The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia and University of Melbourne, Parkville, Victoria, Australia.
Arthritis Rheumatol. 2014 Sep;66(9):2391-402. doi: 10.1002/art.38701.
To examine the impact of the gp130 cytokine family on murine articular cartilage and to explore a potential regulatory role of suppressor of cytokine signaling 3 (SOCS-3) in murine chondrocytes.
In wild-type (WT) mouse chondrocytes, baseline receptor expression levels and gp130 cytokine-induced JAK/STAT signaling were determined by flow cytometry, and expression of SOCS-3 was assessed by quantitative polymerase chain reaction. The role of endogenous SOCS-3 was examined in cartilage explants and chondrocytes from mice with conditional deletion of Socs3 driven by the Col2a1 promoter in vitro (Socs3(Δ/Δcol2) ) and from mice during CD4+ T cell-dependent inflammatory monarthritis. Bone erosions in the murine joints were analyzed by micro-computed tomography.
On chondrocytes from WT mice, gp130 and the oncostatin M (OSM) receptor were strongly expressed, whereas the transmembrane interleukin-6 (IL-6) receptor was expressed at much lower levels. Compared to other gp130 cytokines, OSM was the most potent activator of the JAK/STAT pathway and of SOCS-3 induction. Treatment of Socs3(Δ/Δcol2) mouse cartilage explants and chondrocytes with gp130 cytokines prolonged JAK/STAT signaling, enhanced cartilage degradation, increased the expression