The possible role of TGF-β-induced suppressors of cytokine signaling expression in osteoclast/macrophage lineage commitment in vitro

被引:74
作者
Fox, SW
Haque, SJ
Lovibond, AC
Chambers, TJ
机构
[1] St George Hosp, Sch Med, Dept Cellular Pathol, London SW17 0RE, England
[2] Cleveland Clin Fdn, Dept Canc Biol, Cleveland, OH 44195 USA
[3] Cleveland Clin Fdn, Dept Pulm Crit Care Med, Cleveland, OH 44195 USA
关键词
D O I
10.4049/jimmunol.170.7.3679
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Osteoclast formation is dependent on the ability of TGF-beta to enable receptor activator of NF-kappaB 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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页码:3679 / 3687
页数:9
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