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PubMed2002

Activin A increases the bone mass of grafted bone in C3H/HeJ mice.

Activin A, a member of the TGF-b superfamily, is abundant in bone matrix, but little is known about its physiological role in bone metabolism. The present study was undertaken to determine whether topical activin A can increase the bone mass of isografted bone. The tibiae were bilaterally dissected from a donor C3H/HeJ mouse and transplanted subcutaneously in the dorsal region of a recipient mouse. One isografted tibia was topically infused for either 1, 2, 3, or 4 weeks with activin A, using an osmotic minipump at a dose of 0.02, 0.2, or 2 ng/hr. The other tibia was infused with 0.9% NaCl (control). The following results were obtained: (1) Topical activin A (2 ng/hr) stimulated periosteal bone formation after 2 or 3 weeks. The bone area in a standardized transverse section averaged 1.3 fold that in the control. (2) Numerous cuboidal or conical osteoblasts appeared on the surface of newly formed bone after the infusion of activin A for 2 or 3 weeks. Autoradiographic studies using 3H-proline revealed that the surface area of newly formed bone labelled with autoradiographic silver grains was greater in activin A-treated bone than in the control, suggesting an increased synthesis and secretion of collagen by osteoblasts. (3) Topical activin A increased the number of osteoclasts after 2 to 4 weeks. Furthermore, enhanced or increased bone resorption was observed in the projected anterior site of activin A-treated bone after 4 weeks. These results suggest that topical activin A increases the bone mass of isografted bone by increasing bone turnover.

Activins↗
PubMed1999

Contribution of genetically modified mouse models to the elucidation of bone physiology.

The development over the last few years of genetically modified mouse models has provided a wealth of new information on the intimate cellular mechanisms involved in bone physiology. This article reviews some of the new insights gained into non-collagenous bone proteins. The bone matrix is no longer viewed as a passive support for bone cells, but rather as a key factor in the regulation of cell recruitment, proliferation, and differentiation. Studies using genetically modified mouse models have demonstrated the central importance of transcription factors such as Cbfa1, c-Fos, and c-Src in the differentiation of osteoblasts or osteoclasts from bone marrow stem cells. They have also allowed to identify the main cytokines involved in the regulation of bone cell activities, particularly in estrogen-deprived individuals. A discussion is provided in this article of the studies that identified the main communication pathway between osteoblasts and osteoclasts, in which the mediators are osteoprotegerin and its ligand, and that demonstrated the central position of these two factors in the regulation of osteoclast differentiation and activity.

Animals↗
PubMed2005

[Impedance testing of compact bone tissue in hypokinetic rats].

The bioelectrical impedance method was used for determination of compact bone status in white rats after 28th days of strong hypokinesia. It was shown that the lowering of mechanical loading leads to disturbances in dielectric properties and changes in electrical impedance parameters. These disturbances had different direction and manifestation. It was distinguished the two typical variants of bone dielectric properties changes. The first variant was more characteristic for early stages of hypokinetic osteodestruction, the second variant was more characteristic for the fully development hypokinetic disturbances. It was determine a correlation between the changes in electrical impedance parameters and mane components of bone matrix. The results of this study show that hyperhydratation of bone tissue play important role in hypokinetic changes of bone dielectric properties. Electroimpedance method may be used for early diagnostic of bone state in clinic and experiments.

Animals↗
PubMedDate not supplied

Use of bovine bone graft and bone membrane in defects surgically created in the cranial vault of rabbits. Histologic comparative analysis.

