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At least 811 records · Page 45Linked to original sources
PubMed1987

Osteoblasts synthesize and respond to transforming growth factor-type beta (TGF-beta) in vitro.

Transforming growth factor-type beta (TGF-beta) has been identified as a constituent of bone matrix (Seyedin, S. M., A. Y. Thompson, H. Bentz, D. M. Rosen, J. M. McPherson, A. Conti, N. R. Siegel, G. R. Gallupi, and K. A. Piez, 1986, J. Biol. Chem. 261:5693-5695). We used both developing bone and bone-forming cells in vitro to demonstrate the cellular origin of this peptide. TGF-beta mRNA was detected by Northern analysis in both developing bone tissue and fetal bovine bone-forming cells using human cDNA probes. TGF-beta was shown to be synthesized and secreted by metabolically labeled bone cell cultures by immunoprecipitation from the medium. Further, TGF-beta activity was demonstrated in conditioned media from these cultures by competitive radioreceptor and growth promotion assays. Fetal bovine bone cells (FBBC) were found to have relatively few TGF-beta receptors (5,800/cell) with an extremely low Kd of 2.2 pM (high binding affinity). In contrast to its inhibitory effects on the growth of many cell types including osteosarcoma cell lines, TGF-beta stimulated the growth of subconfluent cultures of FBBC; it had little effect on the production of collagen by these cells. We conclude that bone-forming cells are a source for the TGF-beta that is found in bone, and that these cells may be modulated by this factor in an autocrine fashion.

Animals↗
PubMedDate not supplied

[Features of development of fetal bone organ culture in space flight].

Fetal mouse metatarsals cultured for 4 days onboard international space laboratory IML-1 (STS-42) were investigated using light microscopy and electron microscopy combined with X-ray microanalysis. Bones cultured in microgravity were equal in length to both ground and inflight (1 g) controls. Three zones: epiphyseal, proliferative, and hypertrophic chondrocytes were distinguished and measured in metatarsals isolated from 16-day-old fetuses. In bone cultures exposed to microgravity, hypertrophic zone tended to decrease and epiphyseal area was increased compared to controls. Proliferative zone has equal length both in bones cultured under microgravity and in controls. The same tendency was observed in bone cultures from 17-day-old fetuses. Metatarsals cultured in microgravity have less spreading calcification zone of diaphysis in comparison with both controls. The results suggest that maturation of chondrocytes and calcification of cartilage, but not cell proliferation, are microgravity sensitive processes in developing bones isolated from the organism.

Animals↗
PubMed2002

BMP-2, BMP-4, and PDGF-bb stimulate chemotactic migration of primary human mesenchymal progenitor cells.

For bone development, remodeling, and repair; the recruitment of mesenchymal progenitor cells (MPC) and their differentiation to osteoblasts is mandatory. The process of migration is believed to be regulated in part by growth factors stored within the bone matrix and released by bone resorption. In this study, primary human MPCs and to osteoblasts differentiated progenitor cells were examined for chemotaxis in response to human basic fibroblast growth factor (rhbFGF), human transforming growth factor beta 1 (rhTGF-beta1), human platelet derived growth factor bb (rhPDGF-bb), human bone morphogenetic protein-2 (rhBMP-2), and recombinant bone morphogenetic protein-4 of Xenopus laevis (rxBMP-4) from 0.001 to 1.0 ng/ml each. The results of migration were expressed as a chemotactic index (CI). Migration of primary human progenitor cells was stimulated by rhBMP-2, rxBMP-4, and rhPDGF-bb in a dose-dependent manner. The increase of CI was up to 3.5-fold for rhBMP-2, 3.6-fold for rxBMP-4, and up to 22-fold for rhPDGF-bb, whereas rhTGF-beta1 and rhbFGF did not stimulate cell migration in the concentration range tested. In contrast differentiated progenitor cells behave similar to primary human osteoblasts. RhBMP-2, rhPDGF-bb, and rhTGF-beta1 stimulated the migration from 2.2 to 2.4-fold each, while rxBMP-4 and rhbFGF reached only a CI of 1.7-1.6. The effect of rhBMP-2, rxBMP-4, and rhPDGF-bb as chemoattractive proteins for primary human MPC, including the change in response to growth factors after differentiation suggests a functional role for recruitment of MPCs during bone development and remodeling, as well as fracture healing.

