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The Journal of Immunology, 2003, 170: 3679-3687.
Copyright © 2003 by The American Association of Immunologists

The Possible Role of TGF-{beta}-Induced Suppressors of Cytokine Signaling Expression in Osteoclast/Macrophage Lineage Commitment In Vitro1

Simon W. Fox2,*, S. Jaharul Haque{dagger}, Alison C. Lovibond* and Timothy J. Chambers*

* Department of Cellular Pathology, St. George’s Hospital Medical School, London, United Kingdom; and {dagger} Departments of Cancer Biology and Pulmonary Critical Care Medicine, Cleveland Clinic Foundation, Cleveland, OH 44195

Osteoclast formation is dependent on the ability of TGF-{beta} to enable receptor activator of NF-{kappa}B ligand (RANKL)-induced commitment of hemopoietic precursors to the osteoclastic lineage. The mechanism by which TGF-{beta} enables formation is unknown. One possibility is that TGF-{beta} opposes Janus kinase (JAK)/STAT signals generated by inhibitory cytokines such as IFN-{beta}. The JAK/STAT pathway is activated by cytokines that induce resistance to osteoclast formation, such as IFN-{gamma} and M-CSF, and the effect of these is opposed by TGF-{beta}. Recently, a group of STAT-induced factors, termed suppressors of cytokine signaling (SOCS), has been identified that inhibit JAK/STAT signals. Therefore, we tested the ability of TGF-{beta} to induce SOCS expression in osteoclast precursors and examined the effect of SOCS expression on osteoclast/macrophage lineage commitment. We found that while SOCS mRNA is undetectable in macrophages, osteoclasts express SOCS-3, and TGF-{beta} up-regulates this expression. Furthermore, TGF-{beta} rapidly induces sustained SOCS-3 expression in macrophage/osteoclast precursors. To determine whether SOCS-3 plays a role in osteoclast differentiation we expressed SOCS-3 in precursors using a retroviral system. We found that osteoclast differentiation was significantly enhanced in SOCS-3-infected precursors, and SOCS-3 expression enables formation in the presence of anti-TGF-{beta} Ab. On the other hand, antisense knockdown of SOCS-3 strongly suppressed osteoclast formation and significantly blunted the response to TGF-{beta}. Moreover, like TGF-{beta}, SOCS-3 expression opposed the inhibitory effect of IFN-{beta}. These data suggest that TGF-{beta}-induced expression of SOCS-3 may represent a mechanism by which TGF-{beta} suppresses inhibitory cytokine signaling, priming precursors for a role in bone resorption.




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