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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-κB 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. 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-κB 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. 1,25-dihydroxyvitamin D3 parathyroid hormone interleukin receptor activator of NF-κB ligand soluble IL-6 receptor oncostatin M leukemia inhibitory factor signal transducers and activators of transcription tartrate-resistant acid phosphatase dominant negative vitamin D receptor macrophage-colony stimulating factor base pair core binding factor A-1 The adult skeleton undergoes periodic replacement of old bone by new. During this process, old bone is resorbed by osteoclasts and new bone is formed by osteoblasts (1Manolagas S.C. Jilka R.L. N. Engl. J. Med. 1995; 332: 305-311Crossref PubMed Scopus (1550) Google Scholar). Both osteoblasts and osteoclasts are derived from precursors originating in the bone marrow. The precursors of osteoblasts are multipotent mesenchymal stem cells, while the precursors of osteoclasts are hematopoietic cells of the monocyte/macrophage lineage (2Aubin J.E. Turksen K. Heersche J.N. Noda M. Cellular and Molecular Biology of Bone. Academic Press, Inc., San Diego1993: 1-45Crossref Google Scholar, 3Kurihara N. Chenu C. Miller M. Civin C. Roodman G.D. Endocrinology. 1990; 126: 2733-2741Crossref PubMed Scopus (197) Google Scholar). Osteoclast development depends strictly on support provided by stromal/osteoblastic cells. Moreover, hormones or cytokines that stimulate bone resorption such as 1,25-dihydroxyvitamin D3(1,25(OH)2D3),1parathyroid hormone (PTH), members of the interleukin (IL)-6 family, or IL-1 stimulate osteoclast formation by activating discrete signaling pathways in stromal/osteoblastic cells (4Udagawa N. Takahashi N. Katagiri T. Tamura T. Wada S. Findlay D.M. Martin T.J. Hirota H. Taga T. Kishimoto T. Suda T. J. Exp. Med. 1995; 182: 1461-1468Crossref PubMed Scopus (326) Google Scholar, 5Liu B.Y. Guo J. Lanske B. Divieti P. Kronenberg H.M. Bringhurst F.R. Endocrinology. 1998; 139: 1952-1964Crossref PubMed Google Scholar, 6Takeda S. Yoshizawa T. Fukumoto S. Nagai Y. Murayama H. Matsumoto T. Kato S. Fujita T. J. Bone Miner. Res. 1997; 12 (abstr.): S110Google Scholar). The extent to which these pathways interact, or are dependent on one another, to stimulate osteoclast formation is largely unknown. The mechanistic basis of the dependence of osteoclastogenesis on mesenchymal cell differentiation has recently been established by the discovery of a membrane-bound member of the tumor necrosis factor family of cytokines, receptor activator of NF-κB ligand (RANKL), which is expressed in committed preosteoblastic cells (7Anderson D.M. Maraskovsky E. Billingsley W.L. Dougall W.C. Tometsko M.E. Roux E.R. Teepe M.C. DuBose R.F. Cosman D. Galibert L. Nature. 1997; 390: 175-179Crossref PubMed Scopus (1905) Google Scholar, 8Lacey D.L. Timms E. Tan H.L. Kelley M.J. Dunstan C.R. Burgess T. Elliott R. Colombero A. Elliott G. Scully S. Hsu H. Sullivan J. Hawkins N. Davy E. Capparelli C. Eli A. Qian Y.X. Kaufman S. Sarosi I. Shalhoub V. Senaldi Guo J. Delaney J. Boyle W.J. Cell. 1998; 93: 165-176Abstract Full Text Full Text PDF PubMed Scopus (4546) Google Scholar, 9Yasuda H. Shima N. Nakagawa N. Yamaguchi K. Kinosaki M. Mochizuki S. Tomoyasu A. Yano K. Goto M. Murakami A. Tsuda E. Morinaga T. Higashio Udagawa N. Takahashi N. Suda T. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 3597-3602Crossref PubMed Scopus (3500) Google Scholar). RANKL binds to a specific receptor (RANK) that is expressed in hematopoietic osteoclast progenitors (7Anderson D.M. Maraskovsky E. Billingsley W.L. Dougall W.C. Tometsko M.E. Roux E.R. Teepe M.C. DuBose R.F. Cosman D. Galibert L. Nature. 