCR assays show that WBV mitigated the reductions of tibial alkaline phosphatase (ALP), OCN, Runt-related transcription factor 2 (RUNX2), type I collagen (COL1), BMP2, Wnt3a, Lrp6, and β-catenin mRNA expression, and prevented the increases of tibial sclerostin (SOST), RANK, RANKL, RANL/osteoprotegerin (OPG) gene levels in db/db mice. Our results show that WBV promoted bone quantity and quality in db/db mice with obvious

  16. mTORC2 Signaling Promotes Skeletal Growth and Bone Formation in Mice

    PubMed Central

    Chen, Jianquan; Holguin, Nilsson; Shi, Yu; Silva, Matthew J.; Long, Fanxin

    2015-01-01

    Mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase controlling many physiological processes in mammals. mTOR functions in two distinct protein complexes, namely mTORC1 and mTORC2. Compared to mTORC1, the specific roles of mTORC2 are less well understood. To investigate the potential contribution of mTORC2 to skeletal development and homeostasis, we have genetically deleted Rictor, an essential component of mTORC2, in the limb skeletogenic mesenchyme of the mouse embryo. Loss of Rictor leads to shorter and narrower skeletal elements in both embryos and postnatal mice. In the embryo, Rictor deletion reduces the width but not the length of the initial cartilage anlage. Subsequently, the embryonic skeletal elements are shortened due to a delay in chondrocyte hypertrophy, with no change in proliferation, apoptosis, cell size, or matrix production. Postnatally, Rictor-deficient mice exhibit impaired bone formation, resulting in thinner cortical bone, but the trabecular bone mass is relatively normal thanks to a concurrent decrease in bone resorption. Moreover, Rictor-deficient bones exhibit a lesser anabolic response to mechanical loading. Thus, mTORC2 signaling is necessary for optimal skeletal growth and bone anabolism. PMID:25196701

  17. 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

  18. Muscle forces or gravity: what predominates mechanical loading on bone?

    PubMed

    Kohrt, Wendy M; Barry, Daniel W; Schwartz, Robert S

    2009-11-01

    Most mechanical forces acting on the skeleton are generated either through impact with the ground (i.e., gravitational loading) or through muscle contractions (i.e., muscle loading). If one of these conduits for activating mechanotransduction in bone is more effective than the other with respect to developing or maintaining bone strength, this would have important clinical implications for prescribing physical activity for the prevention or treatment of osteoporosis. This section of the symposium considered whether there is evidence from studies of humans that the effectiveness of physical activity to preserve bone health is dependent on whether the activities stimulate the skeleton primarily through gravitational or muscle loading. Conclusive evidence is lacking, but several lines of research suggest that physical activities that involve impact forces, and therefore generate both gravitation and muscle loading, are most likely to have beneficial effects on bone metabolism and reduce fracture risk.

  19. Cyp26b1 within the growth plate regulates bone growth in juvenile mice

    SciTech Connect

    Minegishi, Yoshiki; Sakai, Yasuo; Yahara, Yasuhito; Akiyama, Haruhiko; Yoshikawa, Hideki; Hosokawa, Ko; Tsumaki, Noriyuki

    2014-11-07

    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, it 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.

  20. Timing of growth hormone treatment affects trabecular bone microarchitecture and mineralization in growth hormone deficient mice.

    PubMed

    Kristensen, Erika; Hallgrímsson, Benedikt; Morck, Douglas W; Boyd, Steven K

    2010-08-01

    Growth hormone (GH) is essential in the development of bone mass, and a growth hormone deficiency (GHD) in childhood is frequently treated with daily injections of GH. It is not clear what effect GHD and its treatment has on bone. It was hypothesized that GHD would result in impaired microarchitecture, and an early onset of treatment would result in a better recovery than late onset. Growth hormone deficient homozygous (lit/lit) mice of both sexes were divided into two treatment groups receiving daily injections of GH, starting at an early (21 days of age) or a late time point (35 days of age, corresponding to the end of puberty). A group of heterozygous mice with normal levels of growth hormone served as controls. In vivo micro-computed tomography scans of the fourth lumbar vertebra were obtained at five time points between 21 and 60 days of age, and trabecular morphology and volumetric BMD were analyzed to determine the effects of GH on bone microarchitecture. Early GH treatment led to significant improvements in bone volume ratio (p=0.006), tissue mineral density (p=0.005), and structure model index (p=0.004) by the study endpoint (day 60), with no detected change in trabecular thickness. Trabecular number increased and trabecular separation decreased in GHD mice regardless of treatment compared to heterozygous mice. This suggests fundamental differences in the structure of trabecular bone in GHD and GH treated mice, reflected by an increased number of thinner trabeculae in these mice compared to heterozygous controls. There were no significant differences between the late treatment group and GHD mice except for connectivity density. Taken together, these results indicate that bone responds to GH treatment initiated before puberty but not to treatment commencing post-puberty, and that GH treatment does not rescue the structure of trabecular bone to that of heterozygous controls. Copyright 2010 Elsevier Inc. All rights reserved.

  1. Bovine bone screws: metrology and effects of chemical processing and ethylene oxide sterilization on bone surface and mechanical properties.

    PubMed

    Haje, D P; Volpon, J B; Moro, C A

    2009-03-01

    We assess the effects of chemical processing, ethylene oxide sterilization, and threading on bone surface and mechanical properties of bovine undecalcified bone screws. In addition, we evaluate the possibility of manufacturing bone screws with predefined dimensions. Scanning electronic microscopic images show that chemical processing and ethylene oxide treatment causes collagen fiber amalgamation on the bone surface. Processed screws hold higher ultimate loads under bending and torsion than the in natura bone group, with no change in pull-out strength between groups. Threading significantly reduces deformation and bone strength under torsion. Metrological data demonstrate the possibility of manufacturing bone screws with standardized dimensions.

  2. A Concert between Biology and Biomechanics: The Influence of the Mechanical Environment on Bone Healing

    PubMed Central

    Glatt, Vaida; Evans, Christopher H.; Tetsworth, Kevin

    2017-01-01

    In order to achieve consistent and predictable fracture healing, a broad spectrum of growth factors are required to interact with one another in a highly organized response. Critically important, the mechanical environment around the fracture site will significantly influence the way bone heals, or if it heals at all. The role of the various biological factors, the timing, and spatial relationship of their introduction, and how the mechanical environment orchestrates this activity, are all crucial aspects to consider. This review will synthesize decades of work and the acquired knowledge that has been used to develop new treatments and technologies for the regeneration and healing of bone. Moreover, it will discuss the current state of the art in experimental and clinical studies concerning the application of these mechano-biological principles to enhance bone healing, by controlling the mechanical environment under which bone regeneration takes place. This includes everything from the basic principles of fracture healing, to the influence of mechanical forces on bone regeneration, and how this knowledge has influenced current clinical practice. Finally, it will examine the efforts now being made for the integration of this research together with the findings of complementary studies in biology, tissue engineering, and regenerative medicine. By bringing together these diverse disciplines in a cohesive manner, the potential exists to enhance fracture healing and ultimately improve clinical outcomes. PMID:28174539

  3. Fatty Infiltration of Skeletal Muscle: Mechanisms and Comparisons with Bone Marrow Adiposity.

    PubMed

    Hamrick, Mark W; McGee-Lawrence, Meghan E; Frechette, Danielle M

    2016-01-01

    Skeletal muscle and bone share common embryological origins from mesodermal cell populations and also display common growth trajectories early in life. Moreover, muscle and bone are both mechanoresponsive tissues, and the mass and strength of both tissues decline with age. The decline in muscle and bone strength that occurs with aging is accompanied in both cases by an accumulation of adipose tissue. In bone, adipocyte (AC) accumulation occurs in the marrow cavities of long bones and is known to increase with estrogen deficiency, mechanical unloading, and exposure to glucocorticoids. The factors leading to accumulation of intra- and intermuscular fat (myosteatosis) are less well understood, but recent evidence indicates that increases in intramuscular fat are associated with disuse, altered leptin signaling, sex steroid deficiency, and glucocorticoid treatment, factors that are also implicated in bone marrow adipogenesis. Importantly, accumulation of ACs in skeletal muscle and accumulation of intramyocellular lipid are linked to loss of muscle strength, reduced insulin sensitivity, and increased mortality among the elderly. Resistance exercise and whole body vibration can prevent fatty infiltration in skeletal muscle and also improve muscle strength. Therapeutic strategies to prevent myosteatosis may improve muscle function and reduce fall risk in the elderly, potentially impacting the incidence of bone fracture.

  4. Measuring the dynamic mechanical response of hydrated mouse bone by nanoindentation

    PubMed Central

    Pathak, Siddhartha; Swadener, J. Gregory; Kalidindi, Surya R.; Courtland, Hayden-William; Jepsen, Karl J.; Goldman, Haviva M.

    2011-01-01

    This study demonstrates a novel approach to characterizing hydrated bone’s viscoelastic behavior at the lamellar length scales using dynamic indentation techniques. We studied the submicron-level viscoelastic response of bone tissue from two different inbred mouse strains, A/J and B6, with known differences in whole bone and tissue-level mechanical properties. Our results show that bone having a higher collagen content or a lower mineral-to-matrix ratio demonstrates a trend towards a larger viscoelastic response. When normalized for anatomical location relative to biological growth patterns in the antero-medial (AM) cortex, bone tissue from B6 femora, known to have a lower mineral-to-matrix ratio, is shown to exhibit a significantly higher viscoelastic response compared to A/J tissue. Newer bone regions with a higher collagen content (closer to the endosteal edge of the AM cortex) showed a trend towards a larger viscoelastic response. Our study demonstrates the feasibility of this technique to be used to study local composition-property relationships in bone. Further, this technique of viscoelastic nanoindentation mapping of the bone surface at these submicron length scales is shown to be highly advantageous in studying sub-surface features, such as porosity, of wet hydrated biological specimens, which are difficult to identify using other methods. PMID:21094478

  5. Controlling dynamic mechanical properties and degradation of composites for bone regeneration by means of filler content.

    PubMed

    Barbieri, Davide; de Bruijn, Joost D; Luo, Xiaoman; Farè, Silvia; Grijpma, Dirk W; Yuan, Huipin

    2013-04-01

    Bone tissue is a dynamic composite system that adapts itself, in response to the surrounding daily (cyclic) mechanical stimuli, through an equilibrium between growth and resorption processes. When there is need of synthetic bone grafts, the biggest issue is to support bone regeneration without causing mechanically-induced bone resorption. Apart from biological properties, such degradable materials should initially support and later leave room to bone formation. Further, dynamic mechanical properties comparable to those of bone are required. In this study we prepared composites comprising calcium phosphate and L-lactide/D-lactide copolymer in various content ratios using the extrusion method. We evaluated the effect of the inorganic filler amount on the polymer phase (i.e. on the post-extrusion intrinsic viscosity). We then studied their in vitro degradation and dynamic mechanical properties (in dry and humid conditions). By increasing the filler content, we observed significant decrease of the intrinsic viscosity of the polymer phase during the extrusion process. Composites containing higher amounts of apatite had faster degradation, and were also mechanically stiffer. But, due to the lower intrinsic viscosity of their polymer phase, they had larger damping properties. Besides this, higher amounts of apatite also rendered the composites more hydrophilic letting them absorb more water and causing them the largest decrease in stiffness. These results show the importance of filler content in controlling the properties of such composites. Further, in this study we observed that the viscoelastic properties of the composite containing 50wt% apatite were comparable to those of dry human cortical bone.

  6. Elbow loading promotes longitudinal bone growth of the ulna and the humerus.

    PubMed

    Zhang, Ping; Yokota, Hiroki

    2012-01-01

    Mechanical stimulation plays a critical role in bone development and growth. In view of recently recognized anabolic responses promoted by a joint-loading modality, we examined the effects of elbow loading on longitudinal growth of the ulna and the humerus. Using a custom-made piezoelectric loader, the left elbow of growing C57/BL/6 female mice was given daily 5-min bouts of dynamic loading for 10 days. The right forelimbs of those mice served as contralateral controls, and the limbs of non-treated mice were used as age-matched controls. The effects of elbow loading were evaluated through measurement of bone length, weight, bone mineral density (BMD), and bone mineral content (BMC), as well as mRNA expression levels of load-sensitive transcription factors such as c-fos, egr1, and atf3. The results revealed that the humerus was elongated by 1.2% compared to the contralateral and age-matched controls (both p < 0.001), while the ulna had become longer than the contralateral control (1.7%; p < 0.05) and the age-match control (3.4%; p < 0.001). Bone lengthening was associated with increases in bone weight, BMD and BMC. Furthermore, the mRNA levels of the selected transcription factors were elevated in the loaded ulna and humerus. Interestingly, the increase was observed not only at the elbow but also at the wrist and shoulder in the loaded limb. The present study demonstrates that joint loading is potentially useful for stimulating bone lengthening and treating limb length discrepancy.

  7. Strategies to engineer tendon/ligament-to-bone interface: Biomaterials, cells and growth factors.

    PubMed

    Font Tellado, Sonia; Balmayor, Elizabeth R; Van Griensven, Martijn

    2015-11-01

    Integration between tendon/ligament and bone occurs through a specialized tissue interface called enthesis. The complex and heterogeneous structure of the enthesis is essential to ensure smooth mechanical stress transfer between bone and soft tissues. Following injury, the interface is not regenerated, resulting in high rupture recurrence rates. Tissue engineering is a promising strategy for the regeneration of a functional enthesis. However, the complex structural and cellular composition of the native interface makes enthesis tissue engineering particularly challenging. Thus, it is likely that a combination of biomaterials and cells stimulated with appropriate biochemical and mechanical cues will be needed. The objective of this review is to describe the current state-of-the-art, challenges and future directions in the field of enthesis tissue engineering focusing on four key parameters: (1) scaffold and biomaterials, (2) cells, (3) growth factors and (4) mechanical stimuli.

  8. 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.

  9. 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.

  10. 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.

  11. Effects of a 1-wk spaceflight on morphological and mechanical properties of growing bone.

    PubMed

    Shaw, S R; Vailas, A C; Grindeland, R E; Zernicke, R F

    1988-01-01

    The morphological and mechanical responses of tibia and humerus were assessed in growing male rats after a 1-wk spaceflight aboard NASA Spacelab 3. In contrast to flights of longer duration, changes in middiaphysial cross-sectional morphology were minimal. Inhibition of longitudinal growth was not found in the tibia but was apparent in the humerus. The normal age-related increase in tibial middiaphysial density was not observed in the flight animals. Three-point bending tests indicated that a 1-wk spaceflight impeded the maturation of bone strength and stiffness, with the effects more pronounced in the tibia than in the humerus. Material property alterations in bone thus overshadowed morphological factors in determining the bone's mechanical response. It is likely that deprivation of normal weight-bearing loads was a major factor contributing to the observed changes, but endocrine and other local factors must also be considered.

  12. [Bone biopsy needles: mechanical properties, needle design and specimen quality].

    PubMed

    Keulers, A; Cunha-Cruz, V C; Bruners, P; Penzkofer, T; Braunschweig, T; Schmitz-Rode, T; Mahnken, A

    2011-03-01

    To quantitatively analyze differences in mechanical properties, needle design including signs of wear, subjective handling and specimen quality of bone biopsy needles. In this study 19 different bone biopsy systems (total 38; 2 /type) were examined. With each biopsy needle five consecutive samples were obtained from vertebral bodies of swine. During puncture a force-torques sensor measured the mechanical properties and subjective handling was assessed. Before and after each biopsy the needles were investigated using a profile projector and signs of wear were recorded. Afterwards, a pathologist semi-quantitatively examined the specimen regarding sample quality. The overall evaluation considered mechanical properties, needle wear, subjective handling and sample quality. Differences were assessed for statistical significance using ANOVA and t-test. Needle diameter (p = 0.003) as well as needle design (p = 0.008) affect the mechanical properties significantly. Franseen design is significantly superior to other needle designs. Besides, length reduction recorded by the profile projector, as a quality criterion showed notable distinctions in between the needle designs. Bone biopsy needles vary significantly in performance. Needle design has an important influence on mechanical properties, handling and specimen quality. Detailed knowledge of those parameters would improve selecting the appropriate bone biopsy needle. © Georg Thieme Verlag KG Stuttgart · New York.

  13. Enhanced reconstruction of long bone architecture by a growth factor mutant combining positive features of GDF-5 and BMP-2.

    PubMed

    Kleinschmidt, Kerstin; Ploeger, Frank; Nickel, Joachim; Glockenmeier, Julia; Kunz, Pierre; Richter, Wiltrud

    2013-08-01

    Non healing bone defects remain a worldwide health problem and still only few osteoinductive growth factors are available for clinical use in bone regeneration. By introducing BMP-2 residues into growth and differentiation factor (GDF)-5 we recently produced a mutant GDF-5 protein BB-1 which enhanced heterotopic bone formation in mice. Designed to combine positive features of GDF-5 and BMP-2, we suspected that this new growth factor variant may improve long bone healing compared to the parent molecules and intended to unravel functional mechanisms behind its action. BB-1 acquired an increased binding affinity to the BMP-IA receptor, mediated enhanced osteogenic induction of human mesenchymal stem cells versus GDF-5 and higher VEGF secretion than BMP-2 in vitro. Rabbit radius defects treated with a BB-1-coated collagen carrier healed earlier and with increased bone volume compared to BMP-2 and GDF-5 according to in vivo micro-CT follow-up. While BMP-2 callus often remained spongy, BB-1 supported earlier corticalis and marrow cavity formation, showing no pseudojoint persistence like with GDF-5. Thus, by combining positive angiogenic and osteogenic features of GDF-5 and BMP-2, only BB-1 restored a natural bone architecture within 12 weeks, rendering this promising growth factor variant especially promising for long bone regeneration. Copyright © 2013 Elsevier Ltd. All rights reserved.

  14. Mechanical unloading of bone in microgravity reduces mesenchymal and hematopoietic stem cell-mediated tissue regeneration.

    PubMed

    Blaber, E A; Dvorochkin, N; Torres, M L; Yousuf, R; Burns, B P; Globus, R K; Almeida, E A C

    2014-09-01

    Mechanical loading of mammalian tissues is a potent promoter of tissue growth and regeneration, whilst unloading in microgravity can cause reduced tissue regeneration, possibly through effects on stem cell tissue progenitors. To test the specific hypothesis that mechanical unloading alters differentiation of bone marrow mesenchymal and hematopoietic stem cell lineages, we studied cellular and molecular aspects of how bone marrow in the mouse proximal femur responds to unloading in microgravity. Trabecular and cortical endosteal bone surfaces in the femoral head underwent significant bone resorption in microgravity, enlarging the marrow cavity. Cells isolated from the femoral head marrow compartment showed significant down-regulation of gene expression markers for early mesenchymal and hematopoietic differentiation, including FUT1(-6.72), CSF2(-3.30), CD90(-3.33), PTPRC(-2.79), and GDF15(-2.45), but not stem cell markers, such as SOX2. At the cellular level, in situ histological analysis revealed decreased megakaryocyte numbers whilst erythrocytes were increased 2.33 fold. Furthermore, erythrocytes displayed elevated fucosylation and clustering adjacent to sinuses forming the marrow-blood barrier, possibly providing a mechanistic basis for explaining spaceflight anemia. Culture of isolated bone marrow cells immediately after microgravity exposure increased the marrow progenitor's potential for mesenchymal differentiation into in-vitro mineralized bone nodules, and hematopoietic differentiation into osteoclasts, suggesting an accumulation of undifferentiated progenitors during exposure to microgravity. These results support the idea that mechanical unloading of mammalian tissues in microgravity is a strong inhibitor of tissue growth and regeneration mechanisms, acting at the level of early mesenchymal and hematopoietic stem cell differentiation.

  15. Role of fibroblast growth factor 2 and Wnt signaling in anabolic effects of parathyroid hormone on bone formation

    PubMed Central

    Fei, Yurong; Hurley, Marja M.

    2012-01-01

    Osteoporosis poses enormous health and economic burden worldwide. One of the very few anabolic agents for osteoporosis is parathyroid hormone (PTH). Although great progress has been made since the FDA approved PTH in 2002, the detailed mechanisms of the bone anabolic effects of intermittent PTH treatment is still not well understood. PTH bone anabolic effect is regulated by extracellular factors. Maximal bone anabolic effect of PTH requires fibroblast growth factor 2 (FGF2) signaling, which might be mediated by transcription factor activating transcription factor 4 (ATF4). Maximal bone anabolic effect of PTH also requires Wnt signaling. Particularly, Wnt antagonists such as sclerostin, dickkopf 1 (DKK1) and secreted frizzled related protein 1 (sFRP1) are promising targets to increase bone formation. Interestingly, FGF2 signaling modulates Wnt/β-Catenin signaling pathway in bone. Therefore, multiple signaling pathways utilized by PTH are cross talking and working together to promote bone formation. Extensive studies on the mechanisms of action of PTH will help to identify new pathways that regulate bone formation, to improve available agents to stimulate bone formation, and to identify potential new anabolic agents for osteoporosis. PMID:22378151

  16. Role of fibroblast growth factor 2 and Wnt signaling in anabolic effects of parathyroid hormone on bone formation.

    PubMed

    Fei, Yurong; Hurley, Marja M

    2012-11-01

    Osteoporosis poses enormous health and economic burden worldwide. One of the very few anabolic agents for osteoporosis is parathyroid hormone (PTH). Although great progress has been made since the FDA approved PTH in 2002, the detailed mechanisms of the bone anabolic effects of intermittent PTH treatment is still not well understood. PTH bone anabolic effect is regulated by extracellular factors. Maximal bone anabolic effect of PTH requires fibroblast growth factor 2 (FGF2) signaling, which might be mediated by transcription factor activating transcription factor 4 (ATF4). Maximal bone anabolic effect of PTH also requires Wnt signaling. Particularly, Wnt antagonists such as sclerostin, dickkopf 1 (DKK1) and secreted frizzled related protein 1 (sFRP1) are promising targets to increase bone formation. Interestingly, FGF2 signaling modulates Wnt/β-Catenin signaling pathway in bone. Therefore, multiple signaling pathways utilized by PTH are cross talking and working together to promote bone formation. Extensive studies on the mechanisms of action of PTH will help to identify new pathways that regulate bone formation, to improve available agents to stimulate bone formation, and to identify potential new anabolic agents for osteoporosis. Copyright © 2012 Wiley Periodicals, Inc.

  17. How does the pathophysiological context influence delivery of bone growth factors?☆

    PubMed Central

    Yu, Xiaohua; Suárez-González, Darilis; Khalil, Andrew S.; Murphy, William L.

