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J Biol Chem, Vol. 274, Issue 27, 19301-19308, July 2, 1999
From the Divisions of 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-
STAT3 Activation in Stromal/Osteoblastic Cells Is Required for
Induction of the Receptor Activator of NF-
B Ligand and Stimulation
of Osteoclastogenesis by gp130-utilizing Cytokines or Interleukin-1
but Not 1,25-Dihydroxyvitamin D3 or Parathyroid
Hormone
,,,
, and
Endocrinology and Metabolism
and Pediatric Hematology/Oncology, Departments of Medicine and
Pediatrics, Center for Osteoporosis and Metabolic Bone Diseases, and
the Central Arkansas Healthcare System, University of Arkansas for
Medical Sciences, Little Rock, Arkansas 72205
B 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.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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