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Query: UMLS:C0005940 (bone disease)
 7,459 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The development of the skeleton requires the coordinated activities of bone-forming osteoblasts and bone-resorbing osteoclasts. The activities of these two cell types are likely to be regulated by TGF-beta, which is abundant in bone matrix. We have used transgenic mice to evaluate the role of TGF-beta 2 in bone development and turnover. Osteoblast-specific overexpression of TGF-beta 2 from the osteocalcin promoter resulted in progressive bone loss associated with increases in osteoblastic matrix deposition and osteoclastic bone resorption. This phenotype closely resembles the bone abnormalities seen in human hyperparathyroidism and osteoporosis. Furthermore, a high level of TGF-beta 2 overexpression resulted in defective bone mineralization and severe hypoplasia of the clavicles, a hallmark of the developmental disease cleidocranial dysplasia. Our results suggest that TGF-beta 2 functions as a local positive regulator of bone remodeling and that alterations in TGF-beta 2 synthesis by bone cells, or in their responsiveness to TGF-beta 2, may contribute to the pathogenesis of metabolic bone disease.
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PMID:Increased expression of TGF-beta 2 in osteoblasts results in an osteoporosis-like phenotype. 856 23

Congenital osteopetrosis in mammals is an inherited bone disease caused by aberrations in osteoclast development and/or function. Colony-stimulating factor-1 (CSF-1) promotes formation of osteoclasts and is produced by osteoblasts. Recently, two osteopetrotic mutations (op mouse and tl rat) have been shown to have reductions in CSF-1 activity, and CSF-1 injections improve the skeletal manifestations in each. Several different CSF-1 transcripts have been described in mouse and human soft tissues, and differential expression of CSF-1 transcripts has been documented. Thus, we compared gene expression for CSF-1 as reflected by mRNA levels in the bones of tl rats and op mice, and also two other osteopetrotic rat mutations (ia and op). In op mouse calvaria the 4.6 kb transcript was reduced while the 2.3 kb transcript was absent. However, no differences were detected in the levels of these transcripts in mutant and normal calvaria of tl stock. In contrast, CSF-1 transcript levels were elevated in op rat mutants and variable in ia mutants compared to normal littermates. Osteoblast cultures derived from neonatal animals of tl and op rat stock showed the same differences seen in calvarial bone in vivo. The mRNA expression of another growth factor, TGF-beta 1, paralleled that of CSF-1 in vivo and in vitro in the rat mutations. These data demonstrate the emerging molecular heterogeneity among osteopetrotic mutations and underscore the need to evaluate the contributions of these and other cytokines to osteoclast differentiation and function in each mutation.
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PMID:Heterogeneity of colony stimulating factor-1 gene expression in the skeleton of four osteopetrotic mutations in rats and mice. 859 94

Transgenic mice which express the simian virus 40 large T-antigen (Tag) under the regulatory control of the hormone responsive rat C3(1) gene develop unusual lesions of heterotopic bone growth associated with mixed tumor formation arising from eccrine sweat glands found only in the foot pads of mice, ischiocavernosus muscle adjacent to bulbourethral glands and occasionally the salivary and mammary glands. These lesions are very similar to mixed tumors arising in several types of human cancers. Based upon electron microscopic examination and immunocytochemical analyses of cellular differentiation markers, the mixed proliferative lesions in this transgenic mouse model begin with the Tag-induced proliferation of epithelial and myoepithelial cells. The proliferation of these two types of cells results in hyperplasia and adenomatous transformation of the epithelial component, whereas the proliferating myoepithelial cells undergo metaplasia to form chondrocytes which deposit extracellular matrix, including collagen fibers. Cartilage develops focally between areas of epithelial proliferation and subsequently ossifies through a process of endochondrial bone formation. The metaplasia of myoepithelial cells to chondrocytes appears to require the inductive interaction of factors produced by the closely associated proliferating epithelial cells, including members of the TGF-beta superfamily. We demonstrate that TGF-beta1 protein accumulates in the extracellular matrix of the lesions, whereas RNA in situ hybridization reveals that BMP-2, another strong inducer of heterotopic bone formation, is overexpressed by the proliferating epithelial cells during the development of ectopic bone. The formation of sarcomatous tumors within the mixed tumors appears to be androgen-dependent and more frequent in mice lacking a normal allele of p53. This process of cartilage and bone induction may mimic epithelial-mesenchymal interactions which occur during embryonic bone formation. These transgenic mice may provide new insights into the processes of ectopic endochondrial bone formation associated with mixed tumor formation and serve as a useful model for human heterotopic bone disease.
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PMID:Heterotopic endochondrial ossification with mixed tumor formation in C3(1)/Tag transgenic mice is associated with elevated TGF-beta1 and BMP-2 expression. 1049 97

