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Osteoclastic Differentiation (osteoclastic + differentiation)
Selected AbstractsIL-23 promotes osteoclast formation by up-regulation of receptor activator of NF-,B (RANK) expression in myeloid precursor cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2008Li Chen Abstract Inflammation-mediated bone loss is a major feature of various bone diseases including rheumatoid arthritis, osteoarthritis and advanced periodontitis. Enhanced osteoclast development or activity at the inflammation site results in bone resorption. IL-23 is a heterodimeric cytokine belonging to the IL-6/IL-12 family that has been implicated in the pathogenesis of rheumatoid arthritis and demonstrated to play a role in osteoclastogenesis via stimulation of IL-17 production. In this study we investigated whether IL-23 contributes to the regulation of osteoclast differentiation independent of the IL-17 pathway. We show that IL-23 dose-dependently up-regulates receptor activator of NF-,B expression in primary murine bone marrow macrophages and RAW264.7 cells and thereby promotes commitment of myeloid precursor cells to receptor activator of NF-,B ligand-mediated osteoclastic differentiation. However, IL-23 by itself is insufficient to induce osteoclastogenesis. Increased osteoclastic differentiation of cells was associated with enhanced cathepsin K expression and dentine resorption indicating enhanced formation of functional osteoclasts. IL-17 was not detectable in culture supernatants and when added to cultures, did not promote differentiation of RAW264.7 cells. These results demonstrate that IL-23 can act directly on myeloid precursor cells in addition to indirectly stimulating receptor activator of NF-,B ligand production in osteoblasts and explains its potency in driving osteoclast development in inflammation-mediated bone pathology. [source] Osteoblast-Derived TGF-,1 Stimulates IL-8 Release Through AP-1 and NF-,B in Human Cancer Cells,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 6 2008Yi-Chin Fong Abstract Introduction: The bone marrow microenvironment is further enriched by growth factors released during osteoclastic bone resorption. It has been reported that the chemokine interleukin (IL)-8 is a potent and direct activator of osteoclastic differentiation and bone resorption. However, the effect of bone-derived growth factors on the IL-8 production in human cancer cells and the promotion of osteoclastogenesis are largely unknown. The aim of this study was to investigate whether osteoblast-derived TGF-,1 is associated with osteolytic bone diseases. Materials and Methods: IL-8 mRNA levels were measured using RT-PCR analysis. MAPK phosphorylation was examined using the Western blot method. siRNA was used to inhibit the expression of TGF-,1, BMP-2, and IGF-1. DNA affinity protein-binding assay and chromatin immunoprecipitation assays were used to study in vitro and in vivo binding of c- fos, c- jun, p65, and p50 to the IL-8 promoter. A transient transfection protocol was used to examine IL-8, NF-,B, and activator protein (AP)-1 activity. Results: Osteoblast conditioned medium (OBCM) induced activation of IL-8, AP-1, and NF-,B promoter in human cancer cells. Osteoblasts were transfected with TGF-,1, BMP-2, or IGF-1 small interfering RNA, and the medium was collected after 48 h. TGF-,1 but not BMP-2 or IGF-1 siRNA inhibited OBCM-induced IL-8 release in human cancer cells. In addition, TGF-,1 also directly induced IL-8 release in human cancer cells. Activation of AP-1 and NF-,B DNA-protein binding and MAPKs after TGF-,1 treatment was shown, and TGF-,1,induced IL-8 promoter activity was inhibited by the specific inhibitors of MAPK cascades. Conclusions: In this study, we provide evidence to show that the osteoblasts release growth factors, including TGF-,1, BMP-2, and IGF-1. TGF-,1 is the major contributor to the activation of extracellular signal-related kinase (ERK), p38, and c-Jun N-terminal kinase (JNK), leading to the activation of AP-1 and NF-,B on the IL-8 promoter and initiation of IL-8 mRNA and protein release, thereby promoting osteoclastogenesis. [source] A Single-Dose Placebo-Controlled Study of AMG 162, a Fully Human Monoclonal Antibody to