    2014-01-01

    “Orthobiologics” represents an important category of therapeutics for the regeneration of bone defects caused by injuries or diseases, and bone growth factors are a particularly rapidly growing sub-category. Clinical application of bone growth factors has accelerated in the last two decades with the introduction of BMPs into clinical bone repair. Optimal use of growth factor-mediated treatments heavily relies on controlled delivery, which can substantially influence the local growth factor dose, release kinetics, and biological activity. The characteristics of the surrounding environment, or “context”, during delivery can dictate growth factor loading efficiency, release and biological activity. This review discusses the influence of the surrounding environment on therapeutic delivery of bone growth factors. We specifically focus on pathophysiological components, including soluble components and cells, and how they can actively influence the therapeutic delivery and perhaps efficacy of bone growth factors. PMID:25453269

  18. Heritability of lumbar trabecular bone mechanical properties in baboons.

    PubMed

    Havill, L M; Allen, M R; Bredbenner, T L; Burr, D B; Nicolella, D P; Turner, C H; Warren, D M; Mahaney, M C

    2010-03-01

    Genetic effects on mechanical properties have been demonstrated in rodents, but not confirmed in primates. Our aim was to quantify the proportion of variation in vertebral trabecular bone mechanical properties that is due to the effects of genes. L3 vertebrae were collected from 110 females and 46 male baboons (6-32 years old) from a single extended pedigree. Cranio-caudally oriented trabecular bone cores were scanned with microCT then tested in monotonic compression to determine apparent ultimate stress, modulus, and toughness. Age and sex effects and heritability (h(2)) were assessed using maximum likelihood-based variance components methods. Additive effects of genes on residual trait variance were significant for ultimate stress (h(2)=0.58), toughness (h(2)=0.64), and BV/TV (h(2)=0.55). When BV/TV was accounted for, the residual variance in ultimate stress accounted for by the additive effects of genes was no longer significant. Toughness, however, showed evidence of a non-BV/TV-related genetic effect. Overall, maximum stress and modulus show strong genetic effects that are nearly entirely due to bone volume. Toughness shows strong genetic effects related to bone volume and shows additional genetic effects (accounting for 10% of the total trait variance) that are independent of bone volume. These results support continued use of bone volume as a focal trait to identify genes related to skeletal fragility, but also show that other focal traits related to toughness and variation in the organic component of bone matrix will enhance our ability to find additional genes that are particularly relevant to fatigue-related fractures.

  19. Recent research on the growth plate: Impact of inflammatory cytokines on longitudinal bone growth.

    PubMed

    Sederquist, Bettina; Fernandez-Vojvodich, Paola; Zaman, Farasat; Sävendahl, Lars

    2014-08-01

    Children with inflammatory diseases usually display abnormal growth patterns as well as delayed puberty. This is a result of several factors related to the disease itself, such as malnutrition, hypercortisolism, and elevated levels of pro-inflammatory cytokines. These factors in combination with glucocorticoid treatment contribute to growth retardation during chronic inflammation by systemically affecting the major regulator of growth, the GH/IGF1 axis. However, recent studies have also shown evidence of a direct effect of these factors at the growth plate level. In conditions of chronic inflammation, pro-inflammatory cytokines are upregulated and released into the circulation. The most abundant of these, tumor necrosis factor α, interleukin 1β (IL1β), and IL6, are all known to directly act on growth plate cartilage to induce apoptosis and thereby suppress bone growth. Both clinical and experimental studies have shown that growth retardation can partly be rescued when these cytokines are blocked. Therefore, therapy modulating the local actions of these cytokines may be effective for preventing growth failure in patients with chronic inflammatory disorders. In this review, we report the current knowledge of inflammatory cytokines and their role in regulating bone growth.

  20. PCL-coated hydroxyapatite scaffold derived from cuttlefish bone: morphology, mechanical properties and bioactivity.

    PubMed

    Milovac, Dajana; Gallego Ferrer, Gloria; Ivankovic, Marica; Ivankovic, Hrvoje

    2014-01-01

    In the present study, poly(ε-caprolactone)-coated hydroxyapatite scaffold derived from cuttlefish bone was prepared. Hydrothermal transformation of aragonitic cuttlefish bone into hydroxyapatite (HAp) was performed at 200°C retaining the cuttlebone architecture. The HAp scaffold was coated with a poly(ε-caprolactone) (PCL) using vacuum impregnation technique. The compositional and morphological properties of HAp and PCL-coated HAp scaffolds were studied by means of X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, thermogravimetric analysis (TGA) and scanning electron microscopy (SEM) with energy dispersive X-ray (EDX) analysis. Bioactivity was tested by immersion in Hank's balanced salt solution (HBSS) and mechanical tests were performed at compression. The results showed that PCL-coated HAp (HAp/PCL) scaffold resulted in a material with improved mechanical properties that keep the original interconnected porous structure indispensable for tissue growth and vascularization. The compressive strength (0.88MPa) and the elastic modulus (15.5MPa) are within the lower range of properties reported for human trabecular bones. The in vitro mineralization of calcium phosphate (CP) that produces the bone-like apatite was observed on both the pure HAp scaffold and the HAp/PCL composite scaffold. The prepared bioactive scaffold with enhanced mechanical properties is a good candidate for bone tissue engineering applications. © 2013.

  1. Platelet derived growth factor secretion and bone healing after Er:YAG laser bone irradiation.

    PubMed

    Kesler, Gavriel; Shvero, Dana Kesler; Tov, Yariv Siman; Romanos, George

    2011-03-01

    Er:YAG laser irradiation has been reported to enhance wound healing. However, no studies have evaluated the synthesis of growth factors after laser irradiation. The present study investigated the effects of laser irradiation on the amount of secretion of platelet derived growth factor (PDGF) in the wound, clarifying the effects of the Er:YAG laser on the bone healing. Osteotomies were prepared in the tibiae of 28 rats using an Er:YAG laser (test group). Maximum power of 8 watts, energy per pulse of 700 mJ, and frequency up to 50 Hz were used. The laser was used with external water irrigation, a spot size of 2 mm, energy per pulse of 500 to 1000 mJ/pulse, and energy density of 32 J/cm(2). Twenty eight additional rats served as a control group and their osteotomies were prepared with a drill 1.3 mm in diameter at 1000 rpm, with simultaneous saline irrigation. Two rats from the tested group and 2 from the control group were sacrificed on each day following surgery (1-14 days), and the tissue specimens were prepared for histologic evaluation. Immunohistochemical staining with anti-PDGF was performed after histologic examination. The difference between the PDGF staining intensities of the 2 treatment groups was analyzed using a multivariate logistic regression test. A significant rise in PDGF staining occurred in both groups 2-3 days following surgery. However, while high PDGF counts remained for the 2-week experimental period in the laser group, PDGF levels in the control group returned to baseline levels 8 days post surgery. The 2 groups (laser and control) were found to be different throughout the experiment, and the rat type was found to be a significant predictor (P  =  .000011). The present study demonstrated that Er:YAG laser irradiation seems to stimulate the secretion of PDGF in osteotomy sites in a rat model. It is possible that the high levels of PDGF are part of the mechanism that Er:YAG irradiation enhances and improves the healing of

  2. Hydroxyapatite-binding peptides for bone growth and inhibition

    DOEpatents

    Bertozzi, Carolyn R [Berkeley, CA; Song, Jie [Shrewsbury, MA; Lee, Seung-Wuk [Walnut Creek, CA

    2011-09-20

    Hydroxyapatite (HA)-binding peptides are selected using combinatorial phage library display. Pseudo-repetitive consensus amino acid sequences possessing periodic hydroxyl side chains in every two or three amino acid sequences are obtained. These sequences resemble the (Gly-Pro-Hyp).sub.x repeat of human type I collagen, a major component of extracellular matrices of natural bone. A consistent presence of basic amino acid residues is also observed. The peptides are synthesized by the solid-phase synthetic method and then used for template-driven HA-mineralization. Microscopy reveal that the peptides template the growth of polycrystalline HA crystals .about.40 nm in size.

  3. Various effects of antidepressant drugs on bone microarchitectecture, mechanical properties and bone remodeling

    SciTech Connect

    Bonnet, N. . E-mail: nicolas.bonnet15@wanadoo.fr; Bernard, P.; Beaupied, H; Bizot, J.C.; Trovero, F.; Courteix, D.; Benhamou, C.L.

    2007-05-15

    The aim of this study was to evaluate the effects of various drugs which present antidepressant properties: selective serotonin-reuptake inhibitors (SSRIs, fluoxetine), serotonin and noradrenaline-reuptake inhibitors (Desipramine) and phosphodiesterase inhibitors (PDE, rolipram and tofisopam) on bone microarchitecture and biomechanical properties. Twelve female mice were studied per group starting at an age of 10 weeks. During 4 weeks, they received subcutaneously either placebo or 20 mg kg{sup -1} day{sup -1} of desipramine, fluoxetine or 10 mg kg{sup -1} day{sup -1} of rolipram or tofisopam. Serum Osteocalcin and CTx were evaluated by ELISA. Bone microarchitecture of the distal femur was characterized by X-ray microCT (Skyscan1072). Mechanical properties were assessed by three-point bending test (Instron 4501) and antidepressant efficacy by forced swimming and open field tests. Fluoxetine displayed lower TbTh (- 6.1%, p < 0.01) and tofisopam higher TbTh (+ 5.0%, p < 0.05) versus placebo. Rolipram and tofisopam treatments induced higher BV/TV than placebo (+ 23.8% and + 18.3% respectively). Desipramine group had significantly higher cortical area (+ 4.8%, p < 0.01) and fluoxetine lower cortical area (- 6.1%, p < 0.01) compared to placebo. The stiffness and Young's modulus were lower in the fluoxetine group (77 {+-} 13 N mm{sup -1}, 6431 {+-} 1182 MPa) than in placebo (101 {+-} 9 N mm{sup -1}, 8441 {+-} 1180 MPa). Bone markers indicated a significantly higher bone formation in tofisopam (+ 8.6%) and a lower in fluoxetine (- 56.1%) compared to placebo. These data suggest deleterious effects for SSRIs, both on trabecular and cortical bone and a positive effect of PDE inhibitors on trabecular bone. Furthermore tofisopam anabolic effect in terms of bone markers, suggests a potential therapeutic effect of the PDE inhibitors on bone.

  4. Effects of Eucommia ulmoides extract on longitudinal bone growth rate in adolescent female rats.

    PubMed

    Kim, Ji Young; Lee, Jeong-Il; Song, MiKyung; Lee, Donghun; Song, Jungbin; Kim, Soo Young; Park, Juyeon; Choi, Ho-Young; Kim, Hocheol

    2015-01-01

    Eucommia ulmoides is one of the popular tonic herbs for the treatment of low back pain and bone fracture and is used in Korean medicine to reinforce muscles and bones. This study was performed to investigate the effects of E. ulmoides extract on longitudinal bone growth rate, growth plate height, and the expressions of bone morphogenetic protein 2 (BMP-2) and insulin-like growth factor 1 (IGF-1) in adolescent female rats. In two groups, we administered a twice-daily dosage of E. ulmoides extract (at 30 and 100 mg/kg, respectively) per os over 4 days, and in a control group, we administered vehicle only under the same conditions. Longitudinal bone growth rate in newly synthesized bone was observed using tetracycline labeling. Chondrocyte proliferation in the growth plate was observed using cresyl violet dye. In addition, we analyzed the expressions of BMP-2 and IGF-1 using immunohistochemistry. Eucommia ulmoides extract significantly increased longitudinal bone growth rate and growth plate height in adolescent female rats. In the immunohistochemical study, E. ulmoides markedly increased BMP-2 and IGF-1 expressions in the proliferative and hypertrophic zones. In conclusion, E. ulmoides increased longitudinal bone growth rate by promoting chondrogenesis in the growth plate and the levels of BMP-2 and IGF-1. Eucommia ulmoides could be helpful for increasing bone growth in children who have growth retardation.

  5. Influence of different mechanical stimuli in a multi-scale mechanobiological isotropic model for bone remodelling.

    PubMed

    Mercuri, E G F; Daniel, A L; Hecke, M B; Carvalho, L

    2016-09-01

    This work represents a study of a mathematical model that describes the biological response to different mechanical stimuli in a cellular dynamics model for bone remodelling. The biological system discussed herein consists of three specialised cellular types, responsive osteoblasts, active osteoblasts and osteoclasts, three types of signalling molecules, transforming growth factor beta (TGF-β), receptor activator of nuclear factor kappa-b ligand (RANKL) and osteoprotegerin (OPG) and the parathyroid hormone (PTH). Three proposals for mechanical stimuli were tested: strain energy density (SED), hydrostatic and deviatoric parts of SED. The model was tested in a two-dimensional geometry of a standard human femur. The spatial discretization was performed by the finite element method while the temporal evolution of the variables was calculated by the 4th order Runge-Kutta method. The obtained results represent the temporal evolution of the apparent density distribution and the mean apparent density and thickness for the cortical bone after 600 days of remodelling simulation. The main contributions of this paper are the coupling of mechanical and biological models and the exploration of how the different mechanical stimuli affect the cellular activity in different types of physical activities. The results revealed that hydrostatic SED stimulus was able to form more cortical bone than deviatoric SED and total SED stimuli. The computational model confirms how different mechanical stimuli can impact in the balance of bone homeostasis. Copyright © 2016 IPEM. Published by Elsevier Ltd. All rights reserved.

  6. MECHANISMS IN ENDOCRINOLOGY: Mechanisms and evaluation of bone fragility in type 1 diabetes mellitus.

    PubMed

    Hough, F S; Pierroz, D D; Cooper, C; Ferrari, S L

    2016-04-01

    Subjects with type 1 diabetes mellitus (T1DM) have decreased bone mineral density and an up to sixfold increase in fracture risk. Yet bone fragility is not commonly regarded as another unique complication of diabetes. Both animals with experimentally induced insulin deficiency syndromes and patients with T1DM have impaired osteoblastic bone formation, with or without increased bone resorption. Insulin/IGF1 deficiency appears to be a major pathogenetic mechanism involved, along with glucose toxicity, marrow adiposity, inflammation, adipokine and other metabolic alterations that may all play a role on altering bone turnover. In turn, increasing physical activity in children with diabetes as well as good glycaemic control appears to provide some improvement of bone parameters, although robust clinical studies are still lacking. In this context, the role of osteoporosis drugs remains unknown.

  7. The Clinical Use of Allografts, Demineralized Bone Matrices, Synthetic Bone Graft Substitutes and Osteoinductive Growth Factors: A Survey Study

    PubMed Central

    Seigerman, Daniel A.

    2005-01-01

    The emergence of new bone grafting options and alternatives has led to significant uncertainty when determining the most appropriate product for surgical procedures requiring bone graft in orthopedics. Allografts, demineralized bone matrices, synthetic bone graft substitutes, and osteoinductive growth factors are all viable options, yet there is a lack of data reporting clinical usage of these products. This correspondence reports on the use of bone grafting products at the Hospital for Special Surgery for a 27-month period and makes recommendations based on surgical usage, safety, and cost. Approximately half (48.6%) of all bone graft substitutes were implanted during spinal surgery. Arthroplasty, trauma, and foot/hand cases all used considerable amounts of bone grafting products as well (20.1%, 19.0%, 12.1%, respectively). Considerable differences were noticed in usage of bone grafting products among each orthopedic discipline. Of all bone graft substitutes used in arthroplasty, 14.4% were demineralized bone matrices, whereas 56.8% were allografts. Demineralized bone matrix grafts were used in 82% of trauma surgery and 89% of foot/hand cases. An increase in synthetic bone graft alternatives was noticed near the end of our investigation period. PMID:18751803

  8. Osteocyte-derived HB-GAM (pleiotrophin) is associated with bone formation and mechanical loading.

    PubMed

    Imai, S; Heino, T J; Hienola, A; Kurata, K; Büki, K; Matsusue, Y; Väänänen, H K; Rauvala, H

    2009-05-01

    HB-GAM (also known as pleiotrophin) is a cell matrix-associated protein that is highly expressed in bone. It affects osteoblast function, and might therefore play a role in bone development and remodeling. We aimed to investigate the role of HB-GAM in bone in vivo and in vitro. The bones of HB-GAM deficient mice with an inbred mouse background were studied by histological, histomorphometrical, radiological, biomechanical and mu-CT analyses and the effect of immobilization was evaluated. HB-GAM localization in vivo was studied. MLO-Y4 osteocytes were subjected to fluid shear stress in vitro, and gene and protein expression were studied by subtractive hybridization, quantitative PCR and Western blot. Human osteoclasts were cultured in the presence of rhHB-GAM and their formation and resorption activities were assayed. In agreement with previous reports, the skeletal structure of the HB-GAM knockout mice developed normally. However, a growth retardation of the weight-bearing bones was observed by 2 months of age, suggesting a link to physical activity. Adult HB-GAM deficient mice were characterized by low bone formation and osteopenia, as well as resistance to immobilization-dependent bone remodeling. HB-GAM was localized around osteocytes and their processes in vivo and furthermore, osteocytic HB-GAM expression was upregulated by mechanical loading in vitro. HB-GAM did not affect on human osteoclast formation or resorption in vitro. Taken together, our results suggest that HB-GAM is an osteocyte-derived factor that could participate in mediating the osteogenic effects of mechanical loading on bone.

  9. Mechanisms of growth cone repulsion

    PubMed Central

    Krull, Catherine E

    2010-01-01

    Research conducted in the last century suggested that chemoattractants guide cells or their processes to appropriate locations during development. Today, we know that many of the molecules involved in cellular guidance can act as chemorepellents that prevent migration into inappropriate territories. Here, we review some of the early seminal experiments and our current understanding of the underlying molecular mechanisms. PMID:20711492

  10. Growth of the flat bones of the membranous neurocranium: a computational model.

    PubMed

    Garzón-Alvarado, Diego A; González, Andres; Gutiérrez, Maria Lucia

    2013-12-01

    This article assumes two stages in the formation of the bones in the calvaria, the first one takes into account the formation of the primary centers of ossification. This step counts on the differentiation from mesenchymal cells into osteoblasts. A molecular mechanism is used based on a system of reaction-diffusion between two antagonistic molecules, which are BMP2 and Noggin. To this effect we used equations whose behavior allows finding Turing patterns that determine the location of the primary centers. In the second step of the model we used a molecule that is expressed by osteoblasts, called Dxl5 and that is expressed from the osteoblasts of each flat bone. This molecule allows bone growth through its borders through cell differentiation adjacent to each bone of the skull. The model has been implemented numerically using the finite element method. The results allow us to observe a good approximation of the formation of flat bones of the membranous skull as well as the formation of fontanelles and sutures.

  11. Fracture Mechanics of Delamination. Initiation and Growth.

    DTIC Science & Technology

    1982-01-01

    transverse cracking, delamina- tion, x- radiography , fracture mechanics, strain energy release rate, finite element, initiation and growth criteria...Battelle Columbus Laboratories, Metals and Ceramics Information Center, 505 King Avenue, Columbus, OH 43201. . . .1 Bell Aerospace Company, Buffalo , NY

  12. Role of nitric oxide and prostaglandins in the bone formation response to mechanical loading.

    PubMed

    Chow, J W

    2000-10-01

    Nitric oxide and prostaglandins are crucial early mediators in mechanically induced bone formation. They are also responsible for the associated induction of gene expression of c-fos and IGF-1 in osteocytes, key mechanosensory cells in bone. Insight into the cellular and molecular mechanisms underlying bone formation has important implications for the maintenance of structural competence of bone.

  13. Fatigue crack growth behavior in equine cortical bone

    NASA Astrophysics Data System (ADS)

    Shelton, Debbie Renee

    2001-07-01

    Objectives for this research were to experimentally determine crack growth rates, da/dN, as a function of alternating stress intensity factor, DeltaK, for specimens from lateral and dorsal regions of equine third metacarpal cortical bone tissue, and to determine if the results were described by the Paris law. In one set of experiments, specimens were oriented for crack propagation in the circumferential direction with the crack plane transverse to the long axis of the bone. In the second set of experiments, specimens were oriented for radial crack growth with the crack plane parallel to the long axis of the bone. Results of fatigue tests from the latter specimens were used to evaluate the hypothesis that crack growth rates differ regionally. The final experiments were designed to determine if crack resistance was dependent on region, proportion of hooped osteons (those with circumferentially oriented collagen fibers in the outer lamellae) or number of osteons penetrated by the crack, and to address the hypothesis that hooped osteons resist invasion by cracks better than other osteonal types. The transverse crack growth data for dorsal specimens were described by the Paris law with an exponent of 10.4 and suggested a threshold stress intensity factor, DeltaKth, of 2.0 MPa·m1/2 and fracture toughness of 4.38 MPa·m 1/2. Similar results were not obtained for lateral specimens because the crack always deviated from the intended path and ran parallel to the loading direction. Crack growth for the dorsal and lateral specimens in the radial orientation was described by the Paris law with exponents of 8.7 and 10.2, respectively, and there were no regional differences in the apparent DeltaK th (0.5 MPa·m1/2) or fracture toughness (1.2 MPa·m 1/2). Crack resistance was not associated with cortical region, proportion of hooped osteons or the number of osteons penetrated by the crack. The extent to which cracks penetrate osteons was influenced by whether the collagen fiber

  14. [The concentration of growth factors in patients with inherent and acquired shortenings of limbs bones].

    PubMed

    Strogov, M V; Luneva, S N; Novikov, K I

    2013-04-01

    The article deals with the results of study of level of growth factors in blood serum of patients with inherent and post-traumatic shortenings of limbs' bones. The detection in blood serum the level of epidermal growth factor insulin-like growth factor I and angiopoetins is proposed to monitor in given patients the reparative bone formation.

  15. Bone pain mechanism in osteoporosis: a narrative review

    PubMed Central

    Mattia, Consalvo; Coluzzi, Flaminia; Celidonio, Ludovica; Vellucci, Renato

    2016-01-01

    Summary Bone pain in elderly people dramatically affects their quality of life, with osteoporosis being the leading cause of skeletal related events. Peripheral and central mechanisms are involved in the pathogenesis of the nervous system sensitization. Osteoporosis in the elderly has been associated with increased density of bone sensory nerve fibers and their pathological modifications, together with an over-expression of nociceptors sensitized by the lowering pH due to the osteoclastic activity. The activation of N-methyl-D-aspartate (NMDA) receptors and the microglia, as a response to a range of pathological conditions, represent the leading cause of central sensitization. Unfortunately, osteoporosis is named the “silent thief” because it manifests with painful manifestation only when a fracture occurs. In the management of patients suffering from bone pain, both the nociceptive and the neuropathic component of chronic pain should be considered in the selection of the analgesic treatment. PMID:27920803

  16. Strengthening mechanisms of bone bonding to crystalline hydroxyapatite in vivo.

    PubMed

    Chen, Q Z; Wong, C T; Lu, W W; Cheung, K M C; Leong, J C Y; Luk, K D K

    2004-08-01

    The formation and strengthening mechanisms of bone bonding of crystalline hydroxyapatite (HA) has been investigated using high-resolution transmission electron microscope (HRTEM) and energy-dispersive X-ray (EDX) analysis. A series of results were obtained: (i) a layer of amorphous HA, which has almost the same chemistry as the implanted HA, was formed on the surface of crystalline HA particles prior to dissolution; (ii) at 3 months a bone-like tissue formed a bonding zone between mature bone and the HA implant, composed of nanocrystalline and amorphous apatite; and (iii) at 6 months, mature bone was in direct contact with HA particles, and collagen fibres were perpendicularly inserted into the surface layer of implanted HA crystals. Findings (i) and (ii) indicated the following dissolution-precipitation process. (i) The crystalline HA transforms into amorphous HA; (ii) the amorphous HA dissolves into the surrounding solution, resulting in over-saturation; and (iii) the nanocrystallites are precipitated from the over-saturated solution in the presence of collagen fibres. A preliminary analysis indicated several conclusions: (i) the transition from crystalline to amorphous HA might be the controlling step in the bone bonding of crystalline HA; (ii) biological interdigitation (or incorporation) of collagen fibres with HA and chemical bonding of a apatite layer were both necessary to strengthen and toughen a bone bond, not only for the bonding between bone and HA at 6 months, but also for the bonding zone at 3 months, which would otherwise be very fragile due to the inherited brittleness of polycrystalline ceramics; and (iii) perpendicular interdigitation is an effective way for collagen fibres to impart their unique combination of flexibility and strength to the interface which they are keying.

