STAT3 activation in stromal/osteoblastic cells is required for induction of the receptor activator of NF-kappaB ligand and stimulation of osteoclastogenesis by gp130-utilizing cytokines or interleukin-1 but not 1,25-dihydroxyvitamin D3 or parathyroid hormone.
Interleukin (IL)-6-type cytokines stimulate osteoclastogenesis by activating gp130 in stromal/osteoblastic cells and may mediate some of the osteoclastogenic effects of other cytokines and hormones. To determine whether STAT3 is a downstream effector of gp130 in the osteoclast support function of stromal/osteoblastic cells and whether the gp130/STAT3 pathway is utilized by other osteoclastogenic agents, we conditionally expressed dominant negative (dn)-STAT3 or dn-gp130 in a stromal/osteoblastic cell line (UAMS-32) that supports osteoclast formation. Expression of either dominant negative protein abolished osteoclast formation stimulated by IL-6 + soluble IL-6 receptor, oncostatin M, or IL-1 but not by parathyroid hormone or 1,25-dihydroxyvitamin D3. Because previous studies suggested that IL-6-type cytokines may stimulate osteoclastogenesis by inducing expression of the tumor necrosis factor-related protein, receptor activator of NF-kappaB ligand (RANKL), we conditionally expressed RANKL in UAMS-32 cells and found that this was sufficient to stimulate osteoclastogenesis. Moreover, dn-STAT3 blocked the ability of either IL-6 + soluble IL-6 receptor or oncostatin M to induce RANKL. These results establish that STAT3 is essential for gp130-mediated osteoclast formation and that the target of STAT3 during this process is induction of RANKL. In addition, this study demonstrates that activation of the gp130-STAT3 pathway in stromal/osteoblastic cells mediates the osteoclastogenic effects of IL-1, but not parathyroid hormone or 1, 25-dihydroxyvitamin D3.
O'Brien
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Departments of Medicine and Pediatrics, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA. obriencharlesa@exchange.uams.edu
Gubrij
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Lin
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Saylors
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Manolagas
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D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D002117:Calcitriol / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D050822:Cytokine Receptor gp130; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D007375:Interleukin-1 / Q000378:metabolism*; D008024:Ligands; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D010006:Osteoblasts / Q000201:enzymology*; D010281:Parathyroid Hormone / Q000378:metabolism*; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D017154:Stromal Cells / Q000201:enzymology*; D015534:Trans-Activators / Q000378:metabolism*; D014162:Transfection
D015703:Antigens, CD; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C494200:Il6st protein, mouse; D007375:Interleukin-1; D008024:Ligands; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D010281:Parathyroid Hormone; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D015534:Trans-Activators; D050822:Cytokine Receptor gp130; D002117:Calcitriol