STAT3 activation in stromal osteoblastic cells is required for induction of the receptor activator of NF-kappa B ligand and stimulation of osteoclastogenesis by gp130-utilizing cytokines or interleukin-1 but not 1,25-dihydroxyvitamin D-3 or parathyroid hormone

Interleukin (IL)-6-type cytokines stimulate osteoclastogenesis by activatin g gp130 in stromal/osteoblastic cells and may mediate some of the osteoclas togenic effects of other cytokines and hormones. To determine whether STAT3 is a downstream effector of gp130 in the osteoclast support function of st romal/osteoblastic cells and whether the gp130/STAT3 pathway is utilized by other osteoclastogenic agents, we conditionally expressed dominant negativ e (dn)-STAT3 or dn-gp130 in a stromal/osteoblastic cell line (UAMS-32) that supports osteoclast formation. Expression of either dominant negative prot ein abolished osteoclast formation stimulated by IL-6 + soluble IL-6 recept or, oncostatin M, or IL-1 but not by parathyroid hormone or 1,25-dihydroxyv itamin D-3. Because previous studies suggested that IL-B-type cytokines may stimulate osteoclastogenesis by inducing expression of the tumor necrosis factor-related protein, receptor activator of NF-kappa B ligand (RANKL), we conditionally expressed RANKL in UAMS-32 cells and found that this was suf ficient to stimulate osteoclastogenesis, Moreover, dn-STAT3 blocked the abi lity of either IL-6 + soluble IL-6 receptor or oncostatin M to induce RANKL , These results establish that STAT3 is essential for gp130-mediated osteoc last formation and that the target of STAT3 during this process is inductio n of RANKL, In addition, this study demonstrates that activation of the gp1 30 STAT3 pathway in stromal/osteoblastic cells mediates the osteoclastogeni c effects of IL-1, but not parathyroid hormone or 1,25-dihydroxyvitamin D-3 .