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At least 1,423 records · Page 79Linked to original sources
PubMed2003

IL-1beta induces and TGF-beta reduces vitamin D3-induced bone resorption in mouse calvarial bone cells.

Bone cells produce multiple growth factors and cytokines that have effects on bone metabolism and can be incorporated into the bone matrix. The present study was designed to extend these observations by examining the interactions between transforming growth factor-beta (TGF-beta) or interleukin-1beta (IL-1beta) and bone cells in a rat long bone culture model. IL-1beta regulates several activities of the osteoblast cells derived from rat long bone explants in vitro. IL-1beta stimulated cellular proliferation and the synthesis of prostaglandin E2 and plasminogen activator activity in the cultured cells in a dose-dependent manner. TGF-B is present in the bone matrix and potentially can be released during bone resorption. TGF-beta reduced basal bone resorption and inhibited vitamin D3 [1,25(OH)2D3]-induced bone resorption in rat long bone cells. These studies support the role of IL-1beta in the pathological modulation of bone cell metabolism, with regard to implication in the pathogenesis of osteoporosis by IL-1beta, and that TGF-beta is positively inhibiting the bone resorption.

Alkaline Phosphatase↗
PubMedDate not supplied

Biochemical characterization of matrix vesicles from bone and cartilage.

Extracellular matrix vesicles from bone and epiphyseal cartilage of femur and tibia of rats were isolated by collagenase digestion (crude vesicles) and further purified by sucrose gradient centrifugation. Fractions containing cells and membranes were also isolated from the two tissues. The alkaline and acid phosphatase and ATPase activities, as well as protein content of all fractions including crude and purified matrix vesicles, were assayed. The crude vesicles from both tissues demonstrated a high alkaline phosphatase specific activity (5-20 times higher than in the cell fraction). The total enzyme activities and protein content were significantly higher in all fractions from cartilage than those from bone. A major peak of alkaline phosphatase activity and protein content was obtained following the sucrose gradient centrifugation. The position of this peak was similar for both tissues. The specific activity of alkaline phosphatase of purified matrix vesicles was significantly higher in bone than in cartilage. The phosphatase activities from cartilage and bone showed a similar pH dependence and a similar response to metal ions. Of the metal ions tested (Na+, Mg2+, Zn2+, and Ca2+) only Zn2+ (at 5 mM concentration) inhibited significantly the alkaline phosphatase activity of purified matrix vesicles. The electrophoretic profile of purified matrix vesicles showed eight major protein bands common for both tissues. In addition, cartilage vesicles appeared to possess two peptides not found in bone.

Acid Phosphatase↗
PubMed1981

Appearance of fibronectin during the differentiation of cartilage, bone, and bone marrow.

Fibronectin has been localized by indirect immunofluorescence during the various phases of endochondral bone formation in response to subcutaneously implanted demineralized bone matrix. Its histologic appearance has been correlated with results of biosynthetic experiments. (a) The implanted collagenous bone matrix was coated with fibronectin before and during mesenchymal cell proliferation. (b) During proliferation of mesenchymal precursor cells, the newly synthesized extracellular matrix exhibited a fibrillar network of fibronectin. (c) During cartilage differentiation, the fibronectin in the extracellular matrix was apparently masked by proteoglycans, as judged by hyaluronidase treatment. (d) Differentiating chondrocytes exhibited a uniform distribution of fibronectin. (e) Fibronectin was present in a cottony array around osteoblasts during osteogenesis. (f) The developing hematopoietic colonies revealed fibronectin associated with them. Therefore, it appears that fibronectin is ubiquitous throughout the development of endochondral bone and bone marrow.

Animals↗
PubMed1982

Regulation of local differentiation of cartilage and bone by extracellular matrix: a cascade type mechanism.

The regenerative potential of the vertebrate skeletal system is well known. Normal cartilage and bone development can be mimicked by implantation of demineralized bone matrix, which induces bone formation locally. The sequential stages of the matrix-induced bone development and recent advances in the underlying biochemical mechanisms are described. The extracellular matrix components have chemotactic, mitogenic and differentiative activities. It would appear that a cascade type mechanism is operative during local differentiation of endochondral bone.