  17. Effects of spaceflight and Insulin-like Growth Factor-1 on rat bone properties

    NASA Astrophysics Data System (ADS)

    Bateman, Ted A.; Ayers, Reed A.; Spetzler, Michael L.; Simske, Steven J.; Zimmerman, Robert J.

    1997-01-01

    Spaceflight induces bone degradation which is analogous to an accelerated onset of osteoporosis in humans (Tilton et al., 1980). In rats, decreased bone formation is indicative of reduced osteoblast activity (Morey and Baylink, 1978). Chiron Corporation (Emeryville, CA) is interested in using the microgravity environment of low-Earth-orbit to test its therapeutic drug, Insulin-like Growth Factor-1 (IGF-1). This pharmaceutic is known to promote osteoblast activity (Schmid et al., 1984) and therefore may encourage bone growth in rats. Chiron sponsored the Immune.3 payload on STS-73 (May 19-29, 1996) through its Center for Space Commercialization (CSC) partner BioServe Space Technologies (University of Colorado and Kansas State University) to investigate the effects of IGF-1 on mitigating the skeletal degradation that affects rats and humans during spaceflight. Twelve rats were flown for 10 days using two Animal Enclosure Modules (AEMs) provided by NASA Ames Research Center. Of the twelve, six received 1.4 mg/day of IGF-1; the other six saline. Sixteen vivarium ground controls received the same treatment on a one day delay. Rat femora and tibiae were examined for bone mineral density via DXA scan. Femora and humeri were measured for physical and compositional properties, as well as mechanically tested in three point flexure. Quantitative histomorphometric examination of tibiae, humeri, fibulae, ribs and cranial bone; and microhardness testing on tibiae and humeri are currently in progress. Flight humeri and vivarium femora were significantly larger than their counterparts; however, significant differences in mechanical properties and mineral density were not concurrent to these mass changes.

  18. Effects of spaceflight and Insulin-like Growth Factor-1 on rat bone properties

    SciTech Connect

    Bateman, T.A.; Ayers, R.A.; Spetzler, M.L.; Simske, S.J.; Zimmerman, R.J.

    1997-01-01

    Spaceflight induces bone degradation which is analogous to an accelerated onset of osteoporosis in humans (Tilton {ital et al.}, 1980). In rats, decreased bone formation is indicative of reduced osteoblast activity (Morey and Baylink, 1978). Chiron Corporation (Emeryville, CA) is interested in using the microgravity environment of low-Earth-orbit to test its therapeutic drug, Insulin-like Growth Factor-1 (IGF-1). This pharmaceutic is known to promote osteoblast activity (Schmid {ital et al.}, 1984) and therefore may encourage bone growth in rats. Chiron sponsored the Immune.3 payload on STS-73 (May 19{endash}29, 1996) through its Center for Space Commercialization (CSC) partner BioServe Space Technologies (University of Colorado and Kansas State University) to investigate the effects of IGF-1 on mitigating the skeletal degradation that affects rats and humans during spaceflight. Twelve rats were flown for 10 days using two Animal Enclosure Modules (AEMs) provided by NASA Ames Research Center. Of the twelve, six received 1.4 mg/day of IGF-1; the other six saline. Sixteen vivarium ground controls received the same treatment on a one day delay. Rat femora and tibiae were examined for bone mineral density via DXA scan. Femora and humeri were measured for physical and compositional properties, as well as mechanically tested in three point flexure. Quantitative histomorphometric examination of tibiae, humeri, fibulae, ribs and cranial bone; and microhardness testing on tibiae and humeri are currently in progress. Flight humeri and vivarium femora were significantly larger than their counterparts; however, significant differences in mechanical properties and mineral density were not concurrent to these mass changes. {copyright} {ital 1997 American Institute of Physics.}

  19. Hepatocyte Growth Factor and Interleukin-6 in Prostate Cancer Bone Metastasis

    DTIC Science & Technology

    2005-03-01

    AD Award Number: DAMD17-02-1-0159 TITLE: Hepatocyte Growth Factor and Interleukin - 6 in Prostate Cancer Bone Metastasis PRINCIPAL INVESTIGATOR...TITLE AND SUBTITLE 5. FUNDING NUMBERS Hepatocyte Growth Factor and Interleukin - 6 in Prostate DAMD17-02-1-0159 Cancer Bone Metastasis 6 . AUTHOR(S...DAMD17-02-1-0159 "Hepatocyte Growth Factor and Interleukin - 6 in Prostate Cancer Bone Metastasis" INTRODUCTION: The hypothesis of this grant proposal

  20. Mechanisms of diabetes mellitus-induced bone fragility.

    PubMed

    Napoli, Nicola; Chandran, Manju; Pierroz, Dominique D; Abrahamsen, Bo; Schwartz, Ann V; Ferrari, Serge L

    2017-04-01

    The risk of fragility fractures is increased in patients with either type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM). Although BMD is decreased in T1DM, BMD in T2DM is often normal or even slightly elevated compared with an age-matched control population. However, in both T1DM and T2DM, bone turnover is decreased and the bone material properties and microstructure of bone are altered; the latter particularly so when microvascular complications are present. The pathophysiological mechanisms underlying bone fragility in diabetes mellitus are complex, and include hyperglycaemia, oxidative stress and the accumulation of advanced glycation endproducts that compromise collagen properties, increase marrow adiposity, release inflammatory factors and adipokines from visceral fat, and potentially alter the function of osteocytes. Additional factors including treatment-induced hypoglycaemia, certain antidiabetic medications with a direct effect on bone and mineral metabolism (such as thiazolidinediones), as well as an increased propensity for falls, all contribute to the increased fracture risk in patients with diabetes mellitus.

  1. Mechanisms for attenuation in cancellous-bone-mimicking phantoms.

    PubMed

    Wear, Keith A

    2008-11-01

    Broadband ultrasound attenuation (BUA) in cancellous bone is useful for prediction of osteoporotic fracture risk, but its causes are not well understood. To investigate attenuation mechanisms, 9 cancellous-bone-mimicking phantoms containing nylon filaments (simulating bone trabeculae) embedded within soft-tissue-mimicking fluid (simulating marrow) were interrogated. The measurements of frequency-dependent attenuation coefficient had 3 separable components: 1) a linear (with frequency) component attributable to absorption in the soft-tissue-mimicking fluid, 2) a quasilinear (with frequency) component, which may include absorption in and longitudinal-shear mode conversion by the nylon filaments, and 3) a nonlinear (with frequency) component, which may be attributable to longitudinal-longitudinal scattering by the nylon filaments. The slope of total linear (with frequency) attenuation coefficient (sum of components #1 and #2) versus frequency was found to increase linearly with volume fraction, consistent with reported measurements on cancellous bone. Backscatter coefficient measurements in the 9 phantoms supported the claim that the nonlinear (with frequency) component of attenuation coefficient (component #3) was closely associated with longitudinal-longitudinal scattering. This work represents the first experimental separation of these 3 components of attenuation in cancellous bone-mimicking phantoms.

  2. The Effect of Altering the Mechanical Loading Environment on the Expression of Bone Regenerating Molecules in Cases of Distraction Osteogenesis

    PubMed Central

    Alzahrani, Mohammad M.; Anam, Emad A.; Makhdom, Asim M.; Villemure, Isabelle; Hamdy, Reggie Charles

    2014-01-01

    Distraction osteogenesis (DO) is a surgical technique where gradual and controlled separation of two bony fragments following an osteotomy leads to the induction of new bone formation in the distracted gap. DO is used for limb lengthening, correction of bony deformities, and the replacement of bone loss secondary to infection, trauma, and tumors. Although DO gives satisfactory results in most cases, one major drawback of this technique is the prolonged period of time the external fixator has to be kept on until the newly formed bone consolidates thus leading to numerous complications. Numerous attempts at accelerating bone formation during DO have been reported. One specific approach is manipulation of the mechanical environment during DO by applying changes in the standard protocol of distraction. Attempts at changing this mechanical environment led to mixed results. Increasing the rate or applying acute distraction, led to poor bone formation in the distracted zone. On the other hand, the addition of compressive forces (such as weight bearing, alternating distraction with compression or by over-lengthening, and then shortening) has been reported to increase bone formation. It still remains unclear why these alterations may lead to changes in bone formation. While the cellular and molecular changes occurring during the standard DO protocol, specifically increased expression of transforming growth factor-β1, platelet-derived growth factor, insulin-like growth factor, basic fibroblast growth factor, vascular endothelial growth factor, and bone morphogenic proteins have been extensively investigated, the literature is sparse on the changes occurring when this protocol is altered. It is the purpose of this article to review the pertinent literature on the changes in the expression of various proteins and molecules as a result of changes in the mechanical loading technique in DO and try to define potential future research directions. PMID:25540639

  3. Molecular mechanisms controlling bone formation during fracture healing and distraction osteogenesis.

    PubMed

    Ai-Aql, Z S; Alagl, A S; Graves, D T; Gerstenfeld, L C; Einhorn, T A

    2008-02-01

    Fracture healing and distraction osteogenesis have important applications in orthopedic, maxillofacial, and periodontal treatment. In this review, the cellular and molecular mechanisms that regulate fracture repair are contrasted with bone regeneration that occurs during distraction osteogenesis. While both processes have many common features, unique differences are observed in the temporal appearance and expression of specific molecular factors that regulate each. The relative importance of inflammatory cytokines in normal and diabetic healing, the transforming growth factor beta superfamily of bone morphogenetic mediators, and the process of angiogenesis are discussed as they relate to bone repair. A complete summary of biological activities and functions of various bioactive factors may be found at COPE (Cytokines & Cells Online Pathfinder Encyclopedia), http://www.copewithcytokines.de/cope.cgi.

  4. Molecular Mechanisms Controlling Bone Formation during Fracture Healing and Distraction Osteogenesis

    PubMed Central

    AI-Aql, Z.S.; Alagl, A.S.; Graves, D.T.; Gerstenfeld, L.C.; Einhorn, T.A.

    2011-01-01

    Fracture healing and distraction osteogenesis have important applications in orthopedic, maxillofacial, and periodontal treatment. In this review, the cellular and molecular mechanisms that regulate fracture repair are contrasted with bone regeneration that occurs during distraction osteogenesis. While both processes have many common features, unique differences are observed in the temporal appearance and expression of specific molecular factors that regulate each. The relative importance of inflammatory cytokines in normal and diabetic healing, the transforming growth factor beta superfamily of bone morphogenetic mediators, and the process of angiogenesis are discussed as they relate to bone repair. A complete summary of biological activities and functions of various bioactive factors may be found at COPE (Cytokines & Cells Online Pathfinder Encyclopedia), http://www.copewithcytokines.de/cope.cgi. PMID:18218835

  5. Material heterogeneity in cancellous bone promotes deformation recovery after mechanical failure.

    PubMed

    Torres, Ashley M; Matheny, Jonathan B; Keaveny, Tony M; Taylor, David; Rimnac, Clare M; Hernandez, Christopher J

    2016-03-15

    Many natural structures use a foam core and solid outer shell to achieve high strength and stiffness with relatively small amounts of mass. Biological foams, however, must also resist crack growth. The process of crack propagation within the struts of a foam is not well understood and is complicated by the foam microstructure. We demonstrate that in cancellous bone, the foam-like component of whole bones, damage propagation during cyclic loading is dictated not by local tissue stresses but by heterogeneity of material properties associated with increased ductility of strut surfaces. The increase in surface ductility is unexpected because it is the opposite pattern generated by surface treatments to increase fatigue life in man-made materials, which often result in reduced surface ductility. We show that the more ductile surfaces of cancellous bone are a result of reduced accumulation of advanced glycation end products compared with the strut interior. Damage is therefore likely to accumulate in strut centers making cancellous bone more tolerant of stress concentrations at strut surfaces. Hence, the structure is able to recover more deformation after failure and return to a closer approximation of its original shape. Increased recovery of deformation is a passive mechanism seen in biology for setting a broken bone that allows for a better approximation of initial shape during healing processes and is likely the most important mechanical function. Our findings suggest a previously unidentified biomimetic design strategy in which tissue level material heterogeneity in foams can be used to improve deformation recovery after failure.

  6. Material heterogeneity in cancellous bone promotes deformation recovery after mechanical failure

    PubMed Central

    Torres, Ashley M.; Matheny, Jonathan B.; Keaveny, Tony M.; Taylor, David; Rimnac, Clare M.; Hernandez, Christopher J.

    2016-01-01

    Many natural structures use a foam core and solid outer shell to achieve high strength and stiffness with relatively small amounts of mass. Biological foams, however, must also resist crack growth. The process of crack propagation within the struts of a foam is not well understood and is complicated by the foam microstructure. We demonstrate that in cancellous bone, the foam-like component of whole bones, damage propagation during cyclic loading is dictated not by local tissue stresses but by heterogeneity of material properties associated with increased ductility of strut surfaces. The increase in surface ductility is unexpected because it is the opposite pattern generated by surface treatments to increase fatigue life in man-made materials, which often result in reduced surface ductility. We show that the more ductile surfaces of cancellous bone are a result of reduced accumulation of advanced glycation end products compared with the strut interior. Damage is therefore likely to accumulate in strut centers making cancellous bone more tolerant of stress concentrations at strut surfaces. Hence, the structure is able to recover more deformation after failure and return to a closer approximation of its original shape. Increased recovery of deformation is a passive mechanism seen in biology for setting a broken bone that allows for a better approximation of initial shape during healing processes and is likely the most important mechanical function. Our findings suggest a previously unidentified biomimetic design strategy in which tissue level material heterogeneity in foams can be used to improve deformation recovery after failure. PMID:26929343

  7. Structure and function of bone marrow hemopoiesis: mechanisms of response to ionizing radiation exposure.

    PubMed

    Fliedner, T M; Graessle, D; Paulsen, C; Reimers, K

    2002-08-01

    marrow unit is exposed to ionizing radiation, a perturbance of the balance between cellular growth pressure and blood flow dynamics can be observed, resulting in a special type of bone marrow hemorrhage and an "excess cell loss" that may result in an non-thrombopenic exhaustion of the stem cell pool. Of great importance is the question as to the mechanisms that allow the bone marrow hemopoiesis to act as one cell renewal system although the bone marrow units are distributed throughout more than 100 bone marrow areas or units in the skeleton. The observation that "the bone marrow" acts and reacts as "one organ" is due to the regulatory mechanisms: the humeral factors (such as erythropoietins, granulopoietins, thrombopoietins etc.), the nerval factors (central nervous regulation) and cellular factors (continuous migration of stem cells through the blood to assure a sufficient stem cell pool size in each bone marrow "sub-unit"). It should be recalled that the bone marrow functions as a physiological chimera and becomes established by the hematogeneic seeding of stem cells to a mesenchymal matrix during embryogenesis. The repopulation of the bone marrow after partial body irradiation, after strongly inhomogeneous radiation exposure or after total body exposure with stem cell transplantation can well be considered as a repetition of the embryogenesis of bone marrow hemopoiesis with the key element of stem cells migrating via the blood to stromal sites of the marrow prepared to accept stem cells to home and start their replication and differentiation if the micro-environmental quality permits. In summary, the radiation biology of bone marrow hemopoiesis requires a thorough understanding of the physiology and pathophysiology of structure, function and regulation not only of the process of cellular renewal but also of the intricate infrastructure.

  8. Insulin-like growth factor-1 receptor in mature osteoblasts is required for periosteal bone formation induced by reloading.

    PubMed

    Kubota, Takuo; Elalieh, Hashem Z; Saless, Neema; Fong, Chak; Wang, Yongmei; Babey, Muriel; Cheng, Zhiqiang; Bikle, Daniel D

    2013-11-01

    Skeletal loading and unloading has a pronounced impact on bone remodeling, a process also regulated by insulin-like growth factor 1 (IGF-1) signaling. Skeletal unloading leads to resistance to the anabolic effect of IGF-1, while reloading after unloading restores responsiveness to IGF-1. However, a direct study of the importance of IGF-1 signaling in the skeletal response to mechanical loading remains to be tested. In this study, we assessed the skeletal response of osteoblast-specific Igf-1 receptor deficient (Igf-1r(-/-) ) mice to unloading and reloading. The mice were hindlimb unloaded for 14 days and then reloaded for 16 days. Igf-1r(-/-) mice displayed smaller cortical bone and diminished periosteal and endosteal bone formation at baseline. Periosteal and endosteal bone formation decreased with unloading in Igf-1r(+/+) mice. However, the recovery of periosteal bone formation with reloading was completely inhibited in Igf-1r(-/-) mice, although reloading-induced endosteal bone formation was not hampered. These changes in bone formation resulted in the abolishment of the expected increase in total cross-sectional area with reloading in Igf-1r(-/-) mice compared to the control mice. These results suggest that the Igf-1r in mature osteoblasts has a critical role in periosteal bone formation in the skeletal response to mechanical loading.

  9. Insulin-like growth factor-1 receptor in mature osteoblasts is required for periosteal bone formation induced by reloading

    NASA Astrophysics Data System (ADS)

    Kubota, Takuo; Elalieh, Hashem Z.; Saless, Neema; Fong, Chak; Wang, Yongmei; Babey, Muriel; Cheng, Zhiqiang; Bikle, Daniel D.

    2013-11-01

    Skeletal loading and unloading has a pronounced impact on bone remodeling, a process also regulated by insulin-like growth factor-1 (IGF-1) signaling. Skeletal unloading leads to resistance to the anabolic effect of IGF-1, while reloading after unloading restores responsiveness to IGF-1. However, a direct study of the importance of IGF-1 signaling in the skeletal response to mechanical loading remains to be tested. In this study, we assessed the skeletal response of osteoblast-specific Igf-1 receptor deficient (Igf-1r-/-) mice to unloading and reloading. The mice were hindlimb unloaded for 14 days and then reloaded for 16 days. Igf-1r-/- mice displayed smaller cortical bone and diminished periosteal and endosteal bone formation at baseline. Periosteal and endosteal bone formation decreased with unloading in Igf-1r+/+ mice. However, the recovery of periosteal bone formation with reloading was completely inhibited in Igf-1r-/- mice, although reloading-induced endosteal bone formation was not hampered. These changes in bone formation resulted in the abolishment of the expected increase in total cross-sectional area with reloading in Igf-1r-/- mice compared to the control mice. These results suggest that the Igf-1r in mature osteoblasts has a critical role in periosteal bone formation in the skeletal response to mechanical loading.

  10. Biological mechanisms of bone and cartilage remodelling--genomic perspective.

    PubMed

    Borovecki, F; Pecina-Slaus, N; Vukicevic, S

    2007-12-01

    Rapid advancements in the field of genomics, enabled by the achievements of the Human Genome Project and the complete decoding of the human genome, have opened an unimaginable set of opportunities for scientists to further unveil delicate mechanisms underlying the functional homeostasis of biological systems. The trend of applying whole-genome analysis techniques has also contributed to a better understanding of physiological and pathological processes involved in homeostasis of bone and cartilage tissues. Gene expression profiling studies have yielded novel insights into the complex interplay of osteoblast and osteoclast regulation, as well as paracrine and endocrine control of bone and cartilage remodelling. Mechanisms of new bone formation responsible for fracture healing and distraction osteogenesis, as well as healing of joint cartilage defects, have also been extensively studied. Microarray experiments have been especially useful in studying pathological processes involved in diseases such as osteoporosis or bone tumours. Existing results show that microarrays hold great promise in areas such as identification of targets for novel therapies or development of new biomarkers and classifiers in skeletal diseases.

  11. Statistical mechanics of stochastic growth phenomena

    NASA Astrophysics Data System (ADS)

    Alekseev, Oleg; Mineev-Weinstein, Mark

    2017-07-01

    We develop statistical mechanics for stochastic growth processes and apply it to Laplacian growth by using its remarkable connection with a random matrix theory. The Laplacian growth equation is obtained from the variation principle and describes adiabatic (quasistatic) thermodynamic processes in the two-dimensional Dyson gas. By using Einstein's theory of thermodynamic fluctuations we consider transitional probabilities between thermodynamic states, which are in a one-to-one correspondence with simply connected domains occupied by gas. Transitions between these domains are described by the stochastic Laplacian growth equation, while the transitional probabilities coincide with a free-particle propagator on an infinite-dimensional complex manifold with a Kähler metric.

  12. Concepts on Low Temperature Mechanical Grain Growth

    SciTech Connect

    Sharon, John Anthony; Boyce, Brad Lee

    2013-11-01

    In metals, as grain size is reduced below 100nm, conventional dislocation plasticity is suppressed resulting in improvements in strength, hardness, and wears resistance. Existing and emerging components use fine grained metals for these beneficial attributes. However, these benefits can be lost in service if the grains undergo growth during the component’s lifespan. While grain growth is traditionally viewed as a purely thermal process that requires elevated temperature exposure, recent evidence shows that some metals, especially those with nanocrystalline grain structure, can undergo grain growth even at room temperature or below due to mechanical loading. This report has been assembled to survey the key concepts regarding how mechanical loads can drive grain coarsening at room temperature and below. Topics outlined include the atomic level mechanisms that facilitate grain growth, grain boundary mobility, and the impact of boundary structure, loading scheme, and temperature.

  13. Role of IGFBP2, IGF-I and IGF-II in regulating long bone growth.

    PubMed

    Fisher, Melanie C; Meyer, Carissa; Garber, Graham; Dealy, Caroline N

    2005-12-01

    The IGF axis is important for long bone development, homeostasis and disease. The activities of IGF-I and IGF-II are regulated by IGF binding proteins (IGFBPs). IGF-I and IGFBP2 are co-expressed in dynamic fashions in the developing long bones of the chick wing, and we have found that IGF-II is present in the cartilage model and surrounding perichondrium, proliferative and hypertrophic chondrocytes and developing periosteum. To gain insight into endogenous roles of IGF-I, IGF-II and IGFBP2 in long bone development, we have overexpressed IGFBP2 in the developing skeletal elements of the embryonic chick wing in vivo, using an RCAS retroviral vector. IGFBP2 overexpression led to an obvious shortening of the long bones of the wing. We have investigated, at the cellular and molecular levels, the mechanism of action whereby IGFBP2 overexpression impairs long bone development in vivo. At an early stage, IGFBP2 excess dramatically inhibits proliferation by the chondrocytes of the cartilage models that prefigure the developing long bones. Later, IGFBP2 excess also reduces proliferation of the maturing chondrocytes and attenuates proliferation by the perichondrium/developing periosteum. IGFBP2 excess does not affect morphological or molecular indicators of chondrocyte maturation, osteoblast differentiation or cell/matrix turnover, such as expression of Ihh, PTHrP, type X collagen and osteopontin, or distribution and relative abundance of putative clast cells. We also have found that IGFBP2 blocks the ability of IGF-I and IGF-II to promote proliferation and matrix synthesis by wing chondrocytes in vitro. Together, our results suggest that the mechanism of action whereby IGFBP2 excess impairs long bone development is to inhibit IGF-mediated proliferation and matrix synthesis by the cartilage model; reduce the proliferation and progression to hypertrophy by the maturing chondrocytes; and attenuate proliferation and formation of the periosteal bony collar. These actions retard

  14. Report of the CCFA pediatric bone, growth and muscle health workshop, New York City, November 11-12, 2011, with updates.