Melorheostosis is a rare bone disease characterized by linear hyperostosis and associated soft tissue abnormalities. The skin overlying the involved bone lesion is often tense, shiny, erythematous, and scleodermatous. In order to look for genes differentially expressed between the normal and involved skin, we cultured skin fibroblasts from the skin lesions of several afflicted patients, and identified differentially expressed genes by reverse dot-blot hybridization. We found that the genes human TGF-beta-induced gene product (betaig-h3), osteoblast-specific factor 2, osteonectin, fibronectin, and type I collagen were all downregulated in the affected skin fibroblasts, with betaig-h3 the most significantly affected. The expression of betaig-h3 was induced by TGF-beta in both affected and normal fibroblasts. In an effort to determine the mechanism of bone and skin abnormalities in melorheostosis, we made recombinant betaig-h3. Both immobilized and soluble recombinant betaig-h3 proteins with or without an RGD motif inhibited bone nodule formation of osteoblasts in vitro. Taken together, our results suggest that altered expression of several adhesion proteins may contribute to the development of hyperostosis and concomitant soft tissue abnormalities of melorheostosis, with betaig-h3 in particular playing an important role in osteogenesis.
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PMID:A TGF-beta-inducible cell adhesion molecule, betaig-h3, is downregulated in melorheostosis and involved in osteogenesis. 1072 84

Myelomatous bone disease affects about 90% patients with multiple myeloma and solitary myeloma as well. In initial stage it is manifested as osteopenia with osteoporosis or osteolytic foci, pathologic fractures followed by neurologic complications. Ethiopathogenitically a role is played by cytokine interactions with local chemokines produced by myeloma cells and activated stromal and hemopoietic cells (osteoblasts, monocytes, macrophages) resp. From the TNF-alpha family glycoprotein complexes are liberated (RANK-L), which support activation and proliferation or are inhibitory (osteoprotegerins). Similarly in the family TGF-beta several izotypes of antiinflammatory cytokines are known (the most important is TGF-beta 1 and the morphogenetic protein-2), which have a fibrotizing effect in bones, because the produced osteoid is insufficiently mineralized. The effect is a pathologic remodelation of the skeleton. In the diagnosis of multiple myeloma the immunological knowledge is used in the initial diagnosis (immunophenotypization, follow up of TNF-alpha, TGF-beta 1, IL-1, IL-6 etc). Important are also biochemistry values of increased osteoresorption (changes of calcium, parathormone, excretion of collagen fission products, osteocalcin, the bone alkaline phosphatase). In the following part the authors inform about favourable results of long-term treatment with bisphosphonates (Bonefos, Ibandronate) in combination with anti-tumor chemotherapy in 364 patients. During a 15 years observation period median survival of 94 months with a 35% probability of 10 year survival was achieved with a significant decrease of bone complications in 58% compared to 14% in the placebo group.
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PMID:[Bone changes in multiple myeloma--current etiopathogenic, diagnostic and therapeutic aspects]. 1219 8

Four growth factors PDGF, bFGF, IGF-II and TGF-beta, which is believed to have biological effects on bone cells, were examined in this study. The aim was to assess the effects of combinations of three and four growth factors on the proliferation and differentiation of osteoblast-like cells. The incorporation of 3H-TdR, 3H-Proline of osteoblast-like cells and alkaline phosphatase content of the cells were tested. The results showed the combinations of three and four growth factors stimulated the synthesis of DNA, collagen and ALP of osteoblast-like cells. These four growth factors interacted synergistically. The combinations of three and four growth factors showed stronger promoting effect on osteoblast-like cells, compared with the combinations of two growth factors. These findings suggest that the combined use of growth factors be a potential way of bone defect reconstruction and treatment of human bone disease.
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PMID:[The effects of combined use of multiple growth factors on proliferation and differentiation of human osteoblast-like cells]. 1221 80

Transforming growth factor-beta1 (TGF-beta1) is secreted as a latent precursor, consisting of a homodimer of the latency-associated peptide and the mature peptide. TGFbeta-1 can only exert its many functions after going from this latent to an active state, in which the binding site of the mature peptide for its receptor is no longer shielded by the latency-associated peptide. We and others reported that mutations in TGFB1 cause Camurati-Engelmann disease, a rare bone disorder. Until now, seven mutations have been published. In this study, we investigate the effect of the LLL12-13ins, Y81H, R218C, H222D, and C225R mutations on the functioning of TGF-beta1 in vitro. A luciferase reporter assay specific for TGF-beta-induced transcriptional response with wild type and mutant TGF-beta1 constructs showed a positive effect of all mutations on TGF-beta1 activity. By way of enzyme-linked immunosorbent assay, we found that in the R218C, H222D, and C225R mutant constructs, this effect is caused by an increase in active TGF-beta1 in the medium of transfected cells. The LLL12-13ins and Y81H mutations on the contrary have a profound effect on secretion; a decreased amount of TGF-beta1 is secreted, but the increased luciferase activity shows that the intracellular accumulation of (aberrant) TGF-beta1 can initiate an enhanced transcriptional response, suggesting the existence of an alternative signaling pathway. Our data indicate that the mutations in the signal peptide and latency-associated peptide facilitate TGF-beta1 signaling, thus causing Camurati-Engelmann disease.
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PMID:Transforming growth factor-beta 1 mutations in Camurati-Engelmann disease lead to increased signaling by altering either activation or secretion of the mutant protein. 1249 41