RANKL, in Postmenopausal WomenJOURNAL OF BONE AND MINERAL RESEARCH, Issue 7 2004Pirow J Bekker Abstract The safety and bone antiresorptive effect of a single subcutaneous dose of AMG 162, a human monoclonal antibody to RANKL, was investigated in 49 postmenopausal women. AMG 162 is a potent antiresorptive agent for diseases such as osteoporosis. Introduction: RANKL is an essential osteoclastic differentiation and activation factor. Materials and Methods: The bone antiresorptive activity and safety of AMG 162, a fully human monoclonal antibody to RANKL, were evaluated in postmenopausal women in this randomized, double-blind, placebo-controlled, single-dose, dose escalation study. Six cohorts of eight to nine women were randomly assigned to receive a single subcutaneous injection of either AMG 162 or placebo (3:1 ratio). AMG 162 doses were 0.01, 0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg. Subjects were followed up to 6 months in all cohorts and 9 months in the three highest dose cohorts. Second morning void urinary N-telopeptide/creatinine (NTX; Osteomark), serum NTX, and serum bone-specific alkaline phosphatase (BALP, Ostase) were assessed as bone turnover markers. Results and Conclusions: Forty-nine women were enrolled. A single subcutaneous dose of AMG 162 resulted in a dose-dependent, rapid (within 12 h), profound (up to 84%), and sustained (up to 6 months) decrease in urinary NTX. At 6 months, there was a mean change from baseline of ,81% in the 3.0 mg/kg AMG 162 group compared with ,10% in the placebo group; serum NTX changes were ,56% and 2%, respectively. BALP levels did not decrease remarkably until after 1 month, indicating that the effect of AMG 162 is primarily antiresorptive. Intact parathyroid hormone (PTH) levels increased up to ,3-fold after 4 days in the 3.0 mg/kg dose group, but returned toward baseline with follow-up. Albumin-adjusted serum calcium did not decrease >10% on average in any group, and no subject had values below 2 mmol/liter. AMG 162 was well tolerated. No related serious adverse events occurred. No clinically meaningful laboratory changes, other than those described above, were observed. In summary, a single subcutaneous dose of AMG 162 resulted in a dose-dependent rapid and sustained decrease from baseline in bone turnover and could be an effective and convenient treatment for osteoporosis. [source] Regulation of osteoclastogenesis and RANK expression by TGF-,1JOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2001Tao Yan Abstract Transforming growth factor-, (TGF-,) has been shown to both inhibit and to stimulate bone resorption and osteoclastogenesis. This may be due, in part, to differential effects on bone marrow stromal cells that support osteoclastogenesis vs. direct effects on osteoclastic precursor cells. In the present study, we used the murine monocytic cell line, RAW 264.7, to define direct effects of TGF-, on pre-osteoclastic cells. In the presence of macrophage-colony stimulating factor (M-CSF) (20 ng/ml) and receptor activator of NF-,B ligand (RANK-L) (50 ng/ml), TGF-,1 (0.01,5 ng/ml) dose-dependently stimulated (by up to 120-fold) osteoclast formation (assessed by the presence of tartrate-resistant acid phosphatase (TRAP) positive multinucleated cells and expression of calcitonin and vitronectin receptors). In addition, TGF-,1 also increased steady state RANK mRNA levels in a time- (by up to 3.5-fold at 48 h) and dose-dependent manner (by up to 2.2-fold at 10 ng/ml). TGF-,1 induction of RANK mRNA levels was present both in undifferentiated RAW cells as well as in cells that had been induced to differentiate into osteoclasts by a 7-day treatment with M-CSF and RANK-L. Using a fluorescence-labeled RANK-L probe, we also demonstrated by flow cytometry that TGF-,1 resulted in a significant increase in the percentage of RANK+ RAW cells (P,<,0.05), as well as an increase in the fluorescence intensity per cell (P,<,0.05), the latter consistent with an increase in RANK protein expression per cell. These data thus indicate that TGF-, directly stimulates osteoclastic differentiation, and this is accompanied by increased RANK mRNA and protein expression. J. Cell. Biochem. 83: 320,325, 2001. © 2001 Wiley-Liss, Inc. [source] | ||||||||||