    PubMed

    Sylvester, Francisco A; Gordon, Catherine M; Thayu, Meena; Burnham, Jon M; Denson, Lee A; Essers, Jonah; Ferrari, Serge; Gupta, Neera; Hewison, Martin; Koletzko, Sibylle; McCabe, Laura; Pappa, Helen; Sanderson, Ian; Ward, Leanne; Zanotti, Stefano

    2013-12-01

    Growth retardation, delayed puberty, decreased bone mass, altered bone architecture, hypovitaminosis D and skeletal muscle mass deficits are common in children with inflammatory bowel diseases. The Crohn's and Colitis Foundation of America sponsored a multidisciplinary workshop on the subject of Bone and Skeletal Growth in Pediatric IBD, held in New York City in November 2011. The topic of the workshop was a key recommendation of the Foundation's Pediatric Challenges meeting in 2005. The Litwin Foundation provided a generous grant to support this crucial research and workshop through the CCFA. The workshop featured 15 presentations by researchers from the United States, Canada, Switzerland, Germany, and the United Kingdom and a number of posters elucidating diverse aspects of the problem of growth retardation and compromised bone health in pediatric Crohn's disease and ulcerative colitis. The workshop comprised original, basic, and clinical research and relevant reviews of underlying genetics, molecular biology, endocrinology, immunology, and bone physiology research. Investigators funded by CCFA and the Litwin Family Foundation are marked by an asterisk after their name in the text. Workshop presentations fell under 3 broad categories: "Mechanisms of Suppression and Growth of Bone Cell Function by Inflammation," "Impact of IBD on Growth and Bone Health," and "Approaches to Address Growth Failure and Low Bone Mass in Children with IBD," summarized herein. We have cited the publications that resulted from this granting mechanism in the appropriate section and references for pertinent updates on each topic.

  15. Mechanisms Limiting Body Growth in Mammals

    PubMed Central

    Lui, Julian C.

    2011-01-01

    Recent studies have begun to provide insight into a long-standing mystery in biology—why body growth in animals is rapid in early life but then progressively slows, thus imposing a limit on adult body size. This growth deceleration in mammals is caused by potent suppression of cell proliferation in multiple tissues and is driven primarily by local, rather than systemic, mechanisms. Recent evidence suggests that this progressive decline in proliferation results from a genetic program that occurs in multiple organs and involves the down-regulation of a large set of growth-promoting genes. This program does not appear to be driven simply by time, but rather depends on growth itself, suggesting that the limit on adult body size is imposed by a negative feedback loop. Different organs appear to use different types of information to precisely target their adult size. For example, skeletal and cardiac muscle growth are negatively regulated by myostatin, the concentration of which depends on muscle mass itself. Liver growth appears to be modulated by bile acid flux, a parameter that reflects organ function. In pancreas, organ size appears to be limited by the initial number of progenitor cells, suggesting a mechanism based on cell-cycle counting. Further elucidation of the fundamental mechanisms suppressing juvenile growth is likely to yield important insights into the pathophysiology of childhood growth disorders and of the unrestrained growth of cancer. In addition, improved understanding of these growth-suppressing mechanisms may someday allow their therapeutic suspension in adult tissues to facilitate tissue regeneration. PMID:21441345

  16. Nanohydroxyapatite Effect on the Degradation, Osteoconduction and Mechanical Properties of Polymeric Bone Tissue Engineered Scaffolds

    PubMed Central

    Salmasi, Shima; Nayyer, Leila; Seifalian, Alexander M.; Blunn, Gordon W.

    2016-01-01

    BACKGROUND Statistical reports show that every year around the world approximately 15 million bone fractures occur; of which up to 10% fail to heal completely and hence lead to complications of non-union healing. In the past, autografts or allografts were used as the “gold standard” of treating such defects. However, due to various limitations and risks associated with these sources of bone grafts, other avenues have been extensively investigated through which bone tissue engineering; in particular engineering of synthetic bone graft substitutes, has been recognised as a promising alternative to the traditional methods. METHODS A selective literature search was performed. RESULTS Bone tissue engineering offers unlimited supply, eliminated risk of disease transmission and relatively low cost. It could also lead to patient specific design and manufacture of implants, prosthesis and bone related devices. A potentially promising building block for a suitable scaffold is synthetic nanohydroxyapatite incorporated into synthetic polymers. Incorporation of nanohydroxyapatite into synthetic polymers has shown promising bioactivity, osteoconductivity, mechanical properties and degradation profile compared to other techniques previously considered. CONCLUSION Scientific research, through extensive physiochemical characterisation, in vitro and in vivo assessment has brought together the optimum characteristics of nanohydroxyapatite and various types of synthetic polymers in order to develop nanocomposites of suitable nature for bone tissue engineering. The aim of the present article is to review and update various aspects involved in incorporation of synthetic nanohydroxyapatite into synthetic polymers, in terms of their potentials to promote bone growth and regeneration in vitro, in vivo and consequently in clinical applications. PMID:28217213

  17. Bone growth resumption following in vivo static and dynamic compression removals on rats.

    PubMed

    Ménard, Anne-Laure; Grimard, Guy; Londono, Irène; Beaudry, Francis; Vachon, Pascal; Moldovan, Florina; Villemure, Isabelle

    2015-12-01

    Mechanical loadings influence bone growth and are used in pediatric treatments of musculoskeletal deformities. This in vivo study aimed at evaluating the effects of static and dynamic compression application and subsequent removal on bone growth, mineralization and neuropathic pain markers in growing rats. Forty-eight immature rats (28 days old) were assigned in two groups (2- and 4 weeks experiment duration) and four subgroups: control, sham, static, and dynamic. Controls had no surgery. A micro-loading device was implanted on the 6th and 8th caudal vertebrae of shams without loading, static loading at 0.2 MPa or dynamic loading at 0.2 MPa ± 30% and 0.1 Hz. In 2-week subgroups, compression was maintained for 15 days prior to euthanasia, while in 4- week subgroups, compression was removed for 10 additional days. Growth rates, histomorphometric parameters and mineralization intensity were quantified and compared. At 2 weeks, growth rates and growth plate heights of loaded groups (static/dynamic)were significantly lower than shams (p b 0.01).However, at 4 weeks, both growth rates and growth plate heights of loaded groups were similar to shams. At 4 weeks, alizarin red intensity was significantly higher in dynamics compared to shams (p b 0.05) and controls (p b 0.01). Both static and dynamic compressions enable growth resumption after loading removal, while preserving growth plate histomorphometric integrity. However, mineralization was enhanced after dynamic loading removal only. Dynamic loading showed promising results for fusionless treatment approaches for musculoskeletal deformities.

  18. Microindentation for In Vivo Measurement of Bone Tissue Mechanical Properties in Humans

    PubMed Central

    Diez-Perez, Adolfo; Güerri, Roberto; Nogues, Xavier; Cáceres, Enric; Peña, Maria Jesus; Mellibovsky, Leonardo; Randall, Connor; Bridges, Daniel; Weaver, James C; Proctor, Alexander; Brimer, Davis; Koester, Kurt J; Ritchie, Robert O; Hansma, Paul K

    2010-01-01

    Bone tissue mechanical properties are deemed a key component of bone strength, but their assessment requires invasive procedures. Here we validate a new instrument, a reference point indentation (RPI) instrument, for measuring these tissue properties in vivo. The RPI instrument performs bone microindentation testing (BMT) by inserting a probe assembly through the skin covering the tibia and, after displacing periosteum, applying 20 indentation cycles at 2 Hz each with a maximum force of 11 N. We assessed 27 women with osteoporosis-related fractures and 8 controls of comparable ages. Measured total indentation distance (46.0 ± 14 versus 31.7 ± 3.3 µm, p = .008) and indentation distance increase (18.1 ± 5.6 versus 12.3 ± 2.9 µm, p = .008) were significantly greater in fracture patients than in controls. Areas under the receiver operating characteristic (ROC) curve for the two measurements were 93.1% (95% confidence interval [CI] 83.1–100) and 90.3% (95% CI 73.2–100), respectively. Interobserver coefficient of variation ranged from 8.7% to 15.5%, and the procedure was well tolerated. In a separate study of cadaveric human bone samples (n = 5), crack growth toughness and indentation distance increase correlated (r = –0.9036, p = .018), and scanning electron microscope images of cracks induced by indentation and by experimental fractures were similar. We conclude that BMT, by inducing microscopic fractures, directly measures bone mechanical properties at the tissue level. The technique is feasible for use in clinics with good reproducibility. It discriminates precisely between patients with and without fragility fracture and may provide clinicians and researchers with a direct in vivo measurement of bone tissue resistance to fracture. © 2010 American Society for Bone and Mineral Research. PMID:20200991

  19. Rapid Establishment of Chemical and Mechanical Properties During Lamellar Bone Formation

    SciTech Connect

    Busa,B.; Miller, L.; Rubin, C.; Qin, Y.; Judex, S.

    2005-01-01

    The development of prophylaxes and treatments of bone diseases that can effectively increase the strength of bone as a structure necessitates a better understanding of the time course by which chemical properties define the stiffness of the material during primary and secondary mineralization. It was hypothesized that these processes would be relatively slow in the actively growing skeleton. Seven-week-old Sprague-Dawley female rats (n = 8) were injected with multiple fluorochrome labels over a time span of 3 weeks and killed. Chemical and mechanical properties of the tibial mid-diaphysis were spatially characterized between the endocortical and periosteal surface by in situ infrared microspectroscopy and nanoindentation. The phosphate-to-protein ratio of bone 2-6 days old was 20% smaller at the periosteal surface and 22% smaller at the endocortical surface (P < 0.05 each) compared to older intracortical regions. The ratios of carbonate to protein, crystallinity, type A/type B carbonate, collagen cross-linking, and bone elastic modulus did not differ significantly between bone 2-6, 10-14, and 8-22 days old and intracortical regions. Intracortical properties of 10-week-old rats, except for the carbonate-to-protein ratio which was 23% smaller (P < 0.01), were not significantly different from intracortical matrix properties of young adult rats (5 months, n = 4). Spatially, the phosphate-to-protein ratio (R{sup 2} = 0.33) and the phosphate-to-carbonate ratio (R{sup 2} = 0.55) were significantly correlated with bone material stiffness, while the combination of all chemical parameters raised the R{sup 2} value to 0.83. These data indicate that lamellar bone has the ability to quickly establish its mechanical and chemical tissue properties during primary and secondary mineralization even when the skeleton experiences rapid growth.

  20. Factors that affect postnatal bone growth retardation in the twitcher murine model of Krabbe disease.

    PubMed

    Contreras, Miguel Agustin; Ries, William Louis; Shanmugarajan, Srinivasan; Arboleda, Gonzalo; Singh, Inderjit; Singh, Avtar Kaur

    2010-01-01

    Krabbe disease is an inherited lysosomal disorder in which galactosylsphingosine (psychosine) accumulates mainly in the central nervous system. To gain insight into the possible mechanism(s) that may be participating in the inhibition of the postnatal somatic growth described in the animal model of this disease (twitcher mouse, twi), we studied their femora. This study reports that twi femora are smaller than of those of wild type (wt), and present with abnormality of marrow cellularity, bone deposition (osteoblastic function), and osteoclastic activity. Furthermore, lipidomic analysis indicates altered sphingolipid homeostasis, but without significant changes in the levels of sphingolipid-derived intermediates of cell death (ceramide) or the levels of the osteoclast-osteoblast coupling factor (sphingosine-1-phosphate). However, there was significant accumulation of psychosine in the femora of adult twi animals as compared to wt, without induction of tumor necrosis factor-alpha or interleukin-6. Analysis of insulin-like growth factor-1 (IGF-1) plasma levels, a liver secreted hormone known to play a role in bone growth, indicated a drastic reduction in twi animals when compared to wt. To identify the cause of the decrease, we examined the IGF-1 mRNA expression and protein levels in the liver. The results indicated a significant reduction of IGF-1 mRNA as well as protein levels in the liver from twi as compared to wt littermates. Our data suggest that a combination of endogenous (psychosine) and endocrine (IGF-1) factors play a role in the inhibition of postnatal bone growth in twi mice; and further suggest that derangements of liver function may be contributing, at least in part, to this alteration.

  1. Mechanical, hormonal and metabolic influences on blood vessels, blood flow and bone.

    PubMed

    Prisby, Rhonda D

    2017-12-01

    Bone tissue is highly vascularized due to the various roles bone blood vessels play in bone and bone marrow function. For example, the vascular system is critical for bone development, maintenance and repair and provides O2, nutrients, waste elimination, systemic hormones and precursor cells for bone remodeling. Further, bone blood vessels serve as egress and ingress routes for blood and immune cells to and from the bone marrow. It is becoming increasingly clear that the vascular and skeletal systems are intimately linked in metabolic regulation and physiological and pathological processes. This review examines how agents such as mechanical loading, parathyroid hormone, estrogen, vitamin D and calcitonin, all considered anabolic for bone, have tremendous impacts on the bone vasculature. In fact, these agents influence bone blood vessels prior to influencing bone. Further, data reveal strong associations between vasodilator capacity of bone blood vessels and trabecular bone volume, and poor associations between estrogen status and uterine mass and trabecular bone volume. Additionally, this review highlights the importance of the bone microcirculation, particularly the vascular endothelium and NO-mediated signaling, in the regulation of bone blood flow, bone interstitial fluid flow and pressure and the paracrine signaling of bone cells. Finally, the vascular endothelium as a mediator of bone health and disease is considered. © 2017 Society for Endocrinology.

  2. Effects of alcohol and nicotine on the mechanical resistance of bone and bone neoformation around hydroxyapatite implants.

    PubMed

    Soares, Evelise V; Fávaro, Wagner J; Cagnon, Valéria H A; Bertran, Celso A; Camilli, José A

    2010-01-01

    The consumption of alcohol or nicotine is harmful to the integrity of bone tissue, hindering or even impeding the fixation and maintenance of bone implants. The aim of the present work was to evaluate the effects of ethanol and nicotine, when consumed alone and simultaneously, on both bone mechanical resistance and bone neoformation around hydroxyapatite implants. Twenty rats were divided into four groups: control (CT), alcohol (A), nicotine (N) and nicotine + alcohol (N + A). After 4 weeks of alcohol and/or nicotine consumption, dense (HAD) and porous (HAP) bodies were respectively implanted in a surgically produced bone defect in the right and left tibiae. After the surgeries, the animals continued to consume alcohol and/or nicotine. After ninety days, the animals were sacrificed and the tibiae and femurs were isolated for histological processing and mechanical assays. All the animals presented newly formed bone tissue close to the HAD and HAP ceramic bodies. The animals of the N + A group presented a smaller volume of neoformed bone. Group A animals presented smaller bone volume around the implants in relation to the animals from group N. Bone resistance to mechanical loads was smallest in animals from the N + A group, followed (in order) by the A and N groups. Thus, it can be concluded that nicotine or alcohol consumption produced negative effects on bone mechanical resistance and on the osteogenesis around the HAD and HAP implants. In addition, the simultaneous consumption of the two substances intensified their harmful effects.

  3. 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

  4. Skeletal Development of Mice Lacking Bone Sialoprotein (BSP) - Impairment of Long Bone Growth and Progressive Establishment of High Trabecular Bone Mass

    PubMed Central

    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

  5. Region-dependent patterns of trabecular bone growth in the human proximal femur: A study of 3D bone microarchitecture from early postnatal to late childhood period.

    PubMed

    Milovanovic, Petar; Djonic, Danijela; Hahn, Michael; Amling, Michael; Busse, Björn; Djuric, Marija

    2017-10-01

    Parallel with body growth and development, bone structure in non-adults is reorganized to achieve the particular design observed in mature individuals. We traced the changes in three-dimensional trabecular microarchitectural design during the phases of locomotor maturation to clarify how human bone adapts to mechanical demands. Micro-CT was performed on biomechanically-relevant subregions of the proximal femur (medial, intermediate and lateral neck regions, intertrochanteric region, metaphyseal region) from early postnatal period to late childhood. Developmental patterns of trabecular microarchitecture showed that gestationally overproduced bone present at birth underwent the most dramatic reduction during the first year, followed by a reversing trend in some of the quantitative parameters (e.g., bone volume fraction, trabecular anisotropy). Certain regional anisotropy already present at birth is further accentuated into the childhood suggesting an adaptation to differential loading environments. Trabecular eccentricity in the femoral neck was particularly accentuated during childhood, giving the medial neck-the site mostly loaded in walking-superior microarchitectural design (high bone volume fraction and anisotropy, the earliest appearance and predominance of plate- and honeycomb-shaped trabeculae). While providing quantitative data on how bone microarchitecture adapts to increasing mechanical demands occurring during the phases of locomotor maturation, the study reveals how regional anisotropy develops in the proximal femur to ensure a functional and competent bone structure. Decomposing the region-specific patterns of bone mass accrual is important in understanding skeletal adaptations to bipedalism, as well for understanding why fractures often occur location-dependent, both in pediatric and elderly individuals. © 2017 Wiley Periodicals, Inc.

  6. Planet formation - Mechanism of early growth

    NASA Technical Reports Server (NTRS)

    Hartmann, W. K.

    1978-01-01

    Experiments in vacuum (approx. 0.5 to 1 mbar) and in air quantify mechanics of collisions, rebound, and fragmentation at low velocities (1-50 m/sec), under the conditions usually postulated for the preplanetary environment in the primitive solar nebula. Such collisions have been little studied experimentally. Contrary to widespread assumptions, accretionary growth of the largest meteoroid- and asteroid-sized bodies in a given swarm results spontaneously from the simple mechanics of these collisions, without other ad hoc sticking mechanisms. The smaller bodies in the swarm are less likely to grow. Granular surfaces form, either by gravitational collapse of dust swarms or by rapid formation of regolith surfaces on solid planetesimals; these surfaces strongly promote further growth by retarding rebound. Growth of large bodies increases modal collision velocities, causing fragmentation of smaller bodies and eventual production of interstellar dust as a by-product of planetesimal interactions.

  7. Planet formation - Mechanism of early growth

    NASA Technical Reports Server (NTRS)

    Hartmann, W. K.

    1978-01-01

    Experiments in vacuum (approx. 0.5 to 1 mbar) and in air quantify mechanics of collisions, rebound, and fragmentation at low velocities (1-50 m/sec), under the conditions usually postulated for the preplanetary environment in the primitive solar nebula. Such collisions have been little studied experimentally. Contrary to widespread assumptions, accretionary growth of the largest meteoroid- and asteroid-sized bodies in a given swarm results spontaneously from the simple mechanics of these collisions, without other ad hoc sticking mechanisms. The smaller bodies in the swarm are less likely to grow. Granular surfaces form, either by gravitational collapse of dust swarms or by rapid formation of regolith surfaces on solid planetesimals; these surfaces strongly promote further growth by retarding rebound. Growth of large bodies increases modal collision velocities, causing fragmentation of smaller bodies and eventual production of interstellar dust as a by-product of planetesimal interactions.

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-01-01

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

  10. Mechanical properties of a biodegradable bone regeneration scaffold

    NASA Technical Reports Server (NTRS)

    Porter, B. D.; Oldham, J. B.; He, S. L.; Zobitz, M. E.; Payne, R. G.; An, K. N.; Currier, B. L.; Mikos, A. G.; Yaszemski, M. J.

    2000-01-01

    Poly (Propylene Fumarate) (PPF), a novel, bulk erosion, biodegradable polymer, has been shown to have osteoconductive effects in vivo when used as a bone regeneration scaffold (Peter, S. J., Suggs, L. J., Yaszemski, M. J., Engel, P. S., and Mikos, A. J., 1999, J. Biomater. Sci. Polym. Ed., 10, pp. 363-373). The material properties of the polymer allow it to be injected into irregularly shaped voids in vivo and provide mechanical stability as well as function as a bone regeneration scaffold. We fabricated a series of biomaterial composites, comprised of varying quantities of PPF, NaCl and beta-tricalcium phosphate (beta-TCP), into the shape of right circular cylinders and tested the mechanical properties in four-point bending and compression. The mean modulus of elasticity in compression (Ec) was 1204.2 MPa (SD 32.2) and the mean modulus of elasticity in bending (Eb) was 1274.7 MPa (SD 125.7). All of the moduli were on the order of magnitude of trabecular bone. Changing the level of NaCl from 20 to 40 percent, by mass, did not decrease Ec and Eb significantly, but did decrease bending and compressive strength significantly. Increasing the beta-TCP from 0.25 g/g PPF to 0.5 g/g PPF increased all of the measured mechanical properties of PPF/NVP composites. These results indicate that this biodegradable polymer composite is an attractive candidate for use as a replacement scaffold for trabecular bone.

  11. Mechanical properties of a biodegradable bone regeneration scaffold.

    PubMed

    Porter, B D; Oldham, J B; He, S L; Zobitz, M E; Payne, R G; An, K N; Currier, B L; Mikos, A G; Yaszemski, M J

    2000-06-01

    Poly (Propylene Fumarate) (PPF), a novel, bulk erosion, biodegradable polymer, has been shown to have osteoconductive effects in vivo when used as a bone regeneration scaffold (Peter, S. J., Suggs, L. J., Yaszemski, M. J., Engel, P. S., and Mikos, A. J., 1999, J. Biomater. Sci. Polym. Ed., 10, pp. 363-373). The material properties of the polymer allow it to be injected into irregularly shaped voids in vivo and provide mechanical stability as well as function as a bone regeneration scaffold. We fabricated a series of biomaterial composites, comprised of varying quantities of PPF, NaCl and beta-tricalcium phosphate (beta-TCP), into the shape of right circular cylinders and tested the mechanical properties in four-point bending and compression. The mean modulus of elasticity in compression (Ec) was 1204.2 MPa (SD 32.2) and the mean modulus of elasticity in bending (Eb) was 1274.7 MPa (SD 125.7). All of the moduli were on the order of magnitude of trabecular bone. Changing the level of NaCl from 20 to 40 percent, by mass, did not decrease Ec and Eb significantly, but did decrease bending and compressive strength significantly. Increasing the beta-TCP from 0.25 g/g PPF to 0.5 g/g PPF increased all of the measured mechanical properties of PPF/NVP composites. These results indicate that this biodegradable polymer composite is an attractive candidate for use as a replacement scaffold for trabecular bone.

  12. Mechanical properties of a biodegradable bone regeneration scaffold

    NASA Technical Reports Server (NTRS)

    Porter, B. D.; Oldham, J. B.; He, S. L.; Zobitz, M. E.; Payne, R. G.; An, K. N.; Currier, B. L.; Mikos, A. G.; Yaszemski, M. J.

    2000-01-01

    Poly (Propylene Fumarate) (PPF), a novel, bulk erosion, biodegradable polymer, has been shown to have osteoconductive effects in vivo when used as a bone regeneration scaffold (Peter, S. J., Suggs, L. J., Yaszemski, M. J., Engel, P. S., and Mikos, A. J., 1999, J. Biomater. Sci. Polym. Ed., 10, pp. 363-373). The material properties of the polymer allow it to be injected into irregularly shaped voids in vivo and provide mechanical stability as well as function as a bone regeneration scaffold. We fabricated a series of biomaterial composites, comprised of varying quantities of PPF, NaCl and beta-tricalcium phosphate (beta-TCP), into the shape of right circular cylinders and tested the mechanical properties in four-point bending and compression. The mean modulus of elasticity in compression (Ec) was 1204.2 MPa (SD 32.2) and the mean modulus of elasticity in bending (Eb) was 1274.7 MPa (SD 125.7). All of the moduli were on the order of magnitude of trabecular bone. Changing the level of NaCl from 20 to 40 percent, by mass, did not decrease Ec and Eb significantly, but did decrease bending and compressive strength significantly. Increasing the beta-TCP from 0.25 g/g PPF to 0.5 g/g PPF increased all of the measured mechanical properties of PPF/NVP composites. These results indicate that this biodegradable polymer composite is an attractive candidate for use as a replacement scaffold for trabecular bone.