PURPOSE: This study was proposed to analyze histologically the process of repairing bone defects created surgically in the cranial vaults of rabbits. MATERIALS AND METHODS: Thirty adult male rabbits (Oryctolagus cunilicus) received, under general anesthesia, bilateral parietal osteotomies by means of a 6-mm-diameter trephine. The bony defects were divided into 4 groups. In group 1 the defect did not receive any treatment; in group 2 the defect was filled with lyophilized bovine bone (Biograft); in group 3 it was filled with bovine bone and covered with a bone matrix membrane (Bioplate); in group 4 it was covered with a bone matrix membrane. Animals were sacrificed in 3 equal groups at 15, 30, and 60 days. The specimens were subjected to routine laboratory procedures to evaluate the degree of bone repair. RESULTS: After 60 days, new bone formation in group 2 was not satisfactory when compared to that of group 3. Large amounts of new bone formation in maturation were seen in group 3. In the defects covered with a membrane the results were similar to those of group 1 (i.e., the cavity was filled with fibrous connective tissue). The implanted bone and membranes were totally resorbed. DISCUSSION AND CONCLUSIONS: The use of a membrane served as a barrier against the migration of cells from the adjacent tissue and the bone graft/membrane preserved the cavity space, resulting in an enhanced osteogenic effect.

Animals↗
PubMed1997

Multiple extracellular signals promote osteoblast survival and apoptosis.

Programed cell death (PCD) or apoptosis is a naturally occurring cell suicide pathway induced in a variety of cell types. In many cases, PCD apparently arises as a result of competition for limiting amounts of survival signals. In this study, we have investigated the potential role of growth factors (GF), cytokines, and osteotropic hormones on osteoblast survival in vitro. Our results indicate that in the absence of any of these factors, osteoblasts rapidly undergo PCD, as determined by cell morphology, mitochondrial function, and nuclei fragmentation. Osteoblast survival was promoted by insulin-like growth factor I (IGF-I), IGF-II, insulin, and basic fibroblast growth factor (bFGF). Platelet-derived growth factor had no effect on osteoblast survival, but this GF potentiated the survival-promoting effects of IGF-I, IGF-II, and insulin. A similar effect occurred when bFGF was added in combination with either of the IGFs or insulin. The effects of the IGFs were blocked by alphaIR-3, an antibody to the type I IGF receptor, whereas the effects of insulin were only partially blocked. This antibody blocked the potentiating effects of platelet-derived growth factor on IGF-I-mediated osteoblast survival, but only partially blocked those of bFGF. Although a 100% survival of osteoblasts was seen in the presence of 2% FCS, the highest level attained by any of the above GF combinations was approximately 75%. The monocyte-derived factor, tumor necrosis factor-alpha (TNF alpha) was the only agent that enhanced PCD in this study. These results suggest that osteoblast survival is promoted by those GFs sequestrated in bone matrix and that the type I, but not the type II, IGF receptor is involved in the response. Our data also indicate that other unidentified GFs or components of the extracellular matrix may be involved in promoting osteoblast survival and that TNF alpha may abrogate their effects in vivo. We propose that these GFs may be released from bone matrix during phases of bone resorption and promote osteoblast survival, thereby playing an important role in bone remodeling, and that PCD induced by TNF alpha may contribute to the bone loss in inflammatory bone disease.

Animals↗
PubMed1998

Osteoblastic responses to TGF-beta during bone remodeling.

Bone remodeling depends on the spatial and temporal coupling of bone formation by osteoblasts and bone resorption by osteoclasts; however, the molecular basis of these inductive interactions is unknown. We have previously shown that osteoblastic overexpression of TGF-beta2 in transgenic mice deregulates bone remodeling and leads to an age-dependent loss of bone mass that resembles high-turnover osteoporosis in humans. This phenotype implicates TGF-beta2 as a physiological regulator of bone remodeling and raises the question of how this single secreted factor regulates the functions of osteoblasts and osteoclasts and coordinates their opposing activities in vivo. To gain insight into the physiological role of TGF-beta in bone remodeling, we have now characterized the responses of osteoblasts to TGF-beta in these transgenic mice. We took advantage of the ability of alendronate to specifically inhibit bone resorption, the lack of osteoclast activity in c-fos-/- mice, and a new transgenic mouse line that expresses a dominant-negative form of the type II TGF-beta receptor in osteoblasts. Our results show that TGF-beta directly increases the steady-state rate of osteoblastic differentiation from osteoprogenitor cell to terminally differentiated osteocyte and thereby increases the final density of osteocytes embedded within bone matrix. Mice overexpressing TGF-beta2 also have increased rates of bone matrix formation; however, this activity does not result from a direct effect of TGF-beta on osteoblasts, but is more likely a homeostatic response to the increase in bone resorption caused by TGF-beta. Lastly, we find that osteoclastic activity contributes to the TGF-beta-induced increase in osteoblast differentiation at sites of bone resorption. These results suggest that TGF-beta is a physiological regulator of osteoblast differentiation and acts as a central component of the coupling of bone formation to resorption during bone remodeling.