Animals↗
PubMed1985

Pathologic studies of the osteoporosis of Von Gierke's disease (glycogenosis 1a).

Pathologic and point count-morphometric studies of ribs, vertebrae, and iliac crests of 7 patients with Von Gierke's glycogenesis type Ia aged 5 months to 30 years were performed. The bone lesion is a pure osteoporosis (reduction in mass of bone matrix) with no evidences of significant physeal cartilage abnormality or of osteitis fibrosa or osteomalacia (reduced mineralization of bone matrix). The osteoporosis was already marked in the youngest patient studied (5 months). The discrepancy between normal and glycogen storage disease (GSD) bones increased progressively with age for ribs and was less severe for vertebrae. Available biochemical data give no indication of primary disturbance of calcium or phosphate metabolism, of parathyroid activity, or of vitamin D metabolism. Clinical data suggest that the osteoporosis of Von Gierke's disease is due to hypoglycemia or a metabolic sequela thereof, such as insulinopenia, but pathologic study of patients treated by newer techniques of maintaining euglycemia in GSD is needed.

Adult↗
PubMed1997

Bovine-derived bone protein as a bone graft substitute in a canine segmental defect model.

OBJECTIVES: To evaluate the efficacy of a bone graft substitute in healing of a segmental defect of a weight-bearing long bone. DESIGN: An established canine model was used to perform a blinded, prospective, randomized study of the performance of bone graft substitute implants. This performance was compared with that of an accepted treatment modality (autograft) in a paired fashion. SETTING: An accredited animal research facility. SUBJECTS AND INTERVENTION: Twenty-eight dogs underwent bilateral radial osteotomies with creation of a 2.5-centimeter defect. On one side, the defect in every dog was filled with autogenous cancellous bone graft (ABG). Contralateral defects received, in a blinded, randomized fashion, cylindrical implants of demineralized bone matrix (DBM) allograft or DBM plus a constant dose (3.0 milligrams) of bovine-derived bone protein (DBM + BP). The defects were stabilized by external fixation. Subjects underwent monthly radiographs and were killed at six, twelve, or twenty-four weeks. Regenerate bone was studied by biomechanical testing and histology. Six animals were studied to determine the dose-response characteristics of the protein preparation. Three received implants containing 0.3 milligram of BP (group 1) and three received 1.0 milligram of BP (group 2). These animals were killed at twelve weeks of follow-up. RESULTS: All twenty-eight ABG radii (100 percent) progressed to radiographic union, as did thirteen of thirteen (100 percent) DBM + BP radii compared with only four of fifteen (27 percent) of DBM radii. The difference between union rates was statistically significant (p < 0.05). Mean values for most biomechanical parameters of DBM + BP radii exceeded those of their contralateral ABG controls at twelve and twenty-four weeks, whereas those for DBM implants did not. Histology revealed microscopic evidence of normal bone healing in all ABG and DBM + BP radii, whereas most DBM radii demonstrated nonunions. In the dose-response arm of the study, six of six ABG radii (100 percent) achieved union; zero of three (0 percent) of group 1 and two of three (67 percent) of group 2 radii achieved grossly stable unions. Biomechanical testing was consistent with radiographic results, indicating that the 3.0-milligram dose was the most effective of those studied. CONCLUSIONS: The DBM + BP composite implants were more effective at healing critical-sized segmental defects than DBM alone in this canine model when a 3.0-milligram per implant dose of BP was used. Biomechanical and histologic properties of the regenerated bone formed by DBM + BP implants was comparable to that of cancellous autograft.

Animals↗
PubMed1998

Continuous administration of basic fibroblast growth factor (FGF-2) accelerates bone induction on rat calvaria--an application of a new drug delivery system.