Becaplermin↗
PubMed2005

Changing patterns of bone and brain metastases in patients with colorectal cancer.

BACKGROUND: Therapeutic advances for patients with metastatic colorectal cancer (CRC) have been associated with prolonged survival. This study was undertaken to test the hypothesis that expanded treatment options and resultant improved survival for patients with metastatic CRC are associated with an increased incidence of metastases at uncommon sites. PATIENTS AND METHODS: Patients with metastatic CRC evaluated from 1993 to 2002 at the Fox Chase Cancer Center were identified. Medical records were abstracted to obtain the following: date of diagnosis/metastasis, primary tumor site, therapeutic agents received, survival, and site(s) of metastases. RESULTS: The records of 1020 patients were reviewed. Incidence of bone and brain metastases were 10.4% (95% CI, 8.6%-12.4%) and 3% (95% CI, 2.2%-4.5%), respectively. Bone metastases were more common with increased numbers of active systemic agents received: 0 (3.7%), 1 (9.4%), 2 (10.9%), 3 (16.3%), and 4/5 (17.4%; P = 0.001; trend test). Patients receiving irinotecan or oxaliplatin were more likely to develop bone metastases (13.2% vs. 8.3%, P = 0.01 for irinotecan; 16.9% vs. 9%, P = 0.003 for oxaliplatin). Patients with primary rectal versus primary colon cancer were more likely to develop bone metastases (16% vs. 8.6%; P = 0.001). Patients with lung metastases were more likely to have bone metastases (16.1% vs. 6.4%; P < 0.0001) or brain metastases (6.2% vs. 1.2%; P < 0.0001) than those without. CONCLUSION: These data demonstrate that the incidence of bone and brain metastases in patients with CRC is more common than previously reported and is associated with receipt of multiple systemic treatments. As survival improves for this patient population, clinicians should be aware of the potential for metastases at previously uncommon sites.

Adenocarcinoma↗
PubMed1996

Ontogeny of the 1,25-dihydroxyvitamin D3 receptor in fetal rat bone.

To gain insights into 1,25-dihydroxyvitamin D3 receptor (VDR) function during fetal bone development, we examined fetal rat tissues from gestational days 13-21 for the presence and distribution of VDR using immunohistochemistry. Prior to ossification, VDR epitopes were observed in the mesenchyme condensing to form skeletal tissues, on day 13 in the developing vertebral column and limbs, and on day 17 of gestation in developing calvaria. Immunostaining for VDR was seen in proliferating and hypertrophic chondrocytes and in osteoblasts of limb buds and the vertebral column by day 17 of gestation. In calvaria, VDR epitopes were observed in osteoblasts by gestational day 19. VDR immunostaining was also evident in the skin of fetal limbs at all gestational ages examined. We show for the first time that the VDR appears very early in the developing fetal rat skeleton, suggesting that the VDR, in concert with its ligand, 1,25-dihydroxyvitamin D3, may play a role in the differentiation of mesenchymal precursors into bone tissue.

Animals↗
PubMed2003

Rationale for the use of bisphosphonates in osteoblastic and osteolytic bone lesions.

Various primary malignancies develop bone metastases, and the resultant skeletal complications cause significant morbidity/mortality in advanced cancer patients. Bone lesions associated with metastases are traditionally classified radiologically as either osteolytic or osteoblastic, and both types of lesions are associated with elevated levels of specific bone resorption markers. Some common aspects in the pathophysiology of bone lesions have prompted speculation that treatments for osteolytic metastases might also be effective for predominantly osteoblastic metastases, such as in prostate cancer. Potent osteoclast activity inhibitors, bisphosphonates have been successful in the treatment of osteolytic tumor bone disease. Zoledronic acid is the first bisphosphonate shown to have a direct clinical benefit in the treatment of osteoblastic bone metastases, reducing the number and rate of skeletal events in prostate cancer patients with metastatic bone disease. Moreover, the shorter, more convenient infusion time and similar safety profile of 4 mg zoledronic acid compared with 90 mg pamidronate presently make zoledronic acid the preferred therapy for treatment of bone metastases in patients with all types of advanced malignancy.