Alendronate↗
PubMed1996

Recent advances in the ultrastructural assessment of osteoclastic resorptive functions.

Ultrastructural enzyme and immunocytochemical studies have made great contributions to clarifying intriguing questions as to the actual role of osteoclastic ruffled borders in bone resorption. In the present study, vacuolar-type H(+)-ATPase and cysteine-proteinase (cathepsin) were localized in osteoclasts by means of light and electron microscopic immunocytochemistry. The specific immunoreactivity of vacuolar-type H(+)-ATPase was detected along the ruffled border membranes, associated pale vacuoles, and cisterns of the rough-surfaced endoplasmic reticulum of osteoclasts. Anti-cathepsin B immunoreaction occurred in Golgi vesicles, lysosomes, pale vesicles and vacuoles, and the extracellular canals of ruffled borders of osteoclasts. The resorbing bone surfaces were also immunoreactive for anti-cathepsin B. In a coculture system of osteoclasts with devitalized dentine slices, a specific H(+)-ATPase inhibitor (bafilomycin A1) markedly reduced both demineralized areas and resorption lacuna formation on the dentine slices. On the other hand, the cathepsin inhibitor, E-64, inhibited only resorption lacuna formation but had no effect on demineralization of the dentine slices. These results suggest that H(+)-ATPase and cathepsins in osteoclasts are involved, respectively, in the extracellular solubilization of apatite crystals and subsequent degradation of bone matrix and that the ruffled border-clear zone complex of osteoclasts is the main site of cell-matrix interactions during bone resorption processes.

Animals↗
PubMed2000

A role for TGFbeta(1) in osteoclast differentiation and survival.

Recently, tumour necrosis factor-related activation-induced cytokine (TRANCE) was shown to be necessary for osteoclast formation. We now report that TGF(beta), a cytokine enriched in bone matrix, is also required. TGF(beta) not only powerfully synergized with TRANCE for induction of osteoclast-like cells (OCL) from bone marrow precursors and monocytes, but OCL formation was abolished by recombinant soluble TGF(beta) receptor II (TGF(beta)sRII). Preincubation in TGF(beta) was as effective as simultaneous incubation with TRANCE. TGF(beta)-preincubation enhanced OCL formation at least partly by preventing the development of resistance to OCL-induction that otherwise occurs when precursors are incubated in M-CSF. OCL formed in TRANCE also showed more rapid apoptosis than OCL in TRANCE plus TGF(beta). Like TGF(beta), incubation on bone matrix prolonged and enhanced the sensitivity of precursors to OCL-induction by TRANCE, and this was reversed by TGF(beta)sRII. Taken together, this data is compelling evidence for a model in which TGF(beta) in matrix or released from bone-lining or other cells maintains and enhances the osteoclast-forming potential of precursors as they migrate towards sites of cell-bound TRANCE. Thus, the specific circumstances necessary for osteoclast formation and survival are TRANCE expression on osteoblastic cells and TGF(beta) in bone.

Carrier Proteins↗
PubMed1990

Relationships between tooth eruption, occlusion and alveolar bone resorption: cytological and cytochemical studies of bone resorption on rat incisor alveolar bone facing the enamel.