Some studies have shown that locally applied basic fibroblast growth factor (FGF-2) enhances bone regeneration at a fracture site, while others have not been in agreement. We developed a new continuous FGF-2 delivery system designed to accelerate cytokine-induced new bone formation. A subperiosteal pocket was surgically formed in 36 eight-week-old male Wistar rats. The rats were administered 0, 1, 10, or 100 ng of FGF-2 contained in a collagen minipellet, mixed with allogeneic demineralized bone matrix in a dome-shaped Millipore filter and then placed into the pocket. New bone formation in the dome was evaluated at 2, 4, and 8 wks after placement. Soft x-ray radiographs disclosed an apparently larger radiopaque region in the 1-ng group at 4 wks compared with those in the other groups. Morphometrical analysis revealed that the new bone area in the 1-g group was significantly larger than that in the 0-g group (p<0.01). In the 100-ng FGF-2 group, new bone formation seemed suppressed. We concluded that continuous slow administration of a small amount of FGF-2 accelerates bone-derived osteogenic cytokine-induced new bone formation.

Animals↗
PubMed2003

Restoration of large bone defects using a hard-setting, injectable putty containing demineralized bone particles compared to cancellous autograft bone.

An injectable, hard-setting, calcium sulfate-based putty containing demineralized bone matrix particles (AlloMatrix II, Wright Medical Technology, Inc, Arlington, Tenn) was compared to autogenous cancellous bone graft to evaluate healing in a canine model. Area fraction of new bone, modulus of elasticity, and compressive strength of new bone were evaluated, as was radiographic and histologic healing. Bilateral defects were created in the proximal humeri, and each defect was implanted with either the putty or autogenous bone according to a randomized schedule. Dogs were euthanized at 6, 13, and 26 weeks. The area fraction, modulus of elasticity, and compressive strength of newly formed bone was not significantly different between the putty and autogenous bone at 6, 13, or 26 weeks. The putty had excellent handling characteristics, was biocompatible, and was as effective as autograft bone in achieving near complete bony restoration of a large, critical-sized defect.

Animals↗
PubMed1994

Transforming growth factor--alpha stimulates chemotaxis of osteoblasts and osteoblast-like cells in vitro.

Homeostatic turnover of bone is believed to be regulated in part by growth factors present in the surrounding environment. The first step during the bone formation process is the recruitment of osteoblasts from the surrounding intact bone to the resorption site. In this study, the effects of TGF-alpha on osteoblast chemotaxis was investigated. Cultures of rat osteoblasts and human osteoblast-like cells were examined for chemotaxis in response to increasing concentrations of TGF-alpha utilizing a modified Boyden Chamber technique. TGF-alpha stimulated a dose-dependent increase in chemotaxis by both cell populations. These results indicate that TGF-alpha may be playing an important role in the early stages of bone matrix regeneration by stimulating osteoblast chemotaxis.

Animals↗
PubMed2001

The metastasis-associated metalloproteinase stromelysin-3 is induced by transforming growth factor-beta in osteoblasts and fibroblasts.

Bone matrix serves as a reservoir of growth factors important in growth and tissue remodeling, and transforming growth factor-beta (TGF-beta) is abundant in bone matrix. Normal processes, such as remodeling, and pathological processes, such as osteolytic metastasis, cause the release of growth factors from the matrix, allowing them to influence the behavior of cells within their microenvironment. Breast cancer metastases frequently establish themselves in the bone compartment, often causing localized osteolysis. Stromelysin-3 is a matrix metalloproteinase associated with tumor metastases. Its expression in host tissues favors the homing and survival of malignant epithelial cells in early tumorigenesis by releasing and/or activating growth factors sequestered in the extracellular matrix. Osteoblasts express stromelysin-3, and Northern and Western blot analysis show that its messenger RNA and protein levels are increased by TGF-beta. Nuclear run-off assays demonstrate activation of gene transcription, and experiments using transcription inhibitors demonstrate stabilization of stromelysin-3 messenger RNA by TGF-beta. Importantly, TGFbeta induces stromelysin-3 in fibroblasts by similar mechanisms, indicating that it is likely to stimulate stromelysin-3 expression in breast stroma. Stimulation of stromelysin-3 expression by TGF-beta in fibroblasts and osteoblasts could play a role in the metastasis of breast cancer cells and their homing and survival in bone.

