Suppressors of cytokine signaling-1 and-3 regulate osteoclastogenesis in the presence of inflammatory cytokines
Suppressors of cytokine signaling-1 and-3 regulate osteoclastogenesis in the presence of inflammatory cytokines
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DOI：
10.4049/jimmunol.174.5.3024
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发表时间：
2005-03-01
影响因子：
4.4
通讯作者：
Yoshimura, A
中科院分区：
文献类型：
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作者：
Ohishi, M;Matsumura, Y;Yoshimura, A
骨代谢与免疫系统有着密切的关系，两者都受到骨微环境中产生的各种常见细胞因子如IFN和IL的调控。细胞因子信号转导抑制因子-1（SOCS 1）和SOCS 3是这些细胞因子的负调节因子。尽管SOCS在破骨细胞分化过程中被诱导，但其在破骨细胞分化和功能中的生理作用尚未阐明。因此，我们使用SOCS 1和SOCS 3缺陷小鼠研究了SOCS 1和SOCS 3在破骨细胞生成中的作用。IFN-γ介导的骨髓源性单核细胞（BCRs）破骨细胞分化的抑制在SOCS 1缺陷BCRs中强烈增强，但在SOCS 1过表达BCRs中减弱。此外，与野生型小鼠相比，SOCS 1小鼠体内LPS诱导的破骨细胞生成和骨破坏受到抑制，表明SOCS 1拮抗IFN-γ对破骨细胞生成的抑制作用。SOCS 3没有改变IFN在破骨细胞生成中的抑制作用，在功能测定的获得和丧失中;然而，IL-6对破骨细胞分化的抑制作用在体外SOCS 3缺陷型BclB中比野生型BclB中更大。此外，IL-6在SOCS 3缺陷小鼠中显著预防LPS诱导的骨破坏，尽管在体内野生型小鼠中它失败了。在SOCS 3缺陷型BCR 4中，TNF-受体相关因子-6和IkappaB的表达水平显著降低，并且在IL-6存在下，NF-κ B配体诱导的IkappaB磷酸化的受体激活剂严重受损。这些数据表明，SOCS 1和SOCS 3通过阻断炎性细胞因子对NF-κ B配体介导的破骨细胞分化信号的受体激活剂的抑制作用来调节破骨细胞生成。选择性抑制破骨细胞前体中的SOCS 1和SOCS 3可能是炎性骨破坏的一种可能的治疗策略。
Bone metabolism and the immune system have a correlative relationship, and both are controlled by various common cytokines, such as IFNs and ILs, produced in the bone microenvironments. The suppressor of cytokine signaling-1 (SOCS1) and SOCS3 are negative regulators of such cytokines. Although SOCSs are shown to be induced during osteoclast differentiation, their physiological roles in osteoclast differentiation and function have not been clarified. Thus, we examined the roles of SOCS1 and SOCS3 in osteoclastogenesis using SOCS1- and SOCS3-deficient mice. IFN-gamma-mediated inhibition of osteoclast differentiation from bone marrow-derived monocytes (BMMs) was strongly enhanced in SOCS1-deficient BMMs, but was diminished in SOCS1-overexpressing BMMs. Moreover, LPS-induced osteoclastogenesis and bone destruction in vivo were suppressed in SOCS1 mice compared with those in wild-type mice, suggesting that SOCS1 antagonizes the inhibitory effect of IFN-gamma on osteoclastogenesis. SOCS3 did not alter the inhibitory effect of IFNs in osteoclastogenesis in both gain and loss of functional assays; however, the suppressive effect of IL-6 on osteoclast differentiation was greater in SOCS3-deficient BMMs than in wild-type BMMs in vitro. In addition, IL-6 significantly prevented LPS-induced bone destruction in SOCS3-deficient mice, although it failed in wild-type mice in vivo. In SOCS3-deficient BMMs, expression levels of TNF-receptor-associated factor-6 and IkappaB were drastically reduced and receptor activator of the NF-kappaB ligand-induced IkappaB phosphorylation was severely impaired in the presence of IL-6. These data suggest that both SOCS1 and SOCS3 regulate osteoclastogenesis by blocking the inhibitory effect of inflammatory cytokines on receptor activator of the NF-kappaB ligand-mediated osteoclast differentiation signals. Selective suppression of SOCS1 and SOCS3 in osteoclast precursors may be a possible therapeutic strategy for inflammatory bone destruction.