The rat labial incisor alveolar bone facing the enamel and bearing the occlusal force was examined by electron microscopy after being compared with the lingual alveolar bone by histological and scanning electron microscopic (SEM) observations. On the labial side, shallow resorptive lacunae were recognized all over the bone surface; these were mainly covered by osteoclasts and some mononuclear cells. The cement line was absent from the bone matrix. On the lingual side, residues of Sharpey's fibers, the bone formation surface and deep resorptive lacunae were observed by SEM. Histologically, bone remodeling areas showing both osteoclasts and active bone-forming osteoblasts on the bone surface, as well as many cement lines in bone matrix, were recognized. Furthermore, electron microscopic and cytochemical studies demonstrated that mononuclear cells located close to osteoclasts displayed osteoblastic characteristics such as alkaline phosphatase activity, a developed Golgi apparatus, and a rough endoplasmic reticulum. These findings indicate that continuous bone resorption occurs on the labial bone surface, while active bone remodeling occurs on the lingual surface. Even on the labial surface, osteoblastic cells close to osteoclasts seem to play an important role in the differentiation and or activation of osteoclasts.

Acid Phosphatase↗
PubMed2000

Capacitively coupled electric fields accelerate proliferation of osteoblast-like primary cells and increase bone extracellular matrix formation in vitro.

Over the last few years, electric and electromagnetic fields have gained more and more significance in the therapy of bone fracture healing and bone disease. Yet, the underlying mechanisms on a cellular and molecular level are not completely understood. In the present study we have investigated the effects of capacitively coupled, pulsed electric fields on cellular proliferation, alkaline phosphatase activity, and matrix protein synthesis of osteoblast-like primary cells in vitro. Cells were derived from bovine periosteum and electrically stimulated by saw-tooth pulses of 100 V external voltage and 16 Hz frequency. This corresponds to an electric field of 6 kV/m across the cell membranes as could be shown by computer simulation. Field application caused acceleration of cell culture development. A significant increase of proliferation concurrent with an enhancement of alkaline phosphatase activity was observed in sub-confluent cultures. Exposure of confluent osteoblast-like primary cells to electric fields resulted in enhanced synthesis and secretion of extracellular matrix-related proteins. These findings suggest that capacitively coupled electric fields accelerate bone cell proliferation and differentiation in vitro and enhance the synthesis of cells leading to promoted matrix formation and maturation.

Alkaline Phosphatase↗
PubMed2004

A central role for the notochord in vertebral patterning.

The vertebrates are defined by their segmented vertebral column, and vertebral periodicity is thought to originate from embryonic segments, the somites. According to the widely accepted 'resegmentation' model, a single vertebra forms from the recombination of the anterior and posterior halves of two adjacent sclerotomes on both sides of the embryo. Although there is supporting evidence for this model in amniotes, it remains uncertain whether it applies to all vertebrates. To explore this, we have investigated vertebral patterning in the zebrafish. Surprisingly, we find that vertebral bodies (centra) arise by secretion of bone matrix from the notochord rather than somites; centra do not form via a cartilage intermediate stage, nor do they contain osteoblasts. Moreover, isolated, cultured notochords secrete bone matrix in vitro, and ablation of notochord cells at segmentally reiterated positions in vivo prevents the formation of centra. Analysis of fss mutant embryos, in which sclerotome segmentation is disrupted, shows that whereas neural arch segmentation is also disrupted, centrum development proceeds normally. These findings suggest that the notochord plays a key, perhaps ancient, role in the segmental patterning of vertebrae.

Animals↗
PubMed1980

Abnormal bone histology in idiopathic hypercalciuria.

Bone histology was evaluated in iliac creast biopsies of 15 patients with idiopathic hypercalciuria of the hyperabsorptive type and recurrent calcium oxalate stone formation. The biopsies were studied using quantitative histomorphometric analysis of undecalcified sections and fluorescent microscopy after double tetracycline labeling. Uring calcium and cAMP excretion were measured under basal conditions and after oral administration of calcium phosphate. Absorptive hypercalciuria was defined as a urinary excretion of calcium of more than 15 meq/24 h and/or a urinary ratio of Ca to Cr of more than 0.2, with a fall in the Ca to Cr ratio of more than 40% after the administration of oral cellulose phosphate. Osteoclastic bone resorption was normal or low in all patients and did not show any recognizable correlation with urinary calcium or urinary cAMP. All but one of the patients showed an increase in the fraction of inactive osteoid. Total osteoid was increased in 60% of the patients. Osteoblastic activity was significantly lower in the patient than in the control subjects. The fraction of mineralizing osteoid seams (i.e. seams with a tetracycline double labeling pattern), was diminished in all patients and the mean rate of apposition of bone matrix was decreased. These findings point to a diminished amount of bone matrix produced by individual osteoblasts and to a delay or cessation of terminal (secondary) mineralization of osteoid seams.