Bone Neoplasms↗
PubMed2004

Vitamin D requirements during pregnancy.

Adequate vitamin D concentrations during pregnancy are necessary to ensure appropriate maternal responses to the calcium demands of the fetus and neonatal handling of calcium. The purpose of this report is to review studies that investigated maternal and neonatal outcomes of vitamin D deficiency or supplementation during pregnancy. Most studies reported included women at high risk of vitamin D deficiency, because of low vitamin D and calcium intake or decreased ability to synthesize endogenous vitamin D (attributable to lack of sun exposure or to heavily pigmented skin). Overall, vitamin D supplementation in these populations leads to improved neonatal handling of calcium. Results concerning benefits for fetal growth and bone development are inconclusive. There is no evidence of a benefit of supplementation during pregnancy above amounts routinely required to prevent vitamin D deficiency.

Adult↗
PubMed1976

Breast-cancer osteolysis, bone metastases, and anti-osteolytic effect of aspirin.

23 (60%) of 38 human breast carcinomas had significant in-vitro osteolytic activity. All patients presenting with bone metastases or hypercalcaemia had active tumours. Over a subsequent three-year follow-up period, bone metastases did not develop in any of the 15 patients with inactive tumours, and metastases at other sites developed in only 2. Of the 23 patients with active tumours, 7 either had, or have since developed bone metastases; in 4 of these hypercalcaemia also developed. 14 tumours, chosen at random, were tested for in-vitro osteolytic activity in the presence and absence of aspirin, which inhibits prostaglandin synthetase. The activity of 8 of the 9 osteolytically active tumours was significantly, though not completely inhibited by aspirin. Although the number of patients is limited, these results indicate that the in-vitro osteolysis assay may detect substances, perhaps including prostaglandins, produced by breast tumours which affect prognosis and contribute to the subsequent formation of bone metastases.

Animals↗
PubMed1976

The influence of the otic capsule in ambystomid skull formation.

In the absence of the otic capsule, or in the presence of capsular materials of varying volume or placement, the bones and cartilages of the contiguous skull showed several sorts of responses. A. The parietal and squamosal bones, and possibly the parasphenoid bone and parachordal cartilage apparently used the capsule as a substrate, spreading over its surface. B. The parietal, squamosal, and exoccipital bones, and the quadrate cartilage were displaced when otic capsule material was absent or oversized. C. The squamosal bone developed at first independently of the capsule but was modified in its shape and size by the capsule in later, possibly inductive, response. D. Stresses resulting from paired otic capsules of unequal size bent the parasphenoid bone and the parachordal cartilage through angles of predictable direction relative to the notochord. E. The paired exoccipital bones developed at different rates when one otic capsule was absent or oversized. The results obtained following manipulation of the otocyst indicate the major role of extrinsic (epigenetic) parameters in normal skeletogenesis and emphasize an apparent discrepancy between the normal and potential expansion of a bone.

Ambystoma↗
PubMed1997

Parathyroid hormone-related peptide and the parathyroid hormone/parathyroid hormone-related peptide receptor in skeletal development.

Parathyroid hormone-related peptide has recently been shown to have important functions in the control of cellular growth and differentiation. Studies using knockout and transgenic technology have played a key part in the development of our understanding of its physiological role in endochondral bone development and adult skeletal homeostasis. Acting, at least partly, through the parathyroid hormone/parathyroid hormone-related peptide receptor, parathyroid hormone-related peptide profoundly influences chondrocytic and osteogenic cell biology. Further understanding of these functions may have important implications in the pathophysiology and treatment of human skeletal disorders, including osteoporosis.

Adult↗
PubMed2003

Sclerostin is a novel secreted osteoclast-derived bone morphogenetic protein antagonist with unique ligand specificity.