  13. Osteoclast precursor interaction with bone matrix induces osteoclast formation directly by an interleukin-1-mediated autocrine mechanism.

    PubMed

    Yao, Zhenqiang; Xing, Lianping; Qin, Chunlin; Schwarz, Edward M; Boyce, Brendan F

    2008-04-11

    Interleukin-1 (IL-1) and tumor necrosis factor (TNF) mediate bone resorption in a variety of diseases affecting bone. Like TNF, IL-1 is secreted by osteoclast precursors (OCPs), but unlike TNF, it does not induce osteoclast formation directly from OCPs in vitro. TNF induces IL-1 expression and activates c-Fos, a transcription factor required in OCPs for osteoclast formation. Here, we examined whether IL-1 can induce osteoclast formation directly from OCPs overexpressing c-Fos and whether interaction with bone matrix affects OCP cytokine expression. We infected OCPs with c-Fos or green fluorescent protein retrovirus, cultured them with macrophage colony-stimulating factor and IL-1 on bone slices or plastic dishes, and assessed osteoclast and resorption pit formation and expression of IL-1 by OCPs. We used a Transwell assay to determine whether OCPs secrete IL-1 when they interact with bone matrix. IL-1 induced osteoclast formation directly from c-Fos-expressing OCPs on plastic. c-Fos-expressing OCPs formed osteoclasts spontaneously on bone slices without addition of cytokines. OCPs on bone secreted IL-1, which induced osteoclast formation from c-Fos-expressing OCPs in the lower Transwell dishes. The bone matrix proteins dentin sialoprotein and osteopontin, but not transforming growth factor-beta, stimulated OCP expression of IL-1 and induced c-Fos-expressing OCP differentiation into osteoclasts. Osteoclasts eroding inflamed joints have higher c-Fos expression compared with osteoclasts inside bone. We conclude that OCPs expressing c-Fos may induce their differentiation directly into osteoclasts by an autocrine mechanism in which they produce IL-1 through interaction with bone matrix. TNF could induce c-Fos expression in OCPs at sites of inflammation in bone to promote this autocrine mechanism and thus amplify bone loss.

  14. Mechanical consequences of different scenarios for simulated bone atrophy and recovery in the distal radius.

    PubMed

    Pistoia, W; van Rietbergen, B; Rüegsegger, P

    2003-12-01

    Metabolic bone diseases such as osteoporosis usually cause a decrease in bone mass and a deterioration of bone microarchitecture leading to a decline in bone strength. Methods to predict bone strength in patients are currently based on bone mass only. It has been suggested that an improved prediction of bone strength might be possible if structural changes are taken into account as well. In this study we evaluated which structural parameters (other than bone mass) are the best predictors for changes in bone mechanical properties of the human radius after different bone atrophy scenarios and whether the original strength of the affected bone can be recovered if bone loss is restored by thickening of the remaining structures. To answer these questions, a human radius was measured with a microcomputer tomography scanner to extract the full three-dimensional architecture of the distal radius at an isotropic resolution of 80 microm. Eight models with modified bone architecture were created and the mechanical variations due to these modifications were studied using microfinite element (micro-FE) simulations. In four models mass was lowered by 20%, either by reducing cortical thickness, trabecular thickness, or number of trabeculae or by overall thinning of structures. In the other four models bone mass was restored to the original value using a trabecular bone thickening procedure. The micro-FE analyses revealed that most load was carried by the cortical bone. For this reason, bone strength was affected most in the reduced cortical thickness model. For the same reason, the trabecular bone atrophy scenarios, all of which affected bone strength in a very similar way, resulted in less dramatic bone strength reduction. The restoration of bone mass did not recover the original bone strength. These findings demonstrate that the importance of different parameters for the prediction of bone strength also depends on the mechanical loading. This could explain why results of

  15. 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.

  16. Estimating Trabecular Bone Mechanical Properties From Non-Invasive Imaging

    NASA Technical Reports Server (NTRS)

    Hogan, Harry A.; Webster, Laurie

    1997-01-01

    An important component in developing countermeasures for maintaining musculoskeletal integrity during long-term space flight is an effective and meaningful method of monitoring skeletal condition. Magnetic resonance imaging (MRI) is an attractive non-invasive approach because it avoids the exposure to radiation associated with X-ray based imaging and also provides measures related to bone microstructure rather than just density. The purpose of the research for the 1996 Summer Faculty Fellowship period was to extend the usefulness of the MRI data to estimate the mechanical properties of trabecular bone. The main mechanical properties of interest are the elastic modulus and ultimate strength. Correlations are being investigated between these and fractal analysis parameters, MRI relaxation times, apparent densities, and bone mineral densities. Bone specimens from both human and equine donors have been studied initially to ensure high-quality MR images. Specimens were prepared and scanned from human proximal tibia bones as well as the equine distal radius. The quality of the images from the human bone appeared compromised due to freezing artifact, so only equine bone was included in subsequent procedures since these specimens could be acquired and imaged fresh before being frozen. MRI scans were made spanning a 3.6 cm length on each of 5 equine distal radius specimens. The images were then sent to Dr. Raj Acharya of the State University of New York at Buffalo for fractal analysis. Each piece was cut into 3 slabs approximately 1.2 cm thick and high-resolution contact radiographs were made to provide images for comparing fractal analysis with MR images. Dual energy X-ray absorptiometry (DEXA) scans were also made of each slab for subsequent bone mineral density determination. Slabs were cut into cubes for mechanical using a slow-speed diamond blade wafering saw (Buehler Isomet). The dimensions and wet weights of each cube specimen were measured and recorded. Wet weights

  17. 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.

  18. 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.

  19. Acetate inhibition of chick bone cell proliferation and bone growth in vitro.

    PubMed

    Saitta, J C; Lipkin, E W; Howard, G A

    1989-06-01

    A hypothesis has been advanced that parenteral solutions as commonly formulated for use in clinical practice have a toxic effect on cell metabolism. A specific component of these solutions, sodium acetate, has been suggested to disrupt normal bone turnover and therefore to contribute to the osteopenia observed in patients receiving hemodialysis and parenteral nutrition (PN). We developed an in vitro model to test the hypothesis that sodium acetate at concentrations that are infused in PN solutions has a deleterious effect on bone metabolism. Osteoblasts and preosteoblasts from 16- to 17-day-old embryonic chick calvaria, and tibiae and femora from 10-day-old embryonic chicks were grown in BGJb medium (control) or in BGJb medium plus sodium acetate (5, 10, or 20 mM). Calvarial cell proliferation was quantified by direct cell counts as well as by incorporation of [3H]TdR into DNA as an index of cell proliferation. Calvarial cell alkaline phosphatase activity was quantified by the ability of extracts of the cultured cells to hydrolyze p-nitrophenyl phosphate to p-nitrophenol, and bone growth was determined by measuring final dry weight. Calvarial cell counts as well as DNA synthesis showed a dose-dependent decrease in the presence of sodium acetate (5-20 mM) compared with controls. [3H]TdR incorporation was decreased a mean 19% with 5 mM, 38% with 10 mM, and 63% with 20 mM acetate. Alkaline phosphatase activity per cell increased 48% with 5 mM, 140% with 10 mM, and 355% with 20 mM acetate. Cell viability as assessed by trypan blue exclusion was identical for test and control media (greater than 95%).(ABSTRACT TRUNCATED AT 250 WORDS)

  20. Cyp26b1 within the growth plate regulates bone growth in juvenile mice.

    PubMed

    Minegishi, Yoshiki; Sakai, Yasuo; Yahara, Yasuhito; Akiyama, Haruhiko; Yoshikawa, Hideki; Hosokawa, Ko; Tsumaki, Noriyuki

    2014-11-07

    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, it 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(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.

  1. Mechanical properties of radiation-sterilised human Bone-Tendon-Bone grafts preserved by different methods.

    PubMed

    Kamiński, A; Gut, G; Marowska, J; Lada-Kozłowska, M; Biwejnis, W; Zasacka, M

    2009-08-01

    Patellar tendon auto- and allo-grafts are commonly used in orthopedic surgery for reconstruction of the anterior cruciate ligaments (ACL). Autografts are mainly used for primary reconstruction, while allografts are useful for revision surgery. To avoid the risk of infectious disease transmission allografts should be radiation-sterilised. As radiation-sterilisation supposedly decreases the mechanical strength of tendon it is important to establish methods of allograft preservation and sterilisation assuring the best quality of grafts and their safety at the same time. Therefore, the purpose of this study was to compare the tensile strength of human patellar tendon (cut out as for ACL reconstruction), preserved by various methods (deep fresh freezing, glycerolisation, lyophilisation) and subsequently radiation-sterilised with doses of 0, 25, 50 or 100 kGy. Bone-Tendon-Bone grafts (BTB) were prepared from cadaveric human patella tendons with both patellar and tibial attachments. BTB grafts were preserved by deep freezing, glycerolisation or lyophilisation and were subsequently radiation-sterilised with doses of 0 (control), 25, 50 or 100 kGy. All samples were subjected to mechanical failure tensile tests with the use of Instron system in order to estimate their mechanical properties. All lyophilised grafts were rehydrated before performing of those tests. Obtained mechanical tests results of examined grafts suggest that deep-frozen irradiated grafts retain their initial mechanical properties to an extent which does not exclude their clinical application.

  2. Cartilage–Specific Over-Expression of CCN Family Member 2/Connective Tissue Growth Factor (CCN2/CTGF) Stimulates Insulin-Like Growth Factor Expression and Bone Growth

    PubMed Central

    Tomita, Nao; Hattori, Takako; Itoh, Shinsuke; Aoyama, Eriko; Yao, Mayumi; Yamashiro, Takashi; Takigawa, Masaharu

    2013-01-01

    Previously we showed that CCN family member 2/connective tissue growth factor (CCN2) promotes the proliferation, differentiation, and maturation of growth cartilage cells in vitro. To elucidate the specific role and molecular mechanism of CCN2 in cartilage development in vivo, in the present study we generated transgenic mice overexpressing CCN2 and analyzed them with respect to cartilage and bone development. Transgenic mice were generated expressing a ccn2/lacZ fusion gene in cartilage under the control of the 6 kb-Col2a1-enhancer/promoter. Changes in cartilage and bone development were analyzed histologically and immunohistologically and also by micro CT. Primary chondrocytes as well as limb bud mesenchymal cells were cultured and analyzed for changes in expression of cartilage–related genes, and non-transgenic chondrocytes were treated in culture with recombinant CCN2. Newborn transgenic mice showed extended length of their long bones, increased content of proteoglycans and collagen II accumulation. Micro-CT analysis of transgenic bones indicated increases in bone thickness and mineral density. Chondrocyte proliferation was enhanced in the transgenic cartilage. In in vitro short-term cultures of transgenic chondrocytes, the expression of col2a1, aggrecan and ccn2 genes was substantially enhanced; and in long-term cultures the expression levels of these genes were further enhanced. Also, in vitro chondrogenesis was strongly enhanced. IGF-I and IGF-II mRNA levels were elevated in transgenic chondrocytes, and treatment of non-transgenic chondrocytes with recombinant CCN2 stimulated the expression of these mRNA. The addition of CCN2 to non-transgenic chondrocytes induced the phosphorylation of IGFR, and ccn2-overexpressing chondrocytes showed enhanced phosphorylation of IGFR. Our data indicates that the observed effects of CCN2 may be mediated in part by CCN2-induced overexpression of IGF-I and IGF-II. These findings indicate that CCN2-overexpression in

  3. Cartilage-specific over-expression of CCN family member 2/connective tissue growth factor (CCN2/CTGF) stimulates insulin-like growth factor expression and bone growth.

    PubMed

    Tomita, Nao; Hattori, Takako; Itoh, Shinsuke; Aoyama, Eriko; Yao, Mayumi; Yamashiro, Takashi; Takigawa, Masaharu

    2013-01-01

    Previously we showed that CCN family member 2/connective tissue growth factor (CCN2) promotes the proliferation, differentiation, and maturation of growth cartilage cells in vitro. To elucidate the specific role and molecular mechanism of CCN2 in cartilage development in vivo, in the present study we generated transgenic mice overexpressing CCN2 and analyzed them with respect to cartilage and bone development. Transgenic mice were generated expressing a ccn2/lacZ fusion gene in cartilage under the control of the 6 kb-Col2a1-enhancer/promoter. Changes in cartilage and bone development were analyzed histologically and immunohistologically and also by micro CT. Primary chondrocytes as well as limb bud mesenchymal cells were cultured and analyzed for changes in expression of cartilage-related genes, and non-transgenic chondrocytes were treated in culture with recombinant CCN2. Newborn transgenic mice showed extended length of their long bones, increased content of proteoglycans and collagen II accumulation. Micro-CT analysis of transgenic bones indicated increases in bone thickness and mineral density. Chondrocyte proliferation was enhanced in the transgenic cartilage. In in vitro short-term cultures of transgenic chondrocytes, the expression of col2a1, aggrecan and ccn2 genes was substantially enhanced; and in long-term cultures the expression levels of these genes were further enhanced. Also, in vitro chondrogenesis was strongly enhanced. IGF-I and IGF-II mRNA levels were elevated in transgenic chondrocytes, and treatment of non-transgenic chondrocytes with recombinant CCN2 stimulated the expression of these mRNA. The addition of CCN2 to non-transgenic chondrocytes induced the phosphorylation of IGFR, and ccn2-overexpressing chondrocytes showed enhanced phosphorylation of IGFR. Our data indicates that the observed effects of CCN2 may be mediated in part by CCN2-induced overexpression of IGF-I and IGF-II. These findings indicate that CCN2-overexpression in transgenic

  4. Modifications to nano- and microstructural quality and the effects on mechanical integrity in Paget's disease of bone.

    PubMed

    Zimmermann, Elizabeth A; Köhne, Till; Bale, Hrishikesh A; Panganiban, Brian; Gludovatz, Bernd; Zustin, Joszef; Hahn, Michael; Amling, Michael; Ritchie, Robert O; Busse, Björn

    2015-02-01

    Paget's disease of bone (PDB) is the second most common bone disease mostly developing after 50 years of age at one or more localized skeletal sites; it is associated with severely high bone turnover, bone enlargement, bowing/deformity, cracking, and pain. Here, to specifically address the origins of the deteriorated mechanical integrity, we use a cohort of control and PDB human biopsies to investigate multiscale architectural and compositional modifications to the bone structure (ie, bone quality) and relate these changes to mechanical property measurements to provide further insight into the clinical manifestations (ie, deformities and bowing) and fracture risk caused by PDB. Here, at the level of the collagen and mineral (ie, nanometer-length scale), we find a 19% lower mineral content and lower carbonate-to-phosphate ratio in PDB, which accounts for the 14% lower stiffness and 19% lower hardness promoting plastic deformation in pathological bone. At the microstructural scale, trabecular regions are known to become densified, whereas cortical bone loses its characteristic parallel-aligned osteonal pattern, which is replaced with a mosaic of lamellar and woven bone. Although we find this loss of anisotropic alignment produces a straighter crack path in mechanically-loaded PDB cases, cortical fracture toughness appears to be maintained due to increased plastic deformation. Clearly, the altered quality of the bone structure in PDB affects the mechanical integrity leading to complications such as bowing, deformities, and stable cracks called fissure fractures associated with this disease. Although the lower mineralization and loss of aligned Haversian structures do produce a lower modulus tissue, which is susceptible to deformities, our results indicate that the higher levels of plasticity may compensate for the lost microstructural features and maintain the resistance to crack growth.

  5. Mechanical forces and their second messengers in stimulating cell growth in vitro

    NASA Technical Reports Server (NTRS)

    Vandenburgh, Herman H.

    1992-01-01

    Mechanical forces play an important role in modulating the growth of a number of different tissues including skeletal muscle, smooth muscle, cardiac muscle, bone, endothelium, epithelium, and lung. As interest increases in the molecular mechanisms by which mechanical forces are transduced into growth alterations, model systems are being developed to study these processes in tissue culture. This paper reviews the current methods available for mechanically stimulating tissue cultured cells. It then outlines some of the putative 'mechanogenic' second messengers involved in altering cell growth. Not surprisingly, many mechanogenic second messengers are the same as those involved in growth factor-induced cell growth. It is hypothesized that from an evolutionary standpoint, some second messenger systems may have initially evolved for unicellular organisms to respond to physical forces such as gravity and mechanical perturbation in their environment. As multicellular organisms came into existence, they appropriated these mechanogenic second messenger cascades for cellular regulation by growth factors.

  6. Mechanical forces and their second messengers in stimulating cell growth in vitro

    NASA Technical Reports Server (NTRS)

    Vandenburgh, Herman H.

    1992-01-01

    Mechanical forces play an important role in modulating the growth of a number of different tissues including skeletal muscle, smooth muscle, cardiac muscle, bone, endothelium, epithelium, and lung. As interest increases in the molecular mechanisms by which mechanical forces are transduced into growth alterations, model systems are being developed to study these processes in tissue culture. This paper reviews the current methods available for mechanically stimulating tissue cultured cells. It then outlines some of the putative 'mechanogenic' second messengers involved in altering cell growth. Not surprisingly, many mechanogenic second messengers are the same as those involved in growth factor-induced cell growth. It is hypothesized that from an evolutionary standpoint, some second messenger systems may have initially evolved for unicellular organisms to respond to physical forces such as gravity and mechanical perturbation in their environment. As multicellular organisms came into existence, they appropriated these mechanogenic second messenger cascades for cellular regulation by growth factors.

  7. Growth patterns of fossil vertebrates as deduced from bone microstructure: case studies from India.

    PubMed

    Ray, S; Mukherjee, D; Bandyopadhyay, S

    2009-11-01

    Bone microstructure is affected by ontogeny, phylogeny, biomechanics and environments. These aspects of life history of an extinct animal, especially its growth patterns, may be assessed as fossil bone generally maintains its histological integrity. Recent studies on the bone histology of fossil vertebrates from India encompass different types of temnospondyls and dicynodonts from different Permian and Triassic horizons. The examined taxa show that they had distinct bone histology and varied growth patterns. The Early Triassic trematosaurids had an overall fast growth, which contrasts with that of the Middle and Late Triassic temnospondyl taxa examined. The dicynodonts on the other hand, were characterized by an overall fast growth with periodic interruptions, variable growth rates dependent on ontogeny and indeterminate growth strategy. A comparative study encompassing several neotherapsid genera including the dicynodonts shows signifi cant evolutionary trends towards determinate growth strategy and reduced developmental plasticity.

  8. Mixed reality temporal bone surgical dissector: mechanical design.

    PubMed

    Hochman, Jordan Brent; Sepehri, Nariman; Rampersad, Vivek; Kraut, Jay; Khazraee, Milad; Pisa, Justyn; Unger, Bertram

    2014-08-08

    The Development of a Novel Mixed Reality (MR) Simulation. An evolving training environment emphasizes the importance of simulation. Current haptic temporal bone simulators have difficulty representing realistic contact forces and while 3D printed models convincingly represent vibrational properties of bone, they cannot reproduce soft tissue. This paper introduces a mixed reality model, where the effective elements of both simulations are combined; haptic rendering of soft tissue directly interacts with a printed bone model. This paper addresses one aspect in a series of challenges, specifically the mechanical merger of a haptic device with an otic drill. This further necessitates gravity cancelation of the work assembly gripper mechanism. In this system, the haptic end-effector is replaced by a high-speed drill and the virtual contact forces need to be repositioned to the drill tip from the mid wand. Previous publications detail generation of both the requisite printed and haptic simulations. Custom software was developed to reposition the haptic interaction point to the drill tip. A custom fitting, to hold the otic drill, was developed and its weight was offset using the haptic device. The robustness of the system to disturbances and its stable performance during drilling were tested. The experiments were performed on a mixed reality model consisting of two drillable rapid-prototyped layers separated by a free-space. Within the free-space, a linear virtual force model is applied to simulate drill contact with soft tissue. Testing illustrated the effectiveness of gravity cancellation. Additionally, the system exhibited excellent performance given random inputs and during the drill's passage between real and virtual components of the model. No issues with registration at model boundaries were encountered. These tests provide a proof of concept for the initial stages in the development of a novel mixed-reality temporal bone simulator.

  9. Mixed reality temporal bone surgical dissector: mechanical design

    PubMed Central

    2014-01-01

    Objective The Development of a Novel Mixed Reality (MR) Simulation. An evolving training environment emphasizes the importance of simulation. Current haptic temporal bone simulators have difficulty representing realistic contact forces and while 3D printed models convincingly represent vibrational properties of bone, they cannot reproduce soft tissue. This paper introduces a mixed reality model, where the effective elements of both simulations are combined; haptic rendering of soft tissue directly interacts with a printed bone model. This paper addresses one aspect in a series of challenges, specifically the mechanical merger of a haptic device with an otic drill. This further necessitates gravity cancelation of the work assembly gripper mechanism. In this system, the haptic end-effector is replaced by a high-speed drill and the virtual contact forces need to be repositioned to the drill tip from the mid wand. Previous publications detail generation of both the requisite printed and haptic simulations. Method Custom software was developed to reposition the haptic interaction point to the drill tip. A custom fitting, to hold the otic drill, was developed and its weight was offset using the haptic device. The robustness of the system to disturbances and its stable performance during drilling were tested. The experiments were performed on a mixed reality model consisting of two drillable rapid-prototyped layers separated by a free-space. Within the free-space, a linear virtual force model is applied to simulate drill contact with soft tissue. Results Testing illustrated the effectiveness of gravity cancellation. Additionally, the system exhibited excellent performance given random inputs and during the drill’s passage between real and virtual components of the model. No issues with registration at model boundaries were encountered. Conclusion These tests provide a proof of concept for the initial stages in the development of a novel mixed-reality temporal bone

  10. Mechanical Properties of a Single Cancellous Bone Trabeculae Taken from Bovine Femur

    NASA Astrophysics Data System (ADS)

    Enoki, Shinichi; Sato, Mitsuhiro; Tanaka, Kazuto; Katayama, Tsutao

    The increase of patients with osteoporosis is becoming a social problem, thus it is an urgent issue to find its prevention and treatment methods. Since cancellous bone is metabolically more active than cortical bone, cancellous bone is often used for diagnosis of osteoporosis and has received much attention within the study of bone. Bone is a hierarchically structured material and its mechanical properties vary at different structural levels, therefore it is important to break down the mechanical testing of bone according to the various levels within bone material. Mechanical properties of cancellous bone is said to be depended on quantities and orientation of trabecular bone. It is supposed that mechanical properties of trabecular bone are constant without depending on any structural arrangement and parts. However, such assumption has not been established in studies of trabecular bone. Furthermore test results have a large margin of error caused by insufficient shape assessment. In this study, three point bending tests of single cancellous bone trabeculae extracted from bovine femur were conducted to evaluate the effects of directions to the femur major axis direction on the mechanical properties. X-ray μCT was used to obtain shape of trabecular bone specimens. Furthermore compression tests of cancellous bone specimens, which were extracted in 10mm cubic geometry, were conducted for evaluation of directional properties.There were small difference in the elastic modulus of the trabecular bones which were extracted in parallel and in perpendicular to the major axis of femur. Considering from the results that the cancellous bone specimens, which were extracted in 10mm cubic geometry, have different elastic properties depending on the tested directions; the bone structure has larger influence than bone material property on the mechanical properties of cancellous bone.