Adult↗
PubMed2003

[Osteoporosis and cardiovascular disease--two sides of the same coin?].

BACKGROUND: Osteoporosis and cardiovascular disease have numerous epidemiologic changes, health economic consequences, and molecular mechanisms in common, which are highlighted in this short review. EPIDEMIOLOGY AND CLINICAL STUDIES: The incidence of osteoporosis and cardiovascular disease is increasing in western societies, and genetic background, nutrition and psychologic factors play important roles in the pathogenesis of both diseases. The presence of a decreased bone mass or osteoporotic vertebral fractures are associated with an increased cardiovascular mortality. Calcaneal bone loss of 1 SD (standard deviation) as measured by osteodensitometry is associated with a 1.31 times increased risk for the occurrence of stroke. MOLECULAR MECHANISMS: The observed increase in interleukin-6 and tumor necrosis factor serum concentrations during the menopause contributes to osteoporotic bone loss and is associated with arteriosclerosis. Furthermore, the presence of hydroxyapatite in arteriosclerotic plaques supports the notion of common pathogenetic mechanisms for both, osteoporosis and arteriosclerosis. Osteopontin, bone GLA protein and bone morphogenetic protein-2, which have first been isolated from the organic bone matrix, are also present in arteriosclerotic plaques. 1,25-dihydroxycholecalciferol potently stimulates bone matrix mineralization and is also a negative regulator of the renin-angiotensin system; therefore vitamin D(3) deficiency in addition to bone metabolism also affects blood pressure. Osteoporosis and arteriosclerosis develop in mice lacking the osteoprotegerin gene and also in klotho gene knockout mice. CONCLUSION: Diagnosis of osteopenia, osteoporosis and osteoporotic vertebral or hip fractures indicates the presence of an increased cardiovascular risk which needs to be addressed by the physician who cares for patients with osteoporosis. The experimental finding of an osteoanabolic effect of statins supports the possibility of common pathogenetic disturbances which may be responsible for the simultaneous and frequent manifestation of osteoporosis and arteriosclerosis in elderly patients.

Animals↗
PubMedDate not supplied

Measurement of microstructural strain in cortical bone.

It is well known that mechanical factors affect bone remodeling such that increased mechanical demand results in net bone formation, whereas decreased demand results in net bone resorption. Current theories suggest that bone modeling and remodeling is controlled at the cellular level through signals mediated by osteocytes. The objective of this study was to investigate how macroscopically applied bone strains similar in magnitude to those that occur in vivo are manifest at the microscopic level in the bone matrix. Using a digital image correlation strain measurement technique, experimentally determined bone matrix strains around osteocyte lacuna resulting from macroscopic strains of approximately 2,000 microstrain (0.2%) reach levels of over 30,000 microstrain (3%) over fifteen times greater than the applied macroscopic strain. Strain patterns were highly heterogeneous and in some locations similar to observed microdamage around osteocyte lacuna indicating the resulting strains may represent the precursors to microdamage. This information may lead to a better understanding of how bone cells are affected by whole bone functional loading.

Animals↗
PubMed2006

Coordinate regulation of fibronectin matrix assembly by the plasminogen activator system and vitronectin in human osteosarcoma cells.