Sclerosteosis is a progressive sclerosing bone dysplasia. Sclerostin (the SOST gene) was originally identified as the sclerosteosis-causing gene. However, the physiological role of sclerostin remains to be elucidated. Sclerostin was intensely expressed in developing bones of mouse embryos. Punctuated expression of sclerostin was localized on the surfaces of both intramembranously forming skull bones and endochondrally forming long bones. Sclerostin-positive cells were identified as osteoclasts. Recombinant sclerostin protein produced in cultured cells was efficiently secreted as a monomer. We examined effects of sclerostin on the activity of BMP2, BMP4, BMP6, and BMP7 for mouse preosteoblastic MC3T3-E1 cells. Sclerostin inhibited the BMP6 and BMP7 activity but not the BMP2 and BMP4 activity. Sclerostin bound to BMP6 and BMP7 with high affinity but bound to BMP2 and BMP4 with lower affinity. In conclusion, sclerostin is a novel secreted osteoclast-derived BMP antagonist with unique ligand specificity. We suggest that sclerostin negatively regulates the formation of bone by repressing the differentiation and/or function of osteoblasts induced by BMPs. Since sclerostin expression is confined to the bone-resorbing osteoclast, it provides a mechanism whereby bone apposition is inhibited in the vicinity of resorption. Our findings indicate that sclerostin plays an important role in bone remodeling and links bone resorption and bone apposition.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Growth hormone changes bone geometry and body composition in patients with juvenile idiopathic arthritis requiring glucocorticoid treatment: a controlled study using peripheral quantitative computed tomography.

Osteopenia and growth retardation have been described in children with chronic arthritis. GH has an impact on both. In the present controlled study, we used peripheral quantitative computed tomography to evaluate forearm bone mass, density, and geometry as well as forearm muscle and fat area in 17 patients with juvenile idiopathic arthritis (JIA) receiving treatment with GH for 3.8 +/- 1.1 yr compared with an untreated age- and sex-matched control group (n = 17). All patients had a mean age of 15.3 +/- 2.5 yr and a mean duration of illness of 8.2 +/- 4.4 yr. Height, weight, body mass index, bone parameters, and muscle area were significantly decreased in both groups compared with those in healthy age-matched children. Compared with untreated JIA patients, GH-treated JIA patients had significant higher bone mineral content as well as total cross-sectional area (CSA), cortical CSA, and muscle CSA. Fat CSA was lower in the GH-treated group. A significant difference between groups for height-corrected cortical and muscle areas was only seen in male patients. Cortical CSA relative to muscle CSA was not different between groups. These findings are compatible with an anabolic effect of GH on muscle and bone development.

Adolescent↗
PubMed2003

Bone formation on two-dimensional poly(DL-lactide-co-glycolide) (PLGA) films and three-dimensional PLGA tissue engineering scaffolds in vitro.

For some bone tissue engineering strategies, direct contact of newly synthesized bone with a scaffold is important for structural continuity and stability at the scaffold/bone interface. Thus, as the polymer degrades, the support function of the scaffold could be adopted by the developing bone structure. This study was designed to determine whether poly(DL-lactide-co-glycolide) with a comonomer ratio of 75:25 supports bone apposition in vitro. Osteogenic cells derived from rat bone marrow cells were cultured for 2 weeks on polymeric two-dimensional films and three-dimensional tissue engineering scaffolds. Bacteriological grade polystyrene and tissue culture polystyrene dishes served as negative and positive controls for interfacial bone deposition, respectively. The surfaces of the prepared substrates were characterized by X-ray photoelectron spectroscopy, dynamic water contact angle, scanning electron microscopy, and atomic force microscopy. After cell culture, the elaborated matrix was examined using scanning electron microscopy, transmission electron microscopy, and energy dispersive spectroscopy. The results show that poly(DL-lactide-co-glycolide) supports appositional bone growth on both two-dimensional films and three-dimensional scaffolds, including the formation of a mineralized cement line matrix. Furthermore, surface topographical features are not required for the adherence of the cement line matrix to the polymer.

Animals↗
PubMed1984

The effects of trifluoperazine on calcifying tissues in the immature rat.