  11. Mechanical behavior of osteoporotic bone at sub-lamellar length scales

    NASA Astrophysics Data System (ADS)

    Jimenez-Palomar, Ines; Shipov, Anna; Shahar, Ron; Barber, Asa

    2015-02-01

    Osteoporosis is a disease known to promote bone fragility but the effect on the mechanical properties of bone material, which is independent of geometric effects, is particularly unclear. To address this problem, micro-beams of osteoporotic bone were prepared using focused ion beam (FIB) microscopy and mechanically tested in compression using an atomic force microscope (AFM) while observing using in situ electron microscopy. This experimental approach was shown to be effective at measuring the subtle changes in the mechanical properties of bone material required to evaluate the effects of osteoporosis. Osteoporotic bone material was found to have lower elastic modulus and increased strain to failure when compared to healthy bone material, while the strength of osteoporotic and healthy bone was similar. A mechanism is suggested based on these results and previous literature that indicates degradation of the organic material in osteoporosis bone is responsible for resultant mechanical properties.

  12. Bone marrow mesenchymal stem cells attenuate silica-induced pulmonary fibrosis via paracrine mechanisms.

    PubMed

    Li, Xiaoli; Wang, Yan; An, Guoliang; Liang, Di; Zhu, Zhonghui; Lian, Ximeng; Niu, Piye; Guo, Caixia; Tian, Lin

    2017-03-15

    The purpose of this study was to investigate the anti-fibrotic effect and possible mechanism of bone marrow mesenchymal stem cells (BMSCs) in silica-induced lung injury and fibrosis in vivo and in vitro. In vivo, rats were exposed to 50mg/ml silica intratracheally. The rats were sacrificed on day 15 or day 30 after intravenous injection of BMSCs. Histopathological examination demonstrated that BMSCs decreased the blue areas of collagen fibers and the number of nodules. Alveolar epithelium was damaged by silica, but it was restored by BMSCs. In vitro, BMSCs co-cultured with RLE-6TN cells in 6-Transwell plates were evaluated to determine the possible mechanism. The results demonstrated that BMSCs downregulated the expression of collagen I and III. BMSCs reversed morphological abnormalities and reduced the proliferation of RLE-6TN cells. These data showed that BMSCs did not give rise to alveolar epithelial cells directly, while the levels of hepatocyte growth factor, keratinocyte growth factor and bone morphogenetic protein -7 increased and expression of tumor necrosis factor-α and transforming growth factor-β1 decreased in the 6TN+Silica+BMSCs group compared with the 6TN+Silica group. Our results revealed that BMSCs exerted anti-fibrotic effects on silica-induced pulmonary fibrosis, which might be associated with paracrine mechanisms rather than differentiation.

  13. WISP1/CCN4: A Potential Target for Inhibiting Prostate Cancer Growth and Spread to Bone

    PubMed Central

    Sonn, Robert; Kilts, Tina M.; de Castro, Luis F.; Maeda, Azusa; Fisher, Larry W.; Robey, Pamela G.; Berendsen, Agnes D.; Li, Li; McCartney-Francis, Nancy; Brown, Aaron C.; Crawford, Nigel P. S.; Molinolo, Alfredo; Jain, Alka; Fedarko, Neal S.; Young, Marian F.

    2013-01-01

    Prostate cancer (PC) is a leading cause of death in men however the factors that regulate its progression and eventual metastasis to bone remain unclear. Here we show that WISP1/CCN4 expression in prostate cancer tissues was up-regulated in early stages of the disease and, further, that it correlated with increased circulating levels of WISP1 in the sera of patients at early stages of the disease. WISP1 was also elevated in the mouse prostate cancer model TRAMP in the hypoplastic diseased tissue that develops prior to advanced carcinoma formation. When the ability of anti-WISP1 antibodies to reduce the spread of PC3-Luc cells to distant sites was tested it showed that twice weekly injections of anti-WISP1 antibodies reduced the number and overall size of distant tumors developed after intracardiac (IC) injection of PC3-Luc cells in mice. The ability of antibodies against WISP1 to inhibit growth of PC3-Luc cancer cells in mice was also evaluated and showed that twice weekly injections of anti-WISP1 antibodies reduced local tumor growth when examined in xenografts. To better understand the mechanism of action, the migration of PC3-Luc cells through membranes with or without a Matrigel™ barrier showed the cells were attracted to WISP1, and that this attraction was inhibited by treatment with anti-WISP1 antibodies. We also show the expression of WISP1 at the bone-tumor interface and in the stroma of early grade cancers suggested WISP1 expression is well placed to play roles in both fostering growth of the cancer and its spread to bone. In summary, the up-regulation of WISP1 in the early stages of cancer development coupled with its ability to inhibit spread and growth of prostate cancer cells makes it both a potential target and an accessible diagnostic marker for prostate cancer. PMID:23977121

  14. 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.

  15. 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.

  16. Postnatal long bone growth in terrestrial placental mammals: allometry, life history, and organismal traits.

    PubMed

    Kilbourne, Brandon M; Makovicky, Peter J

    2012-10-01

    The ontogenetic allometry of long bone proportions is poorly understood in Mammalia. It has previously been suggested that during mammalian ontogeny long bone proportions grow more slender (positive allometry; length ∝ circumference(>1.0) ), although this conclusion was based upon data from a few small-bodied taxa. It remains unknown how ontogenetic long bone allometry varies across Mammalia in terms of both taxonomy and body size. We collected long bone length and circumference data for ontogenetic samples of 22 species of mammals spanning six major clades and three orders of magnitude in body mass. Using reduced major axis bivariate regressions to compare bone length to circumference, we found that isometry and positive allometry are the most widespread patterns of growth across mammals. Negative allometry (i.e., bones growing more robust during ontogeny) occurs in mammals but is largely restricted to cetartiodactyls. Using regression slope as a proxy for long bone allometry, we compared long bone allometry to life history and organismal traits. Neonatal body mass, adult body mass, and growth rate have a negative relationship with long bone allometry. At an adult mass of roughly 15-20 kg, long bone growth shifts from positive allometry to mainly isometry and negative allometry. There were no significant relationships between ontogenetic long bone allometry and either cursoriality or basal metabolic rate. Copyright © 2012 Wiley Periodicals, Inc.

  17. Effects of fibroblast growth factor 2 on osteoblastic proliferation and differentiation by regulating bone morphogenetic protein receptor expression.

    PubMed

    Park, Jun-Beom

    2011-09-01

    Fibroblast growth factors (FGFs) are known to play a critical role in bone growth and development, affecting both osteogenesis and chondrogenesis. Fibroblast growth factor 2 (FGF-2) is produced intracellularly by osteoblasts and secreted into the surrounding matrix in bone.The dose-dependent effects of FGF-2 were tested to examine the relationship between FGF-2 and osteoblast proliferation and differentiation. Tests used included a cell viability test, an alkaline phosphatase activity test, and a Western blot analysis.Cultures growing in the presence of FGF-2 showed an increased value for 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay and a decreased value for alkaline phosphatase activity. Results of the Western blot analysis showed that the addition of FGF-2 seems to decrease osteocalcin and bone morphogenetic protein receptor IA.These data show that FGF-2 in the tested dosage within MC3T3-E1 cells seems to affect proliferation and differentiation. Results of the Western blot analysis may add some possible mechanisms, and it may be suggested that treatment of FGF-2 may have an influence on the expression of bone morphogenetic protein receptors in osteoprecursor cells. Further elucidation of the mechanisms related to this mechanism within the in vivo model may be necessary to ascertain greater detail.

  18. Preventing Cartilage Degeneration in Warfighters by Elucidating Novel Mechanisms Regulating Osteocyte-Mediated Perilacunar Bone Remodeling

    DTIC Science & Technology

    2015-10-01

    quality, and cartilage health in post -traumatic osteoarthritis (PTOA). Few molecular details are known about the regulation of PLR or bone quality...degeneration. 15. SUBJECT TERMS Osteocyte, remodeling, bone, bone quality, post -traumatic osteoarthritis, TGF-beta, mechanical load, matrix...joint health, and their contribution to post -traumatic osteoarthritis (PTOA). Osteocytes sense and respond to mechanical loads, and they are also

  19. Mechanism for diamond growth from methyl radicals

    NASA Astrophysics Data System (ADS)

    Harris, Stephen J.

    1990-06-01

    We use a 9-carbon model compound to describe a proposed mechanism for homoepitaxial growth of diamond from methyl radicals on a hydrogenated, electrically neutral (100) surface. We estimate enthalpy and entropy changes for each step in the mechanism using group additivity methods, taking into account the types of bonding and steric repulsions found on the (100) surface. Rate constants are estimated based on analogous reactions for hydrocarbon molecules, while gas phase species concentrations are taken from our previous measurements. The rate equations are then integrated. The method, which contains no adjustable parameters or phenomenological constants, predicts a growth rate of between 0.06 and 0.6 μm/h, depending on the local details of the surface. Uncertainties related to the use of a model compound rather than diamond are discussed. The analysis demonstrates that the proposed mechanism is feasible.

  20. Increased linear bone growth by GH in the absence of SOCS2 is independent of IGF-1.

    PubMed

    Dobie, Ross; Ahmed, Syed F; Staines, Katherine A; Pass, Chloe; Jasim, Seema; MacRae, Vicky E; Farquharson, Colin

    2015-11-01

    Growth hormone (GH) signaling is essential for postnatal linear bone growth, but the relative importance of GHs actions on the liver and/or growth plate cartilage remains unclear. The importance of liver derived insulin like-growth factor-1 (IGF-1) for endochondral growth has recently been challenged. Here, we investigate linear growth in Suppressor of Cytokine Signaling-2 (SOCS2) knockout mice, which have enhanced growth despite normal systemic GH/IGF-1 levels. Wild-type embryonic ex vivo metatarsals failed to exhibit increased linear growth in response to GH, but displayed increased Socs2 transcript levels (P < 0.01). In the absence of SOCS2, GH treatment enhanced metatarsal linear growth over a 12 day period. Despite this increase, IGF-1 transcript and protein levels were not increased in response to GH. In accordance with these data, IGF-1 levels were unchanged in GH-challenged postnatal Socs2(-/-) conditioned medium despite metatarsals showing enhanced linear growth. Growth-plate Igf1 mRNA levels were not elevated in juvenile Socs2(-/-) mice. GH did however elevate IGF-binding protein 3 levels in conditioned medium from GH challenged metatarsals and this was more apparent in Socs2(-/-) metatarsals. GH did not enhance the growth of Socs2(-/-) metatarsals when the IGF receptor was inhibited, suggesting that IGF receptor mediated mechanisms are required. IGF-2 may be responsible as IGF-2 promoted metatarsal growth and Igf2 expression was elevated in Socs2(-/-) (but not WT) metatarsals in response to GH. These studies emphasise the critical importance of SOCS2 in regulating GHs ability to promote bone growth. Also, GH appears to act directly on the metatarsals of Socs2(-/-) mice, promoting growth via a mechanism that is independent of IGF-1.

  1. 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.

  2. Mechanical Factors and Bone Health: Effects of Weightlessness and Neurologic Injury

    PubMed Central

    Amin, Shreyasee

    2014-01-01

    Bone is a dynamic tissue with homeostasis governed by many factors. Among them, mechanical stimuli appear to be particularly critical for bone structure and strength. With removal of mechanical stimuli, a profound bone loss occurs, as best observed in the extreme examples following exposure to space flight or neurologic impairment. This review provides an overview of the changes in bone density and structure that occur during and after space flight as well as following neurologic injury from stroke and spinal cord injury. It also discusses the potential mechanisms through which mechanical stimuli are postulated to act on bone tissue. PMID:20425519

  3. Mechanical factors and bone health: effects of weightlessness and neurologic injury.

    PubMed

    Amin, Shreyasee

    2010-06-01

    Bone is a dynamic tissue with homeostasis governed by many factors. Among them, mechanical stimuli appear to be particularly critical for bone structure and strength. With removal of mechanical stimuli, a profound bone loss occurs, as best observed in the extreme examples following exposure to space flight or neurologic impairment. This review provides an overview of the changes in bone density and structure that occur during and after space flight as well as following neurologic injury from stroke and spinal cord injury. It also discusses the potential mechanisms through which mechanical stimuli are postulated to act on bone tissue.

  4. APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment

    PubMed Central

    Acharya, Chirag; An, Gang; Moschetta, Michele; Zhong, Mike Y.; Feng, Xiaoyan; Cea, Michele; Cagnetta, Antonia; Wen, Kenneth; van Eenennaam, Hans; van Elsas, Andrea; Qiu, Lugui; Richardson, Paul; Munshi, Nikhil; Anderson, Kenneth C.

    2016-01-01

    Here we show that overexpression or activation of B-cell maturation antigen (BCMA) by its ligand, a proliferation-inducing ligand (APRIL), promotes human multiple myeloma (MM) progression in vivo. BCMA downregulation strongly decreases viability and MM colony formation; conversely, BCMA overexpression augments MM cell growth and survival via induction of protein kinase B (AKT), MAPK, and nuclear factor (NF)-κB signaling cascades. Importantly, BCMA promotes in vivo growth of xenografted MM cells harboring p53 mutation in mice. BCMA-overexpressing tumors exhibit significantly increased CD31/microvessel density and vascular endothelial growth factor compared with paired control tumors. These tumors also express increased transcripts crucial for osteoclast activation, adhesion, and angiogenesis/metastasis, as well as genes mediating immune inhibition including programmed death ligand 1, transforming growth factor β, and interleukin 10. These target genes are consistently induced by paracrine APRIL binding to BCMA on MM cells, which is blocked by an antagonistic anti-APRIL monoclonal antibody hAPRIL01A (01A). 01A is cytotoxic against MM cells even in the presence of protective bone marrow (BM) myeloid cells including osteoclasts, macrophages, and plasmacytoid dendritic cells. 01A further decreases APRIL-induced adhesion and migration of MM cells via blockade of canonical and noncanonical NF-κB pathways. Moreover, 01A prevents in vivo MM cell growth within implanted human bone chips in SCID mice. Finally, the effect of 01A on MM cell viability is enhanced by lenalidomide and bortezomib. Taken together, these data delineate new molecular mechanisms of in vivo MM growth and immunosuppression critically dependent on BCMA and APRIL in the BM microenvironment, further supporting targeting this prominent pathway in MM. PMID:27127303

  5. A periodontal attachment mechanism without alveolar bone. Case report.

    PubMed

    Novak, M J; Polson, A M; Caton, J; Freeman, E; Meitner, S

    1983-02-01

    A 22-year-old black male was referred for periodontal therapy because of radiographic evidence of advanced bone loss associated with the posterior teeth. Clinical examination revealed gingivitis, normal sulcus depths, and minimal loss of clinical attachment. Complete blood counts, serum chemistry, and neutrophil function were within normal limits. Histological, histochemical and ultrastructural analysis of an extracted tooth revealed no loss of attachment; large areas of the cementum were collagen-poor and, ultrastructurally, resembled afibrillar cementum. It is proposed that the periodontal attachment mechanism present in this case was associated with a localized failure in normal periodontal development.

  6. How linear tension converts to curvature: geometric control of bone tissue growth.

    PubMed

    Bidan, Cécile M; Kommareddy, Krishna P; Rumpler, Monika; Kollmannsberger, Philip; Bréchet, Yves J M; Fratzl, Peter; Dunlop, John W C

    2012-01-01

    This study investigated how substrate geometry influences in-vitro tissue formation at length scales much larger than a single cell. Two-millimetre thick hydroxyapatite plates containing circular pores and semi-circular channels of 0.5 mm radius, mimicking osteons and hemi-osteons respectively, were incubated with MC3T3-E1 cells for 4 weeks. The amount and shape of the tissue formed in the pores, as measured using phase contrast microscopy, depended on the substrate geometry. It was further demonstrated, using a simple geometric model, that the observed curvature-controlled growth can be derived from the assembly of tensile elements on a curved substrate. These tensile elements are cells anchored on distant points of the curved surface, thus creating an actin "chord" by generating tension between the adhesion sites. Such a chord model was used to link the shape of the substrate to cell organisation and tissue patterning. In a pore with a circular cross-section, tissue growth increases the average curvature of the surface, whereas a semi-circular channel tends to be flattened out. Thereby, a single mechanism could describe new tissue growth in both cortical and trabecular bone after resorption due to remodelling. These similarities between in-vitro and in-vivo patterns suggest geometry as an important signal for bone remodelling.

  7. Drugs Which Inhibit Osteoclast Function Suppress Tumor Growth through Calcium Reduction in Bone

    PubMed Central

    Li, Xin; Liao, Jinhui; Park, Serk In; Koh, Amy J; Sadler, William D; Pienta, Kenneth J; Rosol, Thomas J; McCauley, Laurie K

    2011-01-01

    Prostate carcinoma frequently metastasizes to bone where the microenvironment facilitates its growth. Inhibition of bone resorption is effective in reducing tumor burden and bone destruction in prostate cancer. However, whether drugs that inhibit osteoclast function inhibit tumor growth independent of inhibition of bone resorption is unclear. Calcium is released during bone resorption and the calcium sensing receptor is an important regulator of cancer cell proliferation. The goal of this investigation was to elucidate the role of calcium released during bone resorption and to determine the impact of drugs which suppress bone resorption on tumor growth in bone. To compare tumor growth in a skeletal versus non-skeletal site, equal numbers of canine prostate cancer cells expressing luciferase (ACE-1luc) prostate cancer cells were inoculated into a simple collagen matrix, neonatal mouse vertebrae (vossicles), human de-proteinized bone, or a mineralized collagen matrix. Implants were placed subcutaneously into athymic mice. Luciferase activity was used to track tumor growth weekly and at one month tumors were dissected for histologic analysis. Luciferase activity and tumor size were greater in vossicles, de-proteinized bone and mineralized collagen matrix versus non-mineralized collagen implants. The human osteoblastic prostate carcinoma cell line C4-2b also grew better in a mineral rich environment with a greater proliferation of C4-2b cells reflected by Ki-67 staining. Zoledronic acid (ZA), a bisphosphonate, and recombinant OPG-Fc, a RANKL inhibitor, were administered to mice bearing vertebral implants (vossicles) containing ACE-1 osteoblastic prostate cancer cells. Vossicles or collagen matrices were seeded with ACE-1luc cells subcutaneously in athymic mice (2 vossicles, 2 collagen implants/mouse). Mice received ZA (5μg/mouse, twice/week), (OPG-Fc at 10mg/kg, 3 times/week) or vehicle, and luciferase activity was measured weekly. Histologic analysis of the tumors

  8. Effects of liver-derived insulin-like growth factor I on bone metabolism in mice.

    PubMed

    Sjögren, Klara; Sheng, Matilda; Movérare, Sofia; Liu, Jun-Li; Wallenius, Kristina; Törnell, Jan; Isaksson, Olle; Jansson, John-Olov; Mohan, Subburaman; Ohlsson, Claes

    2002-11-01

    Insulin-like growth factor (IGF) I is an important regulator of both skeletal growth and adult bone metabolism. To better understand the relative importance of systemic IGF-I versus locally expressed IGF-I we have developed a transgenic mouse model with inducible specific IGF-I gene inactivation in the liver (LI-IGF-I-/-). These mice are growing normally up to 12 weeks of age but have a disturbed carbohydrate and lipid metabolism. In this study, the long-term effects of liver-specific IGF-I inactivation on skeletal growth and adult bone metabolism were investigated. The adult (week 8-55) axial skeletal growth was decreased by 24% in the LI-IGF-I-/- mice whereas no major reduction of the adult appendicular skeletal growth was seen. The cortical cross-sectional bone area, as measured in the middiaphyseal region of the long bones, was decreased in old LI-IGF-I-/- mice. This reduction in the amount of cortical bone was caused mainly by decreased periosteal circumference and was associated with a weaker bone determined by a decrease in ultimate load. In contrast, the amount of trabecular bone was not decreased in the LI-IGF-I-/- mice. DNA microarray analysis of 30-week-old LI-IGF-I-/- and control mice indicated that only four genes were regulated in bone whereas approximately 40 genes were regulated in the liver, supporting the hypothesis that liver-derived IGF-I is of minor importance for adult bone metabolism. In summary, liver-derived IGF-I exerts a small but significant effect on cortical periosteal bone growth and on adult axial skeletal growth while it is not required for the maintenance of the trabecular bone in adult mice.

  9. Additive Effects of Mechanical Marrow Ablation and PTH Treatment on de Novo Bone Formation in Mature Adult Rats

    PubMed Central

    Zhang, Qing; Miller, Christopher; Bible, Jesse; Li, Jiliang; Xu, Xiaoqing; Mehta, Nozer; Gilligan, James; Vignery, Agnès; Scholz, Jodi A Carlson

    2012-01-01

    Mechanical ablation of bone marrow in young rats induces rapid but transient bone growth, which can be enhanced and maintained for three weeks by the administration of parathyroid hormone (PTH). Additionally, marrow ablation, followed by PTH treatment for three months leads to increased cortical thickness. In this study, we sought to determine whether PTH enhances bone formation after marrow ablation in aged rats. Aged rats underwent unilateral femoral marrow ablation and treatment with PTH or vehicle for four weeks. Both femurs from each rat were analyzed by X-ray and pQCT, then analyzed either by microCT, histology or biomechanical testing. Marrow ablation alone induced transient bone formation of low abundance that persisted over four weeks, while marrow ablation followed by PTH induced bone formation of high abundance that also persisted over four weeks. Our data confirms that the osteo-inducive effect of marrow ablation and the additive effect of marrow ablation, followed by PTH, occurs in aged rats. Our observations open new avenues of investigations in the field of tissue regeneration. Local marrow ablation, in conjunction with an anabolic agent, might provide a new platform for rapid site-directed bone growth in areas of high bone loss, such as in the hip and wrist, which are subject to fracture. PMID:24710549

  10. Additive Effects of Mechanical Marrow Ablation and PTH Treatment on de Novo Bone Formation in Mature Adult Rats.

    PubMed

    Zhang, Qing; Miller, Christopher; Bible, Jesse; Li, Jiliang; Xu, Xiaoqing; Mehta, Nozer; Gilligan, James; Vignery, Agnès; Scholz, Jodi A Carlson

    2012-12-05

    Mechanical ablation of bone marrow in young rats induces rapid but transient bone growth, which can be enhanced and maintained for three weeks by the administration of parathyroid hormone (PTH). Additionally, marrow ablation, followed by PTH treatment for three months leads to increased cortical thickness. In this study, we sought to determine whether PTH enhances bone formation after marrow ablation in aged rats. Aged rats underwent unilateral femoral marrow ablation and treatment with PTH or vehicle for four weeks. Both femurs from each rat were analyzed by X-ray and pQCT, then analyzed either by microCT, histology or biomechanical testing. Marrow ablation alone induced transient bone formation of low abundance that persisted over four weeks, while marrow ablation followed by PTH induced bone formation of high abundance that also persisted over four weeks. Our data confirms that the osteo-inducive effect of marrow ablation and the additive effect of marrow ablation, followed by PTH, occurs in aged rats. Our observations open new avenues of investigations in the field of tissue regeneration. Local marrow ablation, in conjunction with an anabolic agent, might provide a new platform for rapid site-directed bone growth in areas of high bone loss, such as in the hip and wrist, which are subject to fracture.

  11. Increased classical endoplasmic reticulum stress is sufficient to reduce chondrocyte proliferation rate in the growth plate and decrease bone growth.