Animals↗
PubMed1994

Developing human lung and kidney are major sites for synthesis of bone morphogenetic protein-3 (osteogenin).

Bone morphogenetic protein-3 (BMP-3; osteogenin) is a member of the transforming growth factor-beta superfamily. We used human BMP-3 cDNA probes and a specific BMP-3 polyclonal peptide antibody to analyze BMP-3 expression and synthesis in human fetal and adult tissues. Northern blot hybridization revealed two mRNA species of 7 and 3 KB. High levels of BMP-3 mRNA were found in fetal lungs. By in situ hybridization, the BMP-3 transcripts were found in lung bronchial epithelium, straight collecting kidney tubules, intestinal mucosa, perichondrium, periosteum, and osteoblasts of human embryos of 6-14 weeks' gestation. Cellular BMP-3 immunostaining co-localized with the distribution of RNA. In addition, bone matrix showed intensive BMP-3 staining. These data suggest that although BMP-3 has been isolated from bone matrix, it may have additional regulatory roles in the morphogenesis and/or function of human lung, kidney, and intestine.

Adult↗
PubMed1996

Ultrastructural analysis of mineralized matrix from human osteoblastic cells: effect of tumor necrosis factor-alpha.

Recent work by a number of investigators has demonstrated that the process of bone matrix formation and mineralization is under the influence of growth factors and cytokines present in the local environment. Utilizing primary and established osteoblast cell culture systems, these studies have examined the regulation of bone matrix protein synthesis and deposition into the extracellular matrix (ECM) and subsequent mineralization. In previous studies, we have utilized the human osteoblastic cell line, HOS TE85, to study the effects of Tumor Necrosis Factor-alpha (TNF-alpha) on the regulation of matrix proteins and proteolytic function in monolayer cultures as well as during the development and calcification of ECM formed by HOS TE85 cells during extended culture. Our studies demonstrate that TNF-alpha inhibited formation and mineralization of nodules. In the study reported here, we evaluated the ultrastructural morphology of the cell-matrix complex formed by HOS TE85 cells in the presence and absence of TNF-alpha at selected time points during the matrix development process utilizing both transmission electron microscopy and light microscopy. In the presence of TNF-alpha, the cell-matrix complex does not develop normally, with a lack of organization and mineralization, when compared to untreated cells. The lack of mineralization appears to result from the lack of normal collagen fibril deposition and formation of an appropriate ECM essential for the mineralization process. These results support our previous observations that TNF-alpha inhibits HOS TE85 cells from forming a mineralizing ECM by inhibiting incorporation of collagen into the ECM and inducing the synthesis of proteolytic enzymes capable of degrading collagen in the ECM.

Calcification, Physiologic↗
PubMed1999

Evidence that conditionally immortalized human osteoblasts express an osteocalcin receptor.