1997; 390: 175-179Crossref PubMed Scopus (1905) Google Scholar). This interaction is necessary and, together with M-CSF, sufficient for osteoclast formation, since mice lacking RANKL are unable to make osteoclasts and since exogenously provided soluble RANKL and M-CSF stimulate osteoclastogenesis in the absence of stromal/osteoblastic cells (8Lacey D.L. Timms E. Tan H.L. Kelley M.J. Dunstan C.R. Burgess T. Elliott R. Colombero A. Elliott G. Scully S. Hsu H. Sullivan J. Hawkins N. Davy E. Capparelli C. Eli A. Qian Y.X. Kaufman S. Sarosi I. Shalhoub V. Senaldi Guo J. Delaney J. Boyle W.J. Cell. 1998; 93: 165-176Abstract Full Text Full Text PDF PubMed Scopus (4546) Google Scholar, 9Yasuda H. Shima N. Nakagawa N. Yamaguchi K. Kinosaki M. Mochizuki S. Tomoyasu A. Yano K. Goto M. Murakami A. Tsuda E. Morinaga T. Higashio Udagawa N. Takahashi N. Suda T. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 3597-3602Crossref PubMed Scopus (3500) Google Scholar, 10Boyle W.J. Kung Y. Lacey D.L. Sarosi I. Dunstan C.R. Timms E. Tan H.L. Elliott G. Kelley M.J. Colombero A. Elliott R. Scully S. Capparelli C. Morony S. Penninger J. Bone. 1998; 23 (abstr.): S189Google Scholar). In addition, it has been demonstrated that many of the cytokines and hormones that stimulate osteoclast formation also stimulate the expression of RANKL in stromal/osteoblastic cells (9Yasuda H. Shima N. Nakagawa N. Yamaguchi K. Kinosaki M. Mochizuki S. Tomoyasu A. Yano K. Goto M. Murakami A. Tsuda E. Morinaga T. Higashio Udagawa N. Takahashi N. Suda T. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 3597-3602Crossref PubMed Scopus (3500) Google Scholar). Members of the IL-6 cytokine family that are capable of stimulating osteoclast formation include IL-6, complexed with its soluble receptor (IL-6 + sIL-6R), IL-11, oncostatin M (OSM), and to a lesser extent, leukemia inhibitory factor (LIF) (11Tamura T. Udagawa N. Takahashi N. Miyaura C. Tanaka S. Yamada Y. Koishihara Y. Ohsugi Y. Kumaki K. Taga T. Kishimoto T. Suda T. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 11924-11928Crossref PubMed Scopus (761) Google Scholar). Cell surface receptor complexes for each of these cytokines contain the protein gp130 T. S. M. Taga T. 1995; PubMed Google Scholar). ligand gp130 either or with the protein receptor or receptor and it is by members of the family of N. G.D. Cell. 1993; Full Text PDF PubMed Scopus Google Scholar). This results in of downstream signaling members of the signal transducers and activators of transcription family of transcription N. G.D. J. Full Text PDF PubMed Google Scholar, C. J. J. C. A. K. Taga T. Kishimoto T. G. S. M. PubMed Scopus Google Scholar). in and which to the and transcription J.E. PubMed Scopus Google Scholar). STAT3 is for of the to gp130 differentiation of cells M. M. S. K. Matsumoto M. Kishimoto T. S. Proc. Natl. Acad. Sci. U. S. A. 93: PubMed Scopus Google Scholar, Y. K. T. M. T. J. PubMed Scopus Google Scholar, K. Y. K. H. M. N. T. M. T. J. PubMed Scopus Google and from T. M. Y. M. Y. Yamaguchi T. K. T. Full Text Full Text PDF PubMed Scopus Google Scholar). other signaling also been as downstream of gp130 and, in some are gp130 activation J. Y. H. J. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar, R. B. B. 1998; PubMed Scopus Google Scholar, R. U. M. V. D. M. J. 1997; Full Text Full Text PDF PubMed Scopus Google and may on a of the by STAT3 R. B. B. 1998; PubMed Scopus Google Scholar). gp130 activation activation of the protein pathway N. G.D. J. Full Text PDF PubMed Google Scholar, T. Taga T. S. Cell. Full Text PDF PubMed Scopus Google Scholar). of the transcription factor protein may also mediate some of the downstream effects of gp130 activation T. Taga T. S. Cell. Full Text PDF PubMed Scopus Google Scholar). gp130 activation to activation of the phosphatase which as a of expression T. Y. A. J. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). In the studies in this we whether STAT3 is for the osteoclastogenic effects of cytokines other to on gp130 that STAT3 is essential downstream effector of the signaling of IL-6-type cytokines during osteoclastogenesis and that the target of STAT3 during this process is induction of RANKL. In addition, we that IL-1 osteoclastogenesis gp130-STAT3 of gp130 or bone cells by from mice and the with essential cells a of in the and for which cells and bone cells a of together with the UAMS-32 stromal/osteoblastic cell line in essential expression of UAMS-32 cells and in