    PubMed

    Kung, Louise H W; Rajpar, M Helen; Preziosi, Richard; Briggs, Michael D; Boot-Handford, Raymond P

    2015-01-01

    Mutations in genes encoding cartilage oligomeric matrix protein and matrilin-3 cause a spectrum of chondrodysplasias called multiple epiphyseal dysplasia (MED) and pseudoachondroplasia (PSACH). The majority of these diseases feature classical endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) as a result of misfolding of the mutant protein. However, the importance and the pathological contribution of ER stress in the disease pathogenesis are unknown. The aim of this study was to investigate the generic role of ER stress and the UPR in the pathogenesis of these diseases. A transgenic mouse line (ColIITgcog) was generated using the collagen II promoter to drive expression of an ER stress-inducing protein (Tgcog) in chondrocytes. The skeletal and histological phenotypes of these ColIITgcog mice were characterised. The expression and intracellular retention of Tgcog induced ER stress and activated the UPR as characterised by increased BiP expression, phosphorylation of eIF2α and spliced Xbp1. ColIITgcog mice exhibited decreased long bone growth and decreased chondrocyte proliferation rate. However, there was no disruption of chondrocyte morphology or growth plate architecture and perturbations in apoptosis were not apparent. Our data demonstrate that the targeted induction of ER stress in chondrocytes was sufficient to reduce the rate of bone growth, a key clinical feature associated with MED and PSACH, in the absence of any growth plate dysplasia. This study establishes that classical ER stress is a pathogenic factor that contributes to the disease mechanism of MED and PSACH. However, not all the pathological features of MED and PSACH were recapitulated, suggesting that a combination of intra- and extra-cellular factors are likely to be responsible for the disease pathology as a whole.

  12. Effects of growth hormone administration for 6 months on bone turnover and bone marrow fat in obese premenopausal women.

    PubMed

    Bredella, Miriam A; Gerweck, Anu V; Barber, Lauren A; Breggia, Anne; Rosen, Clifford J; Torriani, Martin; Miller, Karen K

    2014-05-01

    Abdominal adiposity is associated with low BMD and decreased growth hormone (GH) secretion, an important regulator of bone homeostasis. The purpose of our study was to determine the effects of a short course of GH on markers of bone turnover and bone marrow fat in premenopausal women with abdominal adiposity. In a 6-month, randomized, double-blind, placebo-controlled trial we studied 79 abdominally obese premenopausal women (21-45 y) who underwent daily sc injections of GH vs. placebo. Main outcome measures were body composition by DXA and CT, bone marrow fat by proton MR spectroscopy, P1NP, CTX, 25(OH)D, hsCRP, undercarboxylated osteocalcin (ucOC), preadipocyte factor 1 (Pref 1), apolipoprotein B (ApoB), and IGF-1. GH increased IGF-1, P1NP, 25(OH)D, ucOC, bone marrow fat and lean mass, and decreased abdominal fat, hsCRP, and ApoB compared with placebo (p<0.05). There was a trend toward an increase in CTX and Pref-1. Among all participants, a 6-month increase in IGF-1 correlated with 6-month increase in P1NP (p=0.0005), suggesting that subjects with the greatest increases in IGF-1 experienced the greatest increases in bone formation. A six-month decrease in abdominal fat, hsCRP, and ApoB inversely predicted 6-month change in P1NP, and 6-month increase in lean mass and 25(OH)D positively predicted 6-month change in P1NP (p≤0.05), suggesting that subjects with greatest decreases in abdominal fat, inflammation and ApoB, and the greatest increases in lean mass and 25(OH)D experienced the greatest increases in bone formation. A six-month increase in bone marrow fat correlated with 6-month increase in P1NP (trend), suggesting that subjects with the greatest increases in bone formation experienced the greatest increases in bone marrow fat. Forward stepwise regression analysis indicated that increase in lean mass and decrease in abdominal fat were positive predictors of P1NP. When IGF-1 was added to the model, it became the only predictor of P1NP. GH replacement in

  13. Effects of growth hormone administration for 6 months on bone turnover and bone marrow fat in obese premenopausal women

    PubMed Central

    Bredella, Miriam A.; Gerweck, Anu V.; Barber, Lauren A.; Breggia, Anne; Rosen, Clifford J.; Torriani, Martin; Miller, Karen K.

    2014-01-01

    Purpose Abdominal adiposity is associated with low BMD and decreased growth hormone (GH) secretion, an important regulator of bone homeostasis. The purpose of our study was to determine the effects of a short course of GH on markers of bone turnover and bone marrow fat in premenopausal women with abdominal adiposity. Materials and Methods In a 6-month, randomized, double-blind, placebo-controlled trial we studied 79 abdominally obese premenopausal women (21–45y) who underwent daily sc injections of GH vs. placebo. Main outcome measures were body composition by DXA and CT, bone marrow fat by proton MR spectroscopy, P1NP, CTX, 25(OH)D, hsCRP, undercarboxylated osteocalcin (ucOC), preadipocyte factor 1 (Pref 1), apolipoprotein B (ApoB), and IGF-1. Results GH increased IGF-1, P1NP, 25(OH)D, ucOC, bone marrow fat and lean mass, and decreased abdominal fat, hsCRP, and ApoB compared with placebo (p<0.05). There was a trend toward an increase in CTX and Pref-1. Among all participants, 6-month increase in IGF-1 correlated with 6-month increase in P1NP (p=0.0005), suggesting that subjects with the greatest increases in IGF-1 experienced the greatest increases in bone formation. Six-month decrease in abdominal fat, hsCRP, and ApoB inversely predicted 6-month change in P1NP, and 6-month increase in lean mass and 25(OH)D positively predicted 6-month change in P1NP (p≤0.05), suggesting that subjects with greatest decreases in abdominal fat, inflammation and ApoB, and the greatest increases in lean mass and 25(OH)D experienced the greatest increases in bone formation. Six-month increase in bone marrow fat correlated with 6-month increase in P1NP (trend), suggesting that subjects with the greatest increases in bone formation experienced the greatest increases in bone marrow fat. Forward stepwise regression analysis indicated that increase in lean mass and decrease in abdominal fat were positive predictors of P1NP. When IGF-1 was added to the model, it became the only predictor

  14. Interleukin-1-induced acute bone resorption facilitates the secretion of fibroblast growth factor 23 into the circulation.

    PubMed

    Yamazaki, Miwa; Kawai, Masanobu; Miyagawa, Kazuaki; Ohata, Yasuhisa; Tachikawa, Kanako; Kinoshita, Saori; Nishino, Jin; Ozono, Keiichi; Michigami, Toshimi

    2015-05-01

    Fibroblast growth factor 23 (FGF23), a central regulator of phosphate and vitamin D metabolism, is mainly produced by osteocytes in bone and exerts its effects on distant organs. Despite its endocrine function, the mechanism controlling serum FGF23 levels is not fully understood. Here we tested the hypothesis that osteoclastic bone resorption may play a role in regulating circulating levels of FGF23, using a mouse model where injections of interleukin (IL)-1β into the subcutaneous tissue over the calvaria induced rapid bone resorption. A significant amount of FGF23 was detected in the extracts from mouse bones, which supports the idea that FGF23 stays in bone for a while after its production. IL-1β-induced bone resorption was associated with elevated serum FGF23 levels, an effect abolished by pre-treatment with pamidronate. Fgf23 expression was not increased in either the calvariae or tibiae of IL-1β-injected mice, which suggests that IL-1β facilitated the entry of FGF23 protein into circulation by accelerating bone resorption rather than increasing its gene expression. The direct effect of IL-1β on bone was confirmed when it increased FGF23 levels in the conditioned media of mouse calvariae in organ culture. Repeated treatment of the cultured calvariae with IL-1β led to a refractory phase, where FGF23 was not mobilized by IL-1β anymore. Consistent with the in vivo results, treatment with IL-1β failed to increase Fgf23 mRNA in isolated primary osteocytes and osteoblasts. These results suggest that FGF23 produced by osteocytes remains in bone, and that rapid bone resorption facilitates its entry into the bloodstream.

  15. Porcine skin gelatin hydrolysate promotes longitudinal bone growth in adolescent rats.

    PubMed

    Leem, Kang-Hyun; Lee, Sena; Jang, Aera; Kim, Hye Kyung

    2013-05-01

    Collagen hydrolysates (CHs) are mixtures of peptides obtained by partial hydrolysis of gelatin that are receiving scientific attention as potential oral supplements for the restoration of osteoarticular tissues. The aim of this study was to evaluate the effectiveness of CHs for promoting longitudinal bone growth in growing rats. An in vitro study was carried out in osteoblast-like MG63 cells and the most effective CH on bone formation was selected among 36 various CHs. An in vivo study confirmed the functional effects of a selected CH with molecular weight of <3 kDa on longitudinal bone growth. CHs dose-dependently promoted the longitudinal bone growth and height of the growth plate in adolescent male rats, whereas gelatin failed to affect longitudinal bone growth. Insulin-like growth factor-1 and bone morphogenetic protein-2 in the CH treated group were highly expressed in the growth plate. These results suggest that CHs isolated in this study may provide beneficial effects on bone metabolism of growing animals and humans.

  16. Marked increase in bone formation markers after cinacalcet treatment by mechanisms distinct from hungry bone syndrome in a haemodialysis patient

    PubMed Central

    Goto, Shunsuke; Fujii, Hideki; Matsui, Yutaka; Fukagawa, Masafumi

    2010-01-01

    A 59-year-old female who was on dialysis due to diabetic nephropathy was referred to our hospital for severe hyperparathyroidism refractory to intravenous vitamin D receptor activator treatment. With subsequent cinacalcet hydrochloride treatment, parathyroid hormone (PTH) levels were only slightly suppressed. However, progressive increases were observed in serum alkaline phosphatase (ALP) and bone-specific alkaline phosphatase (BAP) levels with mild hypocalcaemia. A bone biopsy, obtained immediately before surgical parathyroidectomy after 3 months of cinacalcet treatment, revealed no disappearance of osteoclasts. These data suggest that cinacalcet hydrochloride treatment may induce a marked promotion of bone formation by mechanisms distinct from hungry bone syndrome that usually develops after parathyroidectomy. PMID:25949410

  17. Accelerated growth plate mineralization and foreshortened proximal limb bones in fetuin-A knockout mice.

    PubMed

    Seto, Jong; Busse, Björn; 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.

  18. 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

  19. 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.

  20. Mathematical modeling of appendicular bone growth in glaucous-winged gulls.

    PubMed

    Hayward, James L; Henson, Shandelle M; Banks, John C; Lyn, Sheena L

    2009-01-01

    Development of locomotor activity is crucial in tetrapods. In birds, this development leads to different functions for hindlimbs and forelimbs. The emergence of walking and flying as very different complex behavior patterns only weeks after hatching provides an interesting case study in animal development. We measured the diaphyseal lengths and midshaft diameters of three wing bones (humerus, ulna, and carpometacarpus) and three leg bones (femur, tibiotarsus, and tarsometatarsus) of 79 juvenile (ages 0-42 days) and 13 adult glaucous-winged gulls (Larus glaucescens), a semiprecocial species. From a suite of nine alternative mathematical models, we used information-theoretic criteria to determine the best model(s) for length and diameter of each bone as a function of age; that is, we determined the model(s) that obtained the best tradeoff between the minimized sum of squared residuals and the number of parameters used to fit the model. The Janoschek and Holling III models best described bone growth, with at least one of these models yielding an R(2) > or = 0.94 for every dimension except tarsometatarsus diameter (R(2) = 0.87). We used the best growth models to construct accurate allometric comparisons of the bones. Early maximal absolute growth rates characterize the humerus, femur, and tarsometatarsus, bones that assume adult-type support functions relatively early during juvenile development. Leg bone lengths exhibit more rapid but less sustained relative growth than wing bone lengths. Wing bone diameters are initially smaller than leg bone diameters, although this relationship is reversed by fledging. Wing bones and the femur approach adult length by fledging but continue to increase in diameter past fledging; the tibiotarsus and tarsometatarsus approach both adult length and diameter by fledging. In short, the pattern of bone growth in this semiprecocial species reflects the changing behavioral needs of the developing organism.

  1. Increased linear bone growth by GH in the absence of SOCS2 is independent of IGF‐1

    PubMed Central

    Dobie, Ross; Ahmed, Syed F.; Staines, Katherine A.; Pass, Chloe; Jasim, Seema; MacRae, Vicky E.

    2015-01-01

    Growth hormone (GH) signaling is essential for postnatal linear bone growth, but the relative importance of GHs actions on the liver and/or growth plate cartilage remains unclear. The importance of liver derived insulin like‐growth factor‐1 (IGF‐1) for endochondral growth has recently been challenged. Here, we investigate linear growth in Suppressor of Cytokine Signaling‐2 (SOCS2) knockout mice, which have enhanced growth despite normal systemic GH/IGF‐1 levels. Wild‐type embryonic ex vivo metatarsals failed to exhibit increased linear growth in response to GH, but displayed increased Socs2 transcript levels (P < 0.01). In the absence of SOCS2, GH treatment enhanced metatarsal linear growth over a 12 day period. Despite this increase, IGF‐1 transcript and protein levels were not increased in response to GH. In accordance with these data, IGF‐1 levels were unchanged in GH‐challenged postnatal Socs2‐/‐ conditioned medium despite metatarsals showing enhanced linear growth. Growth‐plate Igf1 mRNA levels were not elevated in juvenile Socs2‐/‐ mice. GH did however elevate IGF‐binding protein 3 levels in conditioned medium from GH challenged metatarsals and this was more apparent in Socs2‐/‐ metatarsals. GH did not enhance the growth of Socs2‐/‐ metatarsals when the IGF receptor was inhibited, suggesting that IGF receptor mediated mechanisms are required. IGF‐2 may be responsible as IGF‐2 promoted metatarsal growth and Igf2 expression was elevated in Socs2‐/‐ (but not WT) metatarsals in response to GH. These studies emphasise the critical importance of SOCS2 in regulating GHs ability to promote bone growth. Also, GH appears to act directly on the metatarsals of Socs2‐/‐ mice, promoting growth via a mechanism that is independent of IGF‐1. J. Cell. Physiol. 9999: 2796–2806, 2015. © 2015 Wiley Periodicals, Inc. PMID:25833299

  2. 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

  3. Chondrocytes Directly Transform into Bone Cells in Mandibular Condyle Growth

    PubMed Central

    Jing, Y.; Zhou, X.; Han, X.; Jing, J.; von der Mark, K.; Wang, J.; de Crombrugghe, B.; Hinton, R.J.; Feng, J.Q.

    2015-01-01

    For decades, it has been widely accepted that hypertrophic chondrocytes undergo apoptosis prior to endochondral bone formation. However, very recent studies in long bone suggest that chondrocytes can directly transform into bone cells. Our initial in vivo characterization of condylar hypertrophic chondrocytes revealed modest numbers of apoptotic cells but high levels of antiapoptotic Bcl-2 expression, some dividing cells, and clear alkaline phosphatase activity (early bone marker). Ex vivo culture of newborn condylar cartilage on a chick chorioallantoic membrane showed that after 5 d the cells on the periphery of the explants had begun to express Col1 (bone marker). The cartilage-specific cell lineage–tracing approach in triple mice containing Rosa 26tdTomato (tracing marker), 2.3 Col1GFP (bone cell marker), and aggrecan CreERT2 (onetime tamoxifen induced) or Col10-Cre (activated from E14.5 throughout adult stage) demonstrated the direct transformation of chondrocytes into bone cells in vivo. This transformation was initiated at the inferior portion of the condylar cartilage, in contrast to the initial ossification site in long bone, which is in the center. Quantitative data from the Col10-Cre compound mice showed that hypertrophic chondrocytes contributed to ~80% of bone cells in subchondral bone, ~70% in a somewhat more inferior region, and ~40% in the most inferior part of the condylar neck (n = 4, P < 0.01 for differences among regions). This multipronged approach clearly demonstrates that a majority of chondrocytes in the fibrocartilaginous condylar cartilage, similar to hyaline cartilage in long bones, directly transform into bone cells during endochondral bone formation. Moreover, ossification is initiated from the inferior portion of mandibular condylar cartilage with expansion in one direction. PMID:26341973

  4. Overcoming Therapeutic Resistance of Bone Sarcomas: Overview of the Molecular Mechanisms and Therapeutic Targets for Bone Sarcoma Stem Cells

    PubMed Central

    Ozaki, Toshifumi

    2016-01-01

    Bone sarcomas are heterogeneous malignant tumors that exhibit clinical, histological, and molecular heterogeneity. Recent progress in their multimodal treatment has gradually improved patient prognosis; however, drug resistance and distant metastasis remain unresolved clinical problems. Recent investigations have suggested the existence of cancer stem-like cells (CSCs) in bone sarcomas, which represent a subpopulation of tumor cells with high tumor-forming ability. The hallmarks of CSCs include tumor- and metastasis-forming potential and drug resistance, which are responsible for poor prognoses of bone sarcoma patients. Therefore, elucidation of the molecular mechanisms of CSCs and identification of therapeutic targets could contribute to novel treatment strategies for bone sarcomas and improve patient prognosis. This paper provides an overview of the accumulating knowledge on bone sarcoma stem cells and preclinical analyses to overcome their lethal phenotypes, in addition to a discussion of their potential for novel therapeutics for bone sarcomas. PMID:28115942

  5. Modeling the Mechanical Consequences of Age-Related Trabecular Bone Loss by XFEM Simulation

    PubMed Central

    Fan, Ruoxun; Zhang, Xianbin; Liu, Jun; Jia, Zhengbin; Zhu, Dong

    2016-01-01

    The elderly are more likely to suffer from fracture because of age-related trabecular bone loss. Different bone loss locations and patterns have different effects on bone mechanical properties. Extended finite element method (XFEM) can simulate fracture process and was suited to investigate the effects of bone loss on trabecular bone. Age-related bone loss is indicated by trabecular thinning and loss and may occur at low-strain locations or other random sites. Accordingly, several ideal normal and aged trabecular bone models were created based on different bone loss locations and patterns; then, fracture processes from crack initiation to complete failure of these models were observed by XFEM; finally, the effects of different locations and patterns on trabecular bone were compared. Results indicated that bone loss occurring at low-strain locations was more detrimental to trabecular bone than that occurring at other random sites; meanwhile, the decrease in bone strength caused by trabecular loss was higher than that caused by trabecular thinning, and the effects of vertical trabecular loss on mechanical properties were more severe than horizontal trabecular loss. This study provided a numerical method to simulate trabecular bone fracture and distinguished different effects of the possible occurrence of bone loss locations and patterns on trabecular bone. PMID:27403206

  6. Modeling the Mechanical Consequences of Age-Related Trabecular Bone Loss by XFEM Simulation.

    PubMed

    Fan, Ruoxun; Gong, He; Zhang, Xianbin; Liu, Jun; Jia, Zhengbin; Zhu, Dong

    2016-01-01

    The elderly are more likely to suffer from fracture because of age-related trabecular bone loss. Different bone loss locations and patterns have different effects on bone mechanical properties. Extended finite element method (XFEM) can simulate fracture process and was suited to investigate the effects of bone loss on trabecular bone. Age-related bone loss is indicated by trabecular thinning and loss and may occur at low-strain locations or other random sites. Accordingly, several ideal normal and aged trabecular bone models were created based on different bone loss locations and patterns; then, fracture processes from crack initiation to complete failure of these models were observed by XFEM; finally, the effects of different locations and patterns on trabecular bone were compared. Results indicated that bone loss occurring at low-strain locations was more detrimental to trabecular bone than that occurring at other random sites; meanwhile, the decrease in bone strength caused by trabecular loss was higher than that caused by trabecular thinning, and the effects of vertical trabecular loss on mechanical properties were more severe than horizontal trabecular loss. This study provided a numerical method to simulate trabecular bone fracture and distinguished different effects of the possible occurrence of bone loss locations and patterns on trabecular bone.

  7. The mechanism of grain growth in ceramics

    NASA Technical Reports Server (NTRS)

    Kapadia, C. M.; Leipold, M. H.

    1972-01-01

    The theory of grain boundary migration as a thermally activated process is reviewed, the basic mechanisms in ceramics being the same as in metals. However, porosity and non-stochiometry in ceramic materials give an added dimension to the theory and make quantitative treatment of real systems rather complex. Grain growth is a result of several simultaneous (and sometimes interacting) processes; these are most easily discussed separately, but the overall rate depends on their interaction. Sufficient insight into the nature of rate controlling diffusion mechanisms is necessary before a qualitative understanding of boundary mobility can be developed.

  8. The in situ mechanics of trabecular bone marrow: the potential for mechanobiological response.

    PubMed

    Metzger, Thomas A; Kreipke, Tyler C; Vaughan, Ted J; McNamara, Laoise M; Niebur, Glen L

    2015-01-01

    Bone adapts to habitual loading through mechanobiological signaling. Osteocytes are the primary mechanical sensors in bone, upregulating osteogenic factors and downregulating osteoinhibitors, and recruiting osteoclasts to resorb bone in response to microdamage accumulation. However, most of the cell populations of the bone marrow niche,which are intimately involved with bone remodeling as the source of bone osteoblast and osteoclast progenitors, are also mechanosensitive. We hypothesized that the deformation of trabecular bone would impart mechanical stress within the entrapped bone marrow consistent with mechanostimulation of the constituent cells. Detailed fluid-structure interaction models of porcine femoral trabecular bone and bone marrow were created using tetrahedral finite element meshes. The marrow was allowed to flow freely within the bone pores, while the bone was compressed to 2000 or 3000 microstrain at the apparent level.Marrow properties were parametrically varied from a constant 400 mPas to a power law rule exceeding 85 Pas. Deformation generated almost no shear stress or pressure in the marrow for the low viscosity fluid, but exceeded 5 Pa when the higher viscosity models were used. The shear stress was higher when the strain rate increased and in higher volume fraction bone. The results demonstrate that cells within the trabecular bone marrow could be mechanically stimulated by bone deformation, depending on deformation rate, bone porosity, and bone marrow properties. Since the marrow contains many mechanosensitive cells, changes in the stimulatory levels may explain the alterations in bone marrow morphology with aging and disease, which may in turn affect the trabecular bone mechanobiology and adaptation.

  9. Correlating the nanoscale mechanical and chemical properties of knockout mice bones

    NASA Astrophysics Data System (ADS)

    Kavukcuoglu, Nadire Beril

    Bone is a mineral-organic composite where the organic matrix is mainly type I collagen plus small amounts of non-collagenous proteins including osteopontin (OPN), osteocalcin (OC) and fibrillin 2 (Fbn2). Mature bone undergoes remodeling continually so new bone is formed and old bone resorbed. Uncoupling between the bone resorption and bone formation causes an overall loss of bone mass and leads to diseases like osteoporosis and osteopenia. These are characterized by structural deterioration of the bone tissue and an increased risk of fracture. The non-collagenous bone proteins are known to have a role in regulating bone turnover and to affect the structural integrity of bone. OPN and OC play a key role in bone resorption and formation, while absence of Fbn-2 causes a connective tissue disorder (congenital contractural arachnodactyly) and has been associated with decreased bone mass. In this thesis nanoindentation and Raman-microspectroscopy techniques were used to investigate and correlate the mechanical and chemical properties of cortical femoral bones from OPN deficient (OPN-/-), OC deficient (OC-/-) and Fbn-2 deficient (Fbn2-/-) mice and their age, sex and background matched wild-type controls (OPN+/+, OC+/+ and Fbn2+/+). For OPN the hardness (H) and elastic modulus (E) of under 12 week OPN-/- bones were significantly lower than for OPN+/+ bones, but Raman showed no significant difference. Mechanical properties of bones from mice older than 12 weeks were not significantly different with genotype. However, mineralization and crystallinity from >50 week OPN-/- bones were significantly higher than for OPN+/+ bones. Mechanical properties of OPN-/- bones showed no variation with age, but mineralization, crystallinity and type-B carbonate substitution increased for both genotypes. For OC-/- intra-bone analyses showed that the hardness and crystallinity of the bones were significantly higher, especially in the mid-cortical sections, compared to OC+/+ bones. Fbn2

  10. Anisotropy in the compressive mechanical properties of bovine cortical bone and the mineral and protein constituents.