BACKGROUND: Plasminogen activators are known to play a key role in the remodeling of bone matrix which occurs during tumor progression, bone metastasis and bone growth. Dysfunctional remodeling of bone matrix gives rise to the osteoblastic and osteolytic lesions seen in association with metastatic cancers. The molecular mechanisms responsible for the development of these lesions are not well understood. Studies were undertaken to address the role of the plasminogen activator system in the regulation of fibronectin matrix assembly in the osteoblast-like cell line, MG-63. RESULTS: Treatment of MG-63 cells with P25, a peptide ligand for uPAR, resulted in an increase in assembly of fibronectin matrix which was associated with an increase in the number of activated beta1 integrins on the cell surface. Overexpression of uPAR in MG-63 cells increased the effect of P25 on fibronectin matrix assembly and beta1 integrin activation. P25 had no effect on uPAR null fibroblasts, confirming a role for uPAR in this process. The addition of plasminogen activator inhibitor Type I (PAI-1) to cells increased the P25-induced fibronectin polymerization, as well as the number of activated integrins. This positive regulation of PAI-1 on fibronectin assembly was independent of PAI-1's anti-proteinase activity, but acted through PAI-1 binding to the somatomedin B domain of vitronectin. CONCLUSION: These results indicate that vitronectin modulates fibronectin matrix assembly in osteosarcoma cells through a novel mechanism involving cross-talk through the plasminogen activator system.

Journal Article↗
PubMed1990

Progressive development of the rat osteoblast phenotype in vitro: reciprocal relationships in expression of genes associated with osteoblast proliferation and differentiation during formation of the bone extracellular matrix.

The relationship of cell proliferation to the temporal expression of genes characterizing a developmental sequence associated with bone cell differentiation was examined in primary diploid cultures of fetal calvarial derived osteoblasts by the combined use of autoradiography, histochemistry, biochemistry, and mRNA assays of osteoblast cell growth and phenotypic genes. Modifications in gene expression define a developmental sequence that has 1) three principle periods--proliferation, extracellular matrix maturation, and mineralization--and 2) two restriction points to which the cells can progress but cannot pass without further signals--the first when proliferation is down-regulated and gene expression associated with extracellular matrix maturation is induced, and the second when mineralization occurs. Initially, actively proliferating cells, expressing cell cycle- and cell growth-regulated genes, produce a fibronectin/type I collagen extracellular matrix. A reciprocal and functionally coupled relationship between the decline in proliferative activity and the subsequent induction of genes associated with matrix maturation and mineralization is supported by 1) a temporal sequence of events in which there is an enhanced expression of alkaline phosphatase immediately following the proliferative period, and later, an increased expression of osteocalcin and osteopontin at the onset of mineralization; 2) increased expression of a specific subset of osteoblast phenotype markers, alkaline phosphatase and osteopontin, when proliferation is inhibited by hydroxyurea; and 3) enhanced levels of expression of the osteoblast markers as a function of ascorbic acid-induced collagen deposition, suggesting that the extracellular matrix contributes to both the shutdown of proliferation and the development of the osteoblast phenotype.

Alkaline Phosphatase↗
PubMed2004

Endogenous TGF-beta signaling suppresses maturation of osteoblastic mesenchymal cells.

Transforming growth factor-beta (TGF-beta), one of the most abundant cytokines in bone matrix, has positive and negative effects on bone formation, although the molecular mechanisms of these effects are not fully understood. Bone morphogenetic proteins (BMPs), members of the TGF-beta superfamily, induce bone formation in vitro and in vivo. Here, we show that osteoblastic differentiation of mouse C2C12 cells was greatly enhanced by the TGF-beta type I receptor kinase inhibitor SB431542. Endogenous TGF-beta was found to be highly active, and induced expression of inhibitory Smads during the maturation phase of osteoblastic differentiation induced by BMP-4. SB431542 suppressed endogenous TGF-beta signaling and repressed the expression of inhibitory Smads during this period, possibly leading to acceleration of BMP signaling. SB431542 also induced the production of alkaline phosphatase and bone sialoprotein, and matrix mineralization of human mesenchymal stem cells. Thus, signaling cross-talk between BMP and TGF-beta pathways plays a crucial role in the regulation of osteoblastic differentiation, and TGF-beta inhibitors may be invaluable for the treatment of various bone diseases by accelerating BMP-induced osteogenesis.

Animals↗