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-Induced Suppressors of Cytokine Signaling Expression in Osteoclast/Macrophage Lineage Commitment In Vitro1
* Department of Cellular Pathology, St. George’s Hospital Medical School, London, United Kingdom; and
Departments of Cancer Biology and Pulmonary Critical Care Medicine, Cleveland Clinic Foundation, Cleveland, OH 44195
Osteoclast formation is dependent on the ability of TGF-
to enable receptor activator of NF-
B ligand (RANKL)-induced commitment of hemopoietic precursors to the osteoclastic lineage. The mechanism by which TGF- enables formation is unknown. One possibility is that TGF- opposes Janus kinase (JAK)/STAT signals generated by inhibitory cytokines such as IFN-. The JAK/STAT pathway is activated by cytokines that induce resistance to osteoclast formation, such as IFN-
and M-CSF, and the effect of these is opposed by TGF-. 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- 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- up-regulates this expression. Furthermore, TGF- 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- Ab. On the other hand, antisense knockdown of SOCS-3 strongly suppressed osteoclast formation and significantly blunted the response to TGF-. Moreover, like TGF-, SOCS-3 expression opposed the inhibitory effect of IFN-. These data suggest that TGF--induced expression of SOCS-3 may represent a mechanism by which TGF- suppresses inhibitory cytokine signaling, priming precursors for a role in bone resorption.
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