Osteocalcin (OC) is an abundant noncollagenous bone matrix protein, yet its function is largely unknown. However, targeted ablation of two OC genes in mice lead to increased bone formation (Ducy et al. Nature 382:448-452; 1996). This implied that OC inhibits osteoblast activity, and that these cells express an OC receptor. In order to characterize the putative OC receptor, we used the Cytosensor microphysiometer to measure responses of a proliferative-stage, conditionally immortalized human osteoblast cell line (HOB-03-C5) to purified bovine OC (bOC). The Cytosensor measures a change in the extracellular acidification rate, which is primarily a measurement of metabolic activity. Treatment of the HOB cells for 5-60 sec with 0.17 micromol/L bOC generated a time-dependent, transient increase in the acidification rate that became optimal after 25 sec. Likewise, treatment of the cells for 25 sec with 0.021 to 1.9 micromol/L bOC caused a dose-dependent 70% increase in the acidification rate. Pre-treatment of the cells for 2 h with inhibitors of adenylyl cyclase, phospholipase C, and intracellular calcium release inhibited the response of the cells to bOC by 50%-100%, which suggested that the putative OC receptor was coupled to a G-protein. These observations from the Cytosensor were confirmed by measuring intracellular cyclic-adenosine monophosphate (cAMP) concentrations in response to bOC. Treatment of the cells for 10 min with bOC decreased basal cAMP levels by 65% in a dose-dependent manner with an IC50 of 0.22 microM. However, cotreatment of the cells with forskolin, which activates adenylyl cyclase, blunted this suppression. Moreover, pretreatment of the cells with pertussis toxin for 48 h, which inhibits G(alpha)i proteins, reversed the suppressive effects of bOC on cAMP production. Treatment of the HOB cells for 48 h with 0.19 to 1.5 micromol/L bOC caused a dose-dependent 40% decrease in alkaline phosphatase activity with an IC50 of 0.21 micromol/L, which suggested that OC may inhibit HOB activity. Finally, although the maturation stage, conditionally immortalized HOB-02-C1 cells also responded to bOC as measured by the Cytosensor, two osteosarcoma cell lines, SaOS-2 and ROS 17/2.8, exhibited a 5- to 10-fold lower response to the bone matrix protein, suggesting that the putative OC receptor was downregulated in these cells. However, all of these bone cell lines responded to parathyroid hormone treatment. In conclusion, these results provide evidence that the HOB cells express an OC receptor, and that this receptor appears to be coupled to a G(alpha)-protein.

Adenylate Cyclase Toxin↗
PubMed1992

Advances in osteogenin and related bone morphogenetic proteins in bone induction and repair.

Bone matrix is a repository of growth and differentiation factors as demonstrated by the induction of local cartilage and bone formation in rats. The bone inductive activity, termed osteogenin, can be dissociatively extracted, and it was isolated by heparin affinity, hydroxyapatite and molecular sieve chromatography. Osteogenin has been purified to homogeneity from bovine bone matrix and the sequences of several tryptic peptides have been determined. The sequences were similar to portions of the amino acid sequence deduced from the cDNA clone of bone morphogenetic protein-3 (BMP-3). The carboxyl-terminal quarter of osteogenin has sequence identity to the corresponding regions of two related proteins BMP-2A and BMP-2B. The bone inductive proteins are members of the TGF-beta superfamily, by virtue of the location of the highly conserved cysteines in their carboxyl-terminal region. Osteogenin and related BMPs initiate cartilage and bone formation in vivo. The study of the mechanism of action of these proteins will add considerable new information on the molecular signals controlling endochondral bone formation. In vitro data indicate that osteogenin stimulates the expression of the osteogenic and chondrogenic phenotypes. Our results demonstrate their profound influence on proteoglycan synthesis and degradation in bovine cartilage explant cultures. High affinity specific binding sites have been identified in both MC3T3 cells and articular chondrocytes. In vivo experiments demonstrate the efficacy of primate osteogenin in restoring large calvarial defects in adult baboons, establishing a primary role for osteogenin in therapeutic initiation and promotion of osteogenesis.

Bone Development↗
PubMed1979

Influence of magnesium depletion on matrix-induced endochondral bone formation.

The effect of magnesium deficiency on bone cell differentiation and bone formation was investigated using in vivo matrix-induced endochondral ossification as a test system. Demineralized bone matrix was implanted subcutaneously in young (35-day-old) male Long-Evans rats that had been fed a semisynthetic Mg-deficient diet (50 ppm Mg) for 7 days. Plasma Mg levels were reduced to 25-30% of control values at that time. Control rats were paired the same diet, supplemented to contain 1000 ppm Mg. The implants were harvested 7, 9, 11, 15, and 20 days after implantation and analyzed for Mg and Ca content, 45Ca incorporation, and alkaline phosphatase levels. At each stage, plaques (implants) removed from Mg-deficient rats showed retardation in cartilage and bone differentiation and matrix calcification. Magnesium content was markedly reduced when compared to the control plaques. Histological appearance of the matrix-induced plaques confirmed the retardation in bone development and mineralization suggested by the chemical indicators. Most marked was the virtual absence of bone marrow in 20-day-old plaques in Mg-depleted rats. These data show that bone cell differentiation can occur in a severely Mg-depleted environment, although the onset of mineralization and bone remodeling was delayed and bone marrow differentiation was impaired.