    PubMed

    Novitskaya, Ekaterina; Chen, Po-Yu; Lee, Steve; Castro-Ceseña, Ana; Hirata, Gustavo; Lubarda, Vlado A; McKittrick, Joanna

    2011-08-01

    The mechanical properties of fully demineralized, fully deproteinized and untreated cortical bovine femur bone were investigated by compression testing in three anatomical directions (longitudinal, radial and transverse). The weighted sum of the stress-strain curves of the treated bones was far lower than that of the untreated bone, indicating a strong molecular and/or mechanical interaction between the collagen matrix and the mineral phase. Demineralization and deproteinization of the bone demonstrated that contiguous, stand-alone structures result, showing that bone can be considered an interpenetrating composite material. Structural features of the samples from all groups were studied by optical and scanning electron microscopy. Anisotropic mechanical properties were observed: the radial direction was found to be the strongest for untreated bone, while the longitudinal one was found to be the strongest for deproteinized and demineralized bones. A possible explanation for this phenomenon is the difference in bone microstructure in the radial and longitudinal directions.

  11. Trabecular bone recovers from mechanical unloading primarily by restoring its mechanical function rather than its morphology.

    PubMed

    Ozcivici, Engin; Judex, Stefan

    2014-10-01

    Upon returning to normal ambulatory activities, the recovery of trabecular bone lost during unloading is limited. Here, using a mouse population that displayed a large range of skeletal susceptibility to unloading and reambulation, we tested the impact of changes in trabecular bone morphology during unloading and reambulation on its simulated mechanical properties. Female adult mice from a double cross of BALB/cByJ and C3H/HeJ strains (n=352) underwent 3wk of hindlimb unloading followed by 3wk of reambulation. Normally ambulating mice served as controls (n=30). As quantified longitudinally by in vivo μCT, unloading led to an average loss of 43% of trabecular bone volume fraction (BV/TV) in the distal femur. Finite element models of the μCT tomographies showed that deterioration of the trabecular structure raised trabecular peak Von-Mises (PVM) stresses on average by 27%, indicating a significant increase in the risk of mechanical failure compared to baseline. Further, skewness of the Von-Mises stress distributions (SVM) increased by 104% with unloading, indicating that the trabecular structure became inefficient in resisting the applied load. During reambulation, bone of experimental mice recovered on average only 10% of its lost BV/TV. Even though the addition of trabecular tissue was small during reambulation, PVM and SVM as indicators of risk of mechanical failure decreased by 56% and 57%, respectively. Large individual differences in the response of trabecular bone, together with a large sample size, facilitated stratification of experimental mice based on the level of recovery. As a fraction of all mice, 66% of the population showed some degree of recovery in BV/TV while in 89% and 87% of all mice, PVM and SVM decreased during reambulation, respectively. At the end of the reambulation phase, only 8% of the population recovered half of the unloading induced losses in BV/TV while 50% and 49% of the population recovered half of the unloading induced

  12. Transplanted bone marrow mononuclear cells and MSCs impart clinical benefit to children with osteogenesis imperfecta through different mechanisms.

    PubMed

    Otsuru, Satoru; Gordon, Patricia L; Shimono, Kengo; Jethva, Reena; Marino, Roberta; Phillips, Charlotte L; Hofmann, Ted J; Veronesi, Elena; Dominici, Massimo; Iwamoto, Masahiro; Horwitz, Edwin M

    2012-08-30

    Transplantation of whole bone marrow (BMT) as well as ex vivo-expanded mesenchymal stromal cells (MSCs) leads to striking clinical benefits in children with osteogenesis imperfecta (OI); however, the underlying mechanism of these cell therapies has not been elucidated. Here, we show that non-(plastic)-adherent bone marrow cells (NABMCs) are more potent osteoprogenitors than MSCs in mice. Translating these findings to the clinic, a T cell-depleted marrow mononuclear cell boost (> 99.99% NABMC) given to children with OI who had previously undergone BMT resulted in marked growth acceleration in a subset of patients, unambiguously indicating the therapeutic potential of bone marrow cells for these patients. Then, in a murine model of OI, we demonstrated that as the donor NABMCs differentiate to osteoblasts, they contribute normal collagen to the bone matrix. In contrast, MSCs do not substantially engraft in bone, but secrete a soluble mediator that indirectly stimulates growth, data which provide the underlying mechanism of our prior clinical trial of MSC therapy for children with OI. Collectively, our data indicate that both NABMCs and MSCs constitute effective cell therapy for OI, but exert their clinical impact by different, complementary mechanisms. The study is registered at www.clinicaltrials.gov as NCT00187018.

  13. Bone grafts and growth and differentiation factors for regenerative therapy: a review.

    PubMed

    Rose, L F; Rosenberg, E

    2001-01-01

    Guided bone regeneration, tissue grafts, regenerative barrier membranes, and bone substitute materials have been used to restore inadequate hard and soft tissue structures to make them conducive to proper implant placement. Polypeptide growth and development factors (GDFs) have successfully been applied exogenously to periodontal defects to attract preosteoblasts to the site and accelerate their proliferation to stimulate angiogenesis. This article provides an overview of current modalities for restoring lost bone and soft tissue during the treatment of periodontal disease.

  14. Hepatocyte Growth Factor and Interleukin-6 in Prostate Cancer Bone Metastasis

    DTIC Science & Technology

    2006-06-01

    LHRH agonist on the bone marrow environment. Another strategy of reducing androgen levels is by the downregulation of GnRH receptors in the...Interleukin-6 in Prostate Cancer Bone Metastasis PRINCIPAL INVESTIGATOR: Beatrice S. Knudsen, M.D., Ph.D. CONTRACTING ORGANIZATION...Growth Factor and Interleukin-6 in Prostate Cancer Bone Metastasis 5a. CONTRACT NUMBER 5b. GRANT NUMBER DAMD17-02-1-0159 5c. PROGRAM ELEMENT

  15. Treatment of through-and-through bone lesion using autologous growth factors and xenogeneic bone graft: a case report.

    PubMed

    Taschieri, Silvio; Rosano, Gabriele; Weinstein, Tommaso; Bortolin, Monica; Del Fabbro, Massimo

    2012-03-01

    This pilot case study aimed at evaluating the possibility of achieving optimal hard and soft tissue regeneration using plasma rich in growth factors (PRGF) and anorganic bovine bone (ABB) for the surgical treatment of a large through-and-through periapical bone lesion. Maxillary incisors of a patient with through-and-through periapical lesion of endodontic origin were treated using modern endodontic surgical technique with the adjunct of PRGF. The PRGF clot was positioned over the palatal side of the lesion while the remaining bone defect was grafted with PRGF and ABB. A collagen membrane embedded with plasma very rich in growth factors covered the graft. Post-operative pain and swelling were negligible, and soft tissue healing was very fast. One-year clinical and radiographic outcome showed complete healing and functionality. The addition of PRGF to ABB could improve the regenerative process, reducing postoperative symptoms and resulting in a fast and predictable hard and soft tissue healing.

  16. Alteration of proteoglycan sulfation affects bone growth and remodeling.

    PubMed

    Gualeni, Benedetta; de Vernejoul, Marie-Christine; Marty-Morieux, Caroline; De Leonardis, Fabio; Franchi, Marco; Monti, Luca; Forlino, Antonella; Houillier, Pascal; Rossi, Antonio; Geoffroy, Valerie

    2013-05-01

    Diastrophic dysplasia (DTD) is a chondrodysplasia caused by mutations in the SLC26A2 gene, leading to reduced intracellular sulfate pool in chondrocytes, osteoblasts and fibroblasts. Hence, proteoglycans are undersulfated in the cartilage and bone of DTD patients. To characterize the bone phenotype of this skeletal dysplasia we used the Slc26a2 knock-in mouse (dtd mouse), that was previously validated as an animal model of DTD in humans. X-rays, bone densitometry, static and dynamic histomorphometry, and in vitro studies revealed a primary bone defect in the dtd mouse model. We showed in vivo that this primary bone defect in dtd mice is due to decreased bone accrual associated with a decreased trabecular and periosteal appositional rate at the cell level in one month-old mice. Although the osteoclast number evaluated by histomorphometry was not different in dtd compared to wild-type mice, urine analysis of deoxypyridinoline cross-links and serum levels of type I collagen C-terminal telopeptides showed a higher resorption rate in dtd mice compared to wild-type littermates. Electron microscopy studies showed that collagen fibrils in bone were thinner and less organized in dtd compared to wild-type mice. These data suggest that the low bone mass observed in mutant mice could possibly be linked to the different bone matrix compositions/organizations in dtd mice triggering changes in osteoblast and osteoclast activities. Overall, these results suggest that proteoglycan undersulfation not only affects the properties of hyaline cartilage, but can also lead to unbalanced bone modeling and remodeling activities, demonstrating the importance of proteoglycan sulfation in bone homeostasis.

  17. Alteration of proteoglycan sulfation affects bone growth and remodeling

    PubMed Central

    Gualeni, Benedetta; de Vernejoul, Marie-Christine; Marty-Morieux, Caroline; De Leonardis, Fabio; Franchi, Marco; Monti, Luca; Forlino, Antonella; Houillier, Pascal; Rossi, Antonio; Geoffroy, Valerie

    2013-01-01

    Diastrophic dysplasia (DTD) is a chondrodysplasia caused by mutations in the SLC26A2 gene, leading to reduced intracellular sulfate pool in chondrocytes, osteoblasts and fibroblasts. Hence, proteoglycans are undersulfated in the cartilage and bone of DTD patients. To characterize the bone phenotype of this skeletal dysplasia we used the Slc26a2 knock-in mouse (dtd mouse), that was previously validated as an animal model of DTD in humans. X-rays, bone densitometry, static and dynamic histomorphometry, and in vitro studies revealed a primary bone defect in the dtd mouse model. We showed in vivo that this primary bone defect in dtd mice is due to decreased bone accrual associated with a decreased trabecular and periosteal appositional rate at the cell level in one month-old mice. Although the osteoclast number evaluated by histomorphometry was not different in dtd compared to wild-type mice, urine analysis of deoxypyridinoline cross-links and serum levels of type I collagen C-terminal telopeptides showed a higher resorption rate in dtd mice compared to wild-type littermates. Electron microscopy studies showed that collagen fibrils in bone were thinner and less organized in dtd compared to wild-type mice. These data suggest that the low bone mass observed in mutant mice could possibly be linked to the different bone matrix compositions/organizations in dtd mice triggering changes in osteoblast and osteoclast activities. Overall, these results suggest that proteoglycan undersulfation not only affects the properties of hyaline cartilage, but can also lead to unbalanced bone modeling and remodeling activities, demonstrating the importance of proteoglycan sulfation in bone homeostasis. PMID:23369989

  18. 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

  19. Mechanical growth and morphogenesis of seashells.

    PubMed

    Moulton, D E; Goriely, A; Chirat, R

    2012-10-21

    Seashells grow through the local deposition of mass along the aperture. Many mathematical descriptions of the shapes of shells have been provided over the years, and the basic logarithmic coiling seen in mollusks can be simulated with few parameters. However, the developmental mechanisms underlying shell coiling are largely not understood and the ubiquitous presence of ornamentation such as ribs, tubercles, or spines presents yet another level of difficulty. Here we develop a general model for shell growth based entirely on the local geometry and mechanics of the aperture and mantle. This local description enables us to efficiently describe both arbitrary growth velocities and the evolution of the shell aperture itself. We demonstrate how most shells can be simulated within this framework. We then turn to the mechanics underlying the shell morphogenesis, and develop models for the evolution of the aperture. We demonstrate that the elastic response of the mantle during shell deposition provides a natural mechanism for the formation of three-dimensional ornamentation in shells.

  20. Effects of Decreased Occlusal Loading during Growth on the Mandibular Bone Characteristics

    PubMed Central

    Hichijo, Natsuko; Tanaka, Eiji; Kawai, Nobuhiko; van Ruijven, Leo J.; Langenbach, Geerling E. J.

    2015-01-01

    Background Bone mass and mineralization are largely influenced by loading. The purpose of this study was to evaluate the reaction of the entire mandibular bone in response to decreased load during growth. It is hypothesized that decreased muscular loading will lead to bone changes as seen during disuse, i.e. loss of bone mass. Methods and Findings Ten 21-day-old Wistar strain male rats were divided into two groups (each n=5) and fed on either a hard- or soft-diet for 11 weeks. Micro-computed tomography was used for the investigation of bone mineralization, bone volume, bone volume fraction (BV/TV) and morphological analysis. Mandibular mineralization patterns were very consistent, showing a lower degree of mineralization in the ramus than in the corpus. In the soft-diet group, mineralization below the molars was significantly increased (p<0.05) compared to the hard diet group. Also, bone volume and BV/TV of the condyle and the masseter attachment were decreased in the soft-diet group (p<0.05). Morphological analysis showed inhibited growth of the ramus in the soft-diet group (p<0.05). Conclusion Decreased loading by a soft diet causes significant changes in the mandible. However, these changes are very region-specific, probably depending on the alterations in the local loading regime. The results suggest that muscle activity during growth is very important for bone quality and morphology. PMID:26062027

  1. Endochondral growth in growth plates of three species at two anatomical locations modulated by mechanical compression and tension.

    PubMed

    Stokes, Ian A F; Aronsson, David D; Dimock, Abigail N; Cortright, Valerie; Beck, Samantha

    2006-06-01

    Sustained mechanical loading alters longitudinal growth of bones, and this growth sensitivity to load has been implicated in progression of skeletal deformities during growth. The objective of this study was to quantify the relationship between altered growth and different magnitudes of sustained altered stress in a diverse set of nonhuman growth plates. The sensitivity of endochondral growth to differing magnitudes of sustained compression or distraction stress was measured in growth plates of three species of immature animals (rats, rabbits, calves) at two anatomical locations (caudal vertebra and proximal tibia) with two different ages of rats and rabbits. An external loading apparatus was applied for 8 days, and growth was measured as the distance between fluorescent markers administered 24 and 48 h prior to euthanasia. An apparently linear relationship between stress and percentage growth modulation (percent difference between loaded and control growth plates) was found, with distraction accelerating growth and compression slowing growth. The growth-rate sensitivity to stress was between 9.2 and 23.9% per 0.1 MPa for different growth plates and averaged 17.1% per 0.1 MPa. The growth-rate sensitivity to stress differed between vertebrae and the proximal tibia (15 and 18.6% per 0.1 MPa, respectively). The range of control growth rates of different growth plates was large (30 microns/day for rat vertebrae to 366 microns/day for rabbit proximal tibia). The relatively small differences in growth-rate sensitivity to stress for a diverse set of growth plates suggest that these results might be generalized to other growth plates, including human. These data may be applicable to planning the management of progressive deformities in patients having residual growth.

  2. ENDOCHONDRAL GROWTH IN GROWTH PLATES OF THREE SPECIES AT TWO ANATOMICAL LOCATIONS MODULATED BY MECHANICAL COMPRESSION AND TENSION

    PubMed Central

    Stokes, Ian A.F.; Aronsson, David D.; Dimock, Abigail N.; Cortright, Valerie; Beck., Samantha

    2006-01-01

    SUMMARY Purpose Sustained mechanical loading alters longitudinal growth of bones, and this growth sensitivity to load has been implicated in progression of skeletal deformities during growth. The objective of this study was to quantify the relationship between altered growth and different magnitudes of sustained altered stress in a diverse set of non-human growth plates. Methods The sensitivity of endochondral growth to differing magnitudes of sustained compression or distraction stress was measured in growth plates of three species of immature animals (rats, rabbits, calves) at two anatomical locations (caudal vertebra and proximal tibia) with two different ages of rats and rabbits. An external loading apparatus was applied for eight days and growth was measured as the distance between fluorescent markers administered 24 and 48 hours prior to euthanasia. Results An apparently linear relationship between stress and percentage growth modulation (percent difference between loaded and control growth plates) was found, with distraction accelerating growth and compression slowing growth. The growth-rate sensitivity to stress was between 9.2 and 23.9% per 0.1 MPa for different growth plates, and averaged 17.1% per 0.1 MPa. The growth-rate sensitivity to stress differed between vertebrae and the proximal tibia (15 and 18.6 percent per 0.1 MPa respectively). The range of control growth rates of different growth plates was large (30 microns/day for rat vertebrae to 366 microns/day for rabbit proximal tibia). Conclusions The relatively small differences in growth-rate sensitivity to stress for a diverse set of growth plates suggests that these results might be generalized to other growth plates, including human. These data may be applicable to planning the management of progressive deformities in patients having residual growth. PMID:16705695

  3. 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...

  4. Reduced mechanical load decreases the density, stiffness, and strength of cancellous bone of the mandibular condyle.

    PubMed

    Giesen, E B W; Ding, M; Dalstra, M; van Eijden, T M G J

    2003-05-01

    To investigate the influence of decreased mechanical loading on the density and mechanical properties of the cancellous bone of the human mandibular condyle. Destructive compressive mechanical tests were performed on cancellous bone specimens.Background. Reduced masticatory function in edentate people leads to a reduction of forces acting on the mandible. As bone reacts to its mechanical environment a change in its material properties can be expected. Cylindrical bone specimens were obtained from dentate and edentate embalmed cadavers. Mechanical parameters were determined in the axial and in the transverse directions. Subsequently, density parameters were determined according to a method based on Archimedes' principle. The apparent density and volume fraction of the bone were about 18% lower in the edentate group; no age-related effect on density was found. The decrease of bone in the edentate group was associated with a lower stiffness and strength (about 22% and 28%, respectively). The ultimate strain, however, did not differ between the two groups. Both groups had similar mechanical anisotropy; in axial loading the bone was stiffer and stronger than in transverse loading. Reduced mechanical load had affected the density and herewith the mechanical properties of condylar cancellous bone, but not its anisotropy. The change in material properties of the cancellous bone after loss of teeth indicate that the mandibular condyle is sensitive for changes in its mechanical environment. Therefore, changes in mechanical loading of the condyle have to be accounted for in surgical procedures of the mandible.

  5. Insulin-like growth factor I is required for the anabolic actions of parathyroid hormone on mouse bone

    NASA Technical Reports Server (NTRS)

    Bikle, Daniel D.; Sakata, Takeshi; Leary, Colin; Elalieh, Hashem; Ginzinger, David; Rosen, Clifford J.; Beamer, Wesley; Majumdar, Sharmila; Halloran, Bernard P.

    2002-01-01

    Parathyroid hormone (PTH) is a potent anabolic agent for bone, but the mechanism(s) by which it works remains imperfectly understood. Previous studies have indicated that PTH stimulates insulin-like growth factor (IGF) I production, but it remains uncertain whether IGF-I mediates some or all of the skeletal actions of PTH. To address this question, we examined the skeletal response to PTH in IGF-I-deficient (knockout [k/o]) mice. These mice and their normal littermates (NLMs) were given daily injections of PTH (80 microg/kg) or vehicle for 2 weeks after which their tibias were examined for fat-free weight (FFW), bone mineral content, bone structure, and bone formation rate (BFR), and their femurs were assessed for mRNA levels of osteoblast differentiation markers. In wild-type mice, PTH increased FFW, periosteal BFR, and cortical thickness (C.Th) of the proximal tibia while reducing trabecular bone volume (BV); these responses were not seen in the k/o mice. The k/o mice had normal mRNA levels of the PTH receptor and increased mRNA levels of the IGF-I receptor but markedly reduced basal mRNA levels of the osteoblast markers. Surprisingly, these mRNAs in the k/o bones increased several-fold more in response to PTH than the mRNAs in the bones from their wild-type littermates. These results indicate that IGF-I is required for the anabolic actions of PTH on bone formation, but the defect lies distal to the initial response of the osteoblast to PTH.

  6. Insulin-like growth factor I is required for the anabolic actions of parathyroid hormone on mouse bone

    NASA Technical Reports Server (NTRS)

    Bikle, Daniel D.; Sakata, Takeshi; Leary, Colin; Elalieh, Hashem; Ginzinger, David; Rosen, Clifford J.; Beamer, Wesley; Majumdar, Sharmila; Halloran, Bernard P.

    2002-01-01

    Parathyroid hormone (PTH) is a potent anabolic agent for bone, but the mechanism(s) by which it works remains imperfectly understood. Previous studies have indicated that PTH stimulates insulin-like growth factor (IGF) I production, but it remains uncertain whether IGF-I mediates some or all of the skeletal actions of PTH. To address this question, we examined the skeletal response to PTH in IGF-I-deficient (knockout [k/o]) mice. These mice and their normal littermates (NLMs) were given daily injections of PTH (80 microg/kg) or vehicle for 2 weeks after which their tibias were examined for fat-free weight (FFW), bone mineral content, bone structure, and bone formation rate (BFR), and their femurs were assessed for mRNA levels of osteoblast differentiation markers. In wild-type mice, PTH increased FFW, periosteal BFR, and cortical thickness (C.Th) of the proximal tibia while reducing trabecular bone volume (BV); these responses were not seen in the k/o mice. The k/o mice had normal mRNA levels of the PTH receptor and increased mRNA levels of the IGF-I receptor but markedly reduced basal mRNA levels of the osteoblast markers. Surprisingly, these mRNAs in the k/o bones increased several-fold more in response to PTH than the mRNAs in the bones from their wild-type littermates. These results indicate that IGF-I is required for the anabolic actions of PTH on bone formation, but the defect lies distal to the initial response of the osteoblast to PTH.

  7. Fibroblast growth factor-21 restores insulin sensitivity but induces aberrant bone microstructure in obese insulin-resistant rats.

    PubMed

    Charoenphandhu, Narattaphol; Suntornsaratoon, Panan; Krishnamra, Nateetip; Sa-Nguanmoo, Piangkwan; Tanajak, Pongpun; Wang, Xiaojie; Liang, Guang; Li, Xiaokun; Jiang, Chao; Chattipakorn, Nipon; Chattipakorn, Siriporn

    2017-03-01

    Fibroblast growth factor (FGF)-21 is a potent endocrine factor that improves insulin resistance and obesity-associated metabolic disorders. However, concomitant activation of peroxisome proliferator-activated receptor-γ by FGF-21 makes bone susceptible to osteopenia and fragility fracture. Since an increase in body weight often induced adaptive change in bone by making it resistant to fracture, it was unclear whether FGF-21 would still induce bone defects in overweight rats. Therefore, the present study aimed to investigate bone microstructure and its mechanical properties in high fat diet (HF)-fed rats treated with 0.1 mg/kg/day FGF-21. Eighteen male rats were divided into two groups to receive either a normal diet or HF for 12 weeks. HF rats were then divided into two subgroups to receive either vehicle or FGF-21 for 4 weeks. The results showed that HF led to obesity, dyslipidemia and insulin resistance, as indicated by hyperinsulinemia with euglycemia. In HF rats, there was an increase in tibial yield displacement (an indicator of ability to be deformed without losing toughness, as determined by 3-point bending) without changes in tibial trabecular volumetric bone mineral density (vBMD) or cortical bone parameters, e.g., cortical thickness and bone area. FGF-21 treatment strongly improved the metabolic parameters and increased insulin sensitivity in HF rats. However, FGF-21-treated HF rats showed lower yield displacement, trabecular vBMD, trabecular bone volume, trabecular thickness, and osteoblast surface compared with vehicle-treated HF rats. These findings suggest that, despite being a potent antagonist of insulin resistance and visceral fat accumulation, FGF-21 is associated with bone defects in HF rats.