When the antipsychotic drug trifluoperazine is given to immature rats during stages of rapid bone development, severe localized derangement in their growth plate architecture results. In addition, 3 weeks of treatment with doses of 3 mg/kg body wt/day had marked effects on the anatomic distribution of bone mineral, and on the quantitative chemical composition of the bone matrix. Specifically, ash contents and Ca/P ratios were decreased and mineral crystals appeared larger and/or more perfect in the treated animals. The finding of decreased hexosamine content and alterations in bone lipid composition could be interpreted as specific effects of the drug on calmodulin activity.

Animals↗
PubMed1999

Eosinophilia during fludarabine treatment of chronic lymphocytic leukemia.

Although eosinophilia has been reported as a side effect of purine analogues, there is no report on fludarabine-induced eosinophilia in chronic lymphocytic leukemia (CLL). During chemotherapy with fludarabine and cyclophosphamide, we observed two cases of significant eosinophilia. A 67-year-old patient with CLL developed bone marrow and peripheral blood eosinophilia up to 7.9x10(9)/l, the highest eosinophil count ever reported during treatment with a purine analogue. The eosinophilia persisted for 33 days. Another patient developed bone marrow eosinophilia without eosinophilia in the peripheral blood. These are the first documented cases of fludarabine-induced eosinophilia in CLL, and this side effect may conceivably be more common than previously recognized.

Aged↗
PubMed1993

Delivery systems for bone morphogenetic proteins. A summary of experimental studies in primate models.

The characterization and molecular cloning of the family of the bone morphogenetic proteins (BMPs) have laid the foundation for the cellular and molecular analysis of bone development and regeneration. A carrier substratum is required, however, to optimize osteogenic activity initiated by BMPs bound to the surface of the carrier. Native and recombinant human (rh) BMPs induce local endochondral bone formation in conjunction with the insoluble collagenous bone matrix, the inactive residue obtained after dissociative extraction of the matrix with chaotropic agents. While the cellular and molecular biology of BMPs and related members is advancing at a furious pace, progress in the formulation and implementation of novel delivery systems has been slow. The creation of inorganic nonimmunogenic carriers with defined geometries capable of delivering BMPs in the absence of the collagenous matrix is a crucial goal for skeletal reconstructionists and molecular biologists alike. Significant advances in skeletal reconstruction may be expected when novel carrier substrata are implemented for delivery of optimal doses of now available recombinant human BMPs.

Animals↗
PubMed1994

Longitudinal evaluation of elastase as a marker for the progression of periodontitis.

To determine whether elastase levels in gingival crevicular fluid (GCF) could serve as a marker for the progression of periodontitis, we monitored GCF elastase and periodontal status in selected sites in 32 periodontally healthy volunteers and 31 periodontitis patients at intervals over a 6-month period. Clinical measurements included plaque index, gingival index, bleeding on probing, suppuration, probing depth, clinical attachment level, and relative attachment level measured with an automated disk probe. GCF elastase, detected by reaction with a fluorescent substrate, was assessed visually against fluorescence standards and quantitatively with a fluorometer. Bone loss was detected by subtraction radiography of standardized vertical bite-wing radiographs at baseline and 6 months. Mean visual elastase scores (VES) and quantitative elastase measurements were significantly higher (P < 0.001) in sites from periodontitis patients than in sites from healthy volunteers. When bone loss was used as the criterion for disease progression, significantly higher (P < 0.001) visual and quantitative GCF elastase levels were found at progressing sites than in nonprogressing sites in the periodontitis patients. The odds ratios (OR) for the event of developing bone loss with positive 4-minute and 8-minute VES tests were 4.2 (P < 0.001) and 7.4 (P < 0.001), respectively. When corrected for the tendency of progressing sites to be clustered within a subpopulation of patients, the OR for developing bone loss with the 4-minute and 8-minute VES tests were 3.1 (P < 0.007) and 4.9 (P < 0.001), respectively. These data indicate that sites with high levels of elastase are at significantly greater risk for progressive bone loss as assessed by digital subtraction radiography.

Adult↗