Alkaline Phosphatase↗
PubMed1999

Expression of the gene encoding the matrix gla protein by mature osteoblasts in human fracture non-unions.

BACKGROUND: Osteoblast phenotypic abnormality, namely the expression of collagen type III, has been shown previously in fracture non-union woven bone. AIMS: To investigate osteoblasts from fracture non-unions for evidence of gene expression of non-collagenous bone matrix proteins that have been implicated in mineralisation, namely matrix gla protein (MGP), osteonectin, osteopontin, and osteocalcin. MGP is a consistent component of bone matrix, but there are no reports of osteoblasts in the skeleton expressing the gene for MGP, and the site of synthesis of skeletal MGP (perhaps the liver) has yet to be determined. METHODS: Biopsies from normally healing human fractures and non-unions were examined by means of in situ hybridisation, using 35S labelled probes and autoradiography to disclose levels of gene expression. RESULTS: In normally healing fractures, mature osteoblasts on woven bone were negative for MGP mRNA, but positive for osteonectin, osteopontin, and osteocalcin mRNA molecules. In non-unions, osteoblasts displayed a novel phenotype: they were positive for MGP mRNA, in addition to osteonectin, osteopontin, and osteocalcin mRNA molecules. CONCLUSIONS: Mature osteoblasts in slowly healing fractures have an unusual phenotype: they express the gene encoding MGP, which indicates that control of osteoblast gene expression in non-unions is likely to be abnormal. This might be of importance in the pathogenesis of non-uniting human fractures, and is of current interest given the emerging status of MGP as an inhibitor of mineralisation.

1-Carboxyglutamic Acid↗
PubMed2006

Pamidronate does not adversely affect bone intrinsic material properties in children with osteogenesis imperfecta.

Cyclical intravenous pamidronate therapy increases bone mass in children with osteogenesis imperfecta (OI), but the effect on the intrinsic material properties of bone is unknown at present. Thus, a possible influence of pamidronate treatment on bone quality at the material level might negate the beneficial effects of the gain in bone mass and lead to bone fragility in the long term. In the present study, we used transiliac bone biopsy samples and assessed the intrinsic material properties of the bone tissue at the micron-level by combined backscattered electron imaging and nanoindentation. Paired iliac bone samples from 14 patients (age 3 to 17 years) with severe OI before and after 2.5 +/- 0.5 years (mean +/- SD) of pamidronate treatment as well as age-matched controls were examined. Bone histomorphometry was performed in all samples and confirmed an increase of bone mass in treated patients. Backscattered electron imaging was used to measure the weighted mean calcium content (Ca(Mean)), the most frequent calcium content (Ca(Peak)), the variation in mineralization (Ca(Width)) and the amount of lowly mineralized areas (Ca(Low)) that correspond to sites of primary mineralization. Nanoindentation was performed in a subgroup of 6 patients and 6 controls to determine hardness and elastic modulus. Compared to controls, untreated OI patients had a significantly higher degree of bone matrix mineralization (Ca(Peak) +7%, P < 0.001) and a strong reduction of Ca(Low) (-38%, P < 0.001) despite enhanced bone formation, as well as increased hardness (+21%, P < 0.01) and elastic modulus (+13%, P < 0.01). However, none of these parameters was significantly altered by the subsequent pamidronate treatment. This shows that OI bone is stiffer and more mineralized and that, despite the enhanced bone formation rate in these patients, areas of primary mineralization are hardly visible. We also conclude that pamidronate treatment in children with OI does not have an adverse effect on the intrinsic material properties of bone and, as a consequence, that a long-term administration of the drug might not increase brittleness and fragility of the bone matrix. The antifracture effectiveness of pamidronate treatment in OI, as shown in previous clinical studies, has to be explained by the increase of mainly cortical bone volume.

Adolescent↗