the or absence of for the of bone cells. In either hormones or cytokines the and the in for of the was with cells and for tartrate-resistant acid phosphatase and in some for the of receptor as G. Jilka R.L. G. S. G. S.C. J. PubMed Scopus Google Scholar). The ability of the cells to resorption was by on of bone of P. the of cells with and by derived from the provided by Miller Miller J. PubMed Google Scholar). The was by the downstream of the to a by by of the as a the from the of to the was J.E. Cell. PubMed Scopus Google Scholar). The expression was from by the of a the from of the The was derived from the by of from the which the the leukemia R.L. 1998; PubMed Scopus Google Scholar, J.E. 1990; Scholar). In addition, the was with a and the was from the and the of to make the To the dn-STAT3 expression a the was from from M. A. V. M. J. Full Text Full Text PDF PubMed Scopus Google and downstream of the of to To the dn-gp130 expression a of by a was the of from T. M. K. M. Taga T. Kishimoto T. J. Google Scholar). This in of gp130 acid the gp130 was downstream of the of to The RANKL was from from UAMS-32 cells, from the (7Anderson D.M. Maraskovsky E. Billingsley W.L. Dougall W.C. Tometsko M.E. Roux E.R. Teepe M.C. DuBose R.F. Cosman D. Galibert L. Nature. 1997; 390: 175-179Crossref PubMed Scopus (1905) Google Scholar). The of the was a To the RANKL expression the was downstream of the of to the cell line T. A. M. D. L. C. Res. 1998; Google and a and either or UAMS-32 cells to in the of for and in for The cells to of the with the in the of of from UAMS-32 cells, in the absence or of for as S.C. T. Y. G. T. E. S.C. J. 1997; PubMed Scopus Google Scholar). The of Inc., Inc., and The of the a was Inc., of UAMS-32 cells, in was as S.C. J. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). The in this from I. a by of from the from a K. Y. K. H. M. N. T. M. T. J. PubMed Scopus Google Scholar). to from of the UAMS-32 cells and for in the absence or of IL-6 + and or to the cells, and for was the to and the The utilized in this a to the of RANKL (7Anderson D.M. Maraskovsky E. Billingsley W.L. Dougall W.C. Tometsko M.E. Roux E.R. Teepe M.C. DuBose R.F. Cosman D. Galibert L. Nature. 1997; 390: 175-179Crossref PubMed Scopus (1905) Google a pair for M-CSF from M. Martin M. E.R. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google and a for was with a In to study the of STAT3 in it was necessary to a stromal/osteoblastic cell line that supports osteoclast formation in to IL-6-type cytokines as as other the of bone cell that of stromal/osteoblastic cells, expression of and the ability to a in I. Jilka R.L. S.C. Bone. 1998; 23 (abstr.): Scholar). with bone cells, as a of osteoclast of these the formation of cells that and of cells T. Udagawa N. Takahashi N. of Bone Academic Press, Inc., San Scholar). the studies we one of these on its ability to support cell formation in to osteoclastogenic UAMS-32 cells cell formation with IL-6 + IL-1, or The of as as the ability to resorption on bone and that the cells in To determine whether STAT3 is a downstream effector of gp130 in the osteoclast support function of stromal/osteoblastic cells, we to a of this protein that the of STAT3 in UAMS-32 cells. this we utilized a STAT3 protein in which the was to A. V. M. J. Full Text Full Text PDF PubMed Scopus Google Scholar). This was to of STAT3 as as of a by STAT3 and in a dominant negative A. V. M. J. Full Text Full Text PDF PubMed Scopus Google Scholar). The dn-STAT3 has been the with the to specific of this protein To determine pathways by gp130 activation mediate the effects of other osteoclast inducing agents, we a This protein a to acid by a the STAT3 and binding from the gp130 and is to a dominant negative of gp130 A. S. T. Hirota H. K. T. Taga T. Kishimoto T. Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus Google Scholar). we to UAMS-32 cells with either dn-STAT3 or in we unable to cell that expressed of the dominant negative or that demonstrated gp130 signaling for this is that the cell for some of gp130 or STAT3 may for or In to this we expressed these dominant negative in UAMS-32 cells in a the expression M. H. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). This was by a of cells with a the protein, This of cells was with a either dn-STAT3 or dn-gp130 the of the or of dn-STAT3 in cells with was by with The dn-STAT3 was in of cells in the of the the cells in the absence of expression of dn-STAT3 was of the with that the and the dominant negative which the a in in the absence of that the dominant negative STAT3 was in of the results with the cells the with that the but not the dominant gp130 that dn-gp130 expression not protein To that the dominant negative each of cells was with a that is to In the absence of the dominant negative IL-6 + or stimulated the of this induction of either dn-STAT3 or dn-gp130 blocked this These results that of from of these cells results in expression of either dn-STAT3 or dn-gp130 that are sufficient to the of the signaling by IL-6-type cytokine To determine gp130-mediated osteoclast support we the ability of UAMS-32 cells conditionally dn-STAT3 to support osteoclast formation in to either IL-6 + or as as other In the of with IL-6 + or in of osteoclast formation. the in the absence of in dn-STAT3 osteoclast formation in to either IL-6 + or was osteoclast formation in to IL-1 was also by expression of Expression of dn-STAT3 on or osteoclast formation, that dn-STAT3 not a negative on cell but blocked specific pathways to osteoclast the results UAMS-32 cells conditionally dn-gp130 in studies demonstrated that stimulate the of RANKL and together with M-CSF, this protein the differentiation of hematopoietic precursors osteoclasts in the absence of stromal/osteoblastic cells (8Lacey D.L. Timms E. Tan H.L. Kelley M.J. Dunstan C.R. Burgess T. Elliott R. Colombero A. Elliott G. Scully S. Hsu H. Sullivan J. Hawkins N. Davy E. Capparelli C. Eli A. Qian Y.X. Kaufman S. Sarosi I. Shalhoub V. Senaldi Guo J. Delaney J. Boyle W.J. Cell. 1998; 93: 165-176Abstract Full Text Full Text PDF PubMed Scopus (4546) Google Scholar, 9Yasuda H. Shima N. Nakagawa N. Yamaguchi K. Kinosaki M. Mochizuki S. Tomoyasu A. Yano K. Goto M. Murakami A. Tsuda E. Morinaga T. Higashio Udagawa N. Takahashi N. Suda T. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 3597-3602Crossref PubMed Scopus (3500) Google Scholar). these studies not established whether RANKL is the target of gp130 activation for support of osteoclast formation by stromal/osteoblastic cells. it is that in to inducing RANKL may stimulate osteoclast formation in by the of cytokines such as or by stromal/osteoblastic cells N. Elliott J. A. J. H. M. T.J. Martin T.J. J. Exp. Med. 1997; PubMed Scopus Google Scholar). To determine IL-6-type cytokines or other induce support of osteoclast formation by stimulating RANKL expression in stromal/osteoblastic cells, we that each of these was to stimulate RANKL expression in UAMS-32 cells RANKL was conditionally expressed in UAMS-32 cells the expression of RANKL expression by of was sufficient in to stimulate osteoclast formation in the UAMS-32 cells, the for by IL-6-type cytokines or other the that dn-STAT3 blocked IL-6-type or osteoclastogenesis and that expression of RANKL in UAMS-32 cells the for we that the dn-STAT3 blocked osteoclast formation by the stimulated expression of RANKL. To determine this was the we UAMS-32 cells conditionally dn-STAT3 with IL-6-type cytokines or and RANKL expression by In the absence of dn-STAT3 or IL-6 + stimulated the expression of RANKL which was in cells with in the of dn-STAT3 RANKL by or IL-6 + was or RANKL expression was results in cells conditionally dn-gp130 of these with M-CSF demonstrated that this was expressed by UAMS-32 cells and was by hormone or cytokine In induction of dn-STAT3 in UAMS-32 cells also of RANKL by IL-1 but not by not for the signaling pathways by gp130 activation in osteoclastogenesis has been suggested by that gp130 activation by IL-6, IL-11, or osteoclast formation in a of in of osteoclastogenesis T. Udagawa N. Takahashi N. of Bone Academic Press, Inc., San Scholar, G. G. Jilka R.L. S.C. J. 93: PubMed Scopus Google Scholar, E. Udagawa N. H. Tamura T. M. Taga T. Suda T. Martin T.J. J. Exp. Med. PubMed Scopus