The development of pharmaceutical treatments for bone disease can be enhanced by computational models that predict their effects on resorption and rates of remodeling. Therefore, a simple mathematical model was formulated to simulate erosion depth and duration of resorption, using Michaelis-Menten (M-M) equations to describe changing rates of cellular activity during the two phases of bone resorption. The model was based on histomorphometric data and cellular interactions that occur in the bone microenvironment cited from the literature. Availability of bone substrate for osteoclastic activity during Phase I was assumed to be limited by the ratio of RANKL (ligand for receptor activator for nuclear factor kappaB) to osteoprotegerin (OPG) ('effective RANKL'). The required presence of marrow stromal cell produced macrophage-colony stimulating factor (M-CSF) for osteoclast action was represented as a factor equal to 1 for healthy bone. Growth factors released from the matrix during Phase I were assumed to cause two negative feedback effects: (1) the inhibitory effect of transforming growth factor-beta1 (TGFbeta1)-induced production of OPG by marrow osteoblast stromal cells, reducing effective RANKL; (2) the apoptosis of osteoclast nuclei assumed to occur at high concentrations of TGFbeta. This signaled the end of Phase I. During Phase II, cellular activity to remove the collagen fibrils left behind by osteoclasts was also simulated by Michaelis-Menten kinetic equations. Results of sensitivity analysis revealed variation in resorption depth and duration to fluctuate within 6% and 7% of the baseline value for changes in most input parameters. However, resorption depth was reduced and the duration of resorption lengthened by both a decrease in matrix TGFbeta and an increase the apoptotic threshold. Furthermore, the duration of resorption, but not erosion depth, was sensitive to changes in the maximum rate of cellular activity during removal of collagen fibrils. This mathematical model, which simulates the changing rates of cellular activity, has identified factors that reduce the duration and depth of resorption. It also suggests new targets for modeling therapeutic intervention to slow the rate of bone remodeling.
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PMID:Sensitivity analysis of a novel mathematical model identifies factors determining bone resorption rates. 1545 99

betaig-h3 is an extracellular matrix (ECM) protein induced by TGF-beta, and it has motifs interacting with the alpha3beta1, alphavbeta5, and alphavbeta3 integrins. Our previous study shows the role of betaig-h3 in osteoblast differentiation and its involvement in melorheostosis, a rare bone disease. Here we demonstrate that betaig-h3 expression is down-regulated during the early stage of differentiation of the murine preosteoblastic cell line, KS483. The recombinant betaig-h3 and its FAS1 domain significantly inhibited in vitro osteoblast differentiation as evaluated by matrix mineralization/bone nodule formation. Furthermore, inhibition of expression of osteoblast differentiation marker genes [such as type I collagen, alkaline phosphatase, and osteocalcin (OC)] was accompanied by suppression of osteoblast-specific transcription factors, Cbfa1/Runx2 and osterix. Flow cytometric analyses, cell adhesion, and inhibition assays disclosed alphavbeta3 and alphavbeta5 as the principal integrins mediating the adhesion of osteoblastic cells to betaig-h3. The disruption of interactions between betaig-h3 and osteoblasts by a function-blocking antibody specific for alphavbeta3 but not for alphavbeta5 abolished the inhibitory effect of betaig-h3 on osteoblast differentiation. We suggest that these interacting integrins may play an important role in betaig-h3-mediated inhibition of osteoblast differentiation.
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PMID:Beta ig-h3 mediates osteoblast adhesion and inhibits differentiation. 1578 Sep 49

The three mammalian Runt homology domain transcription factors (Runx1, Runx2, Runx3) support biological control by functioning as master regulatory genes for the differentiation of distinct tissues. Runx proteins also function as cell context-dependent tumor suppressors or oncogenes. Abnormalities in Runx mediated gene expression are linked to cell transformation and tumor progression. Runx2 is expressed in mesenchymal linage cells committed to the osteoblast phenotype and is essential for bone formation. This skeletal transcription factor is aberrantly expressed at high levels in breast and prostate tumors and cells that aggressively metastasize to the bone environment. In cancer cells, Runx2 activates expression of bone matrix and adhesion proteins, matrix metalloproteinases and angiogenic factors that have long been associated with metastasis. In addition, Runx2 mediates the responses of cells to signaling pathways hyperactive in tumors, including BMP/TGFbeta and other growth factor signals. Runx2 forms co-regulatory complexes with Smads and other co-activator and co-repressor proteins that are organized in subnuclear domains to regulate gene transcription. These activities of Runx2 contribute to tumor growth in bone and the accompanying osteolytic disease, established by interfering with Runx2 functions in metastatic breast cancer cells. Inhibition of Runx2 in MDA-MB-231 cells transplanted to bone decreased tumorigenesis and prevented osteolysis. This review evaluates evidence that Runx2 regulates early metastatic events in breast and prostate cancers, tumor growth, and osteolytic bone disease. Consideration is given to the potential for inhibition of this transcription factor as a therapeutic strategy upstream of the regulatory events contributing to the complexity of metastasis to bone.
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PMID:Regulatory roles of Runx2 in metastatic tumor and cancer cell interactions with bone. 1716 30


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