Google Scholar). In addition, mice and or mice not the in osteoclast formation and bone that in R.L. G. G. G. B. H. S.C. PubMed Scopus Google Scholar, V. R. E. A. M. Tanaka H. G. J. PubMed Scopus Google Scholar, T. Jilka R.L. G. H. R. S.C. J. 1995; 95: PubMed Scopus Google Scholar). its in the bone by of IL-6 to a in other with bone resorption as by or of IL-6 and the IL-6 receptor in with or bone and and S.C. Jilka R.L. T. of Bone Academic Press, Inc., San Scholar). osteoclast formation is in mice or IL-6 or in gp130 that gp130-mediated osteoclast formation may in (1Manolagas S.C. Jilka R.L. N. Engl. J. Med. 1995; 332: 305-311Crossref PubMed Scopus (1550) Google Scholar). The results of the in studies in this for the some of the downstream by gp130 in stromal/osteoblastic cells, that are essential for osteoclast formation from hematopoietic the in this that activation of the transcription factor STAT3 in stromal/osteoblastic cells is for gp130-mediated osteoclastogenesis and that the target of STAT3 for osteoclastogenesis is RANKL. In addition, results to that the pathway mediates not the osteoclastogenic effects of IL-6-type cytokines but also of in the in utilized in the the osteoclastogenic effects of or of the gp130-STAT3 and each been to stimulate osteoclast formation in other (11Tamura T. Udagawa N. Takahashi N. Miyaura C. Tanaka S. Yamada Y. Koishihara Y. Ohsugi Y. Kumaki K. Taga T. Kishimoto T. Suda T. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 11924-11928Crossref PubMed Scopus (761) Google Scholar, G. G. Jilka R.L. S.C. J. 93: PubMed Scopus Google Scholar, E. Udagawa N. H. Tamura T. M. Taga T. Suda T. Martin T.J. J. Exp. Med. PubMed Scopus Google these cytokines unable to in A. and S. C. The for this is that UAMS-32 cells sufficient of the specific for these of these cytokines gp130 for signal and STAT3 in cells with or T. S. M. Taga T. 1995; PubMed Google Scholar). it is as is the with and IL-6 + in STAT3 is for the induction of RANKL (9Yasuda H. Shima N. Nakagawa N. Yamaguchi K. Kinosaki M. Mochizuki S. Tomoyasu A. Yano K. Goto M. Murakami A. Tsuda E. Morinaga T. Higashio Udagawa N. Takahashi N. Suda T. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 3597-3602Crossref PubMed Scopus (3500) Google and of osteoclast formation (11Tamura T. Udagawa N. Takahashi N. Miyaura C. Tanaka S. Yamada Y. Koishihara Y. Ohsugi Y. Kumaki K. Taga T. Kishimoto T. Suda T. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 11924-11928Crossref PubMed Scopus (761) Google Scholar, G. G. Jilka R.L. S.C. J. 93: PubMed Scopus Google by or in other and also gp130 activation J. Y. H. J. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar, R. B. B. 1998; PubMed Scopus Google and since may complexes with STAT3 J.E. PubMed Scopus Google Scholar, R. U. M. V. D. M. J. 1997; Full Text Full Text PDF PubMed Scopus Google we the that these other together with in gp130-mediated osteoclastogenesis. that many gp130 are in mice D. K. R. M. Cell. Full Text Full Text PDF PubMed Scopus Google and that and STAT3 to target of R. B. B. 1998; PubMed Scopus Google Scholar). In studies with dominant negative of these other to establish whether a in osteoclastogenesis. results the that other gp130 signaling pathways may also for the osteoclastogenic to IL-6-type cytokines, since of by pathway J. E. J. Cell. 1997; PubMed Scopus Google is for activation of target J.E. Cell. 1995; Full Text PDF PubMed Scopus Google Scholar). on by and Suda T. Udagawa N. Takahashi N. of Bone Academic Press, Inc., San that osteoclastogenic function by activating one of signaling pathways in stromal/osteoblastic the vitamin D receptor pathway by the protein pathway by or and the gp130 pathway by IL-6-type that that IL-1, or may stimulate osteoclastogenesis in by stimulating the of one or members of the IL-6-type cytokine we that osteoclast formation in to IL-1, or in of bone and cells G. G. Jilka R.L. S.C. J. 93: PubMed Scopus Google Scholar). that abolished osteoclast formation and by osteoclast formation by or in a E. Udagawa N. H. Tamura T. M. Taga T. Suda T. Martin T.J. J. Exp. Med. PubMed Scopus Google Scholar). in as as in studies IL-6 in the bone effects of G. G. Jilka R.L. S.C. J. 93: PubMed Scopus Google Scholar, A. M. S.C. Jilka R.L. K. J. Bone Miner. Res. 1997; 12 (abstr.): Scopus Google Scholar). R. G. Roodman G.D. J. Bone Miner. Res. 1998; PubMed Scopus Google found that osteoclast development in in to IL-1 or tumor necrosis factor but not to or by IL-6 The of essential of gp130-STAT3 activation in but not or osteoclast formation in is in with the studies of but not with the IL-6-type cytokines in the osteoclastogenic effects of or The of may not it is established that activation of gp130 on hematopoietic osteoclast precursors T. Yamaguchi Y. Suda J. Y. A. Y. Exp. Google Scholar, J. H.L. B. Roodman G.D. J. 1995; 95: PubMed Scopus Google Scholar). it is that the in or osteoclast formation by or in the studies from of osteoclast of provided by stromal/osteoblastic cells, RANKL or In we the gp130-STAT3 pathway in a stromal/osteoblastic cell line that supports osteoclast formation that or of IL-6-type cytokines on hematopoietic cells been In to the that IL-1 osteoclast formation pathways also utilized by T. Udagawa N. Takahashi N. of Bone Academic Press, Inc., San the in cells, together with that of cells, that the osteoclastogenic effects of IL-1 are not by the pathways as but by the gp130 signaling IL-1 and are capable of stimulating IL-6-type cytokine in bone cells or bone cell G. Jilka R.L. G. S. G. S.C. J. PubMed Scopus Google Scholar, J. Cell. PubMed Scopus Google Scholar, M.J. S. J. Bone Miner. Res. PubMed Scopus Google Scholar, J. Bone Miner. Res. 1997; PubMed Scopus Google signaling pathways J. Bone Miner. Res. 1997; PubMed Scopus Google Scholar). This together with the that gp130 activation is for but not osteoclast formation, that IL-1 not may the of the ligand binding of the for IL-6-type cytokines in stromal/osteoblastic cells. results the that IL-1 may activating the gp130-STAT3 pathway J. Y. Cell. PubMed Scopus Google Scholar). RANKL is expressed in and bone cells (7Anderson D.M. Maraskovsky E. Billingsley W.L. Dougall W.C. Tometsko M.E. Roux E.R. Teepe M.C. DuBose R.F. Cosman D. Galibert L. Nature. 1997; 390: 175-179Crossref PubMed Scopus (1905) Google Scholar, 8Lacey D.L. Timms E. Tan H.L. Kelley M.J. Dunstan C.R. Burgess T. Elliott R. Colombero A. Elliott G. Scully S. Hsu H. Sullivan J. Hawkins N. Davy E. Capparelli C. Eli A. Qian Y.X. Kaufman S. Sarosi I. Shalhoub V. Senaldi Guo J. Delaney J. Boyle W.J. Cell. 1998; 93: 165-176Abstract Full Text Full Text PDF PubMed Scopus (4546) Google Scholar, 9Yasuda H. Shima N. Nakagawa N. Yamaguchi K. Kinosaki M. Mochizuki S. Tomoyasu A. Yano K. Goto M. Murakami A. Tsuda E. Morinaga T. Higashio Udagawa N. Takahashi N. Suda T. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 3597-3602Crossref PubMed Scopus (3500) Google Scholar). found and that activation of the gp130 or signaling pathways results in RANKL expression in cells of the lineage but not other mesenchymal cell I. Jilka R.L. S.C. Bone. 1998; 23 (abstr.): Scholar). the gp130 and pathways in these other cell we that expression of RANKL in cells of the stromal/osteoblastic lineage by a In we that new protein is for gp130 or RANKL it that activation of gp130 or on stromal/osteoblastic cells the expression of a that the of RANKL the cell of RANKL expression is to expression of this in the RANKL is is to that and the cell that of are also the cell that of the transcription factor P. R. V. G. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). we recently that the and RANKL contain and that of these the of the RANKL S.C. Bone. 1998; 23 (abstr.): PubMed Google Scholar). the expression of RANKL in cells of the stromal/osteoblastic lineage in by the expression of In to the expression of we that the of for RANKL expression may the of the and osteoclastogenesis. In the in this the of STAT3 activation for RANKL induction and the of osteoclastogenesis by cytokines that gp130 and that the osteoclastogenic of IL-1 in IL-6-type of the signaling pathways by may specific for in of or osteoclast formation. T. and R. Jilka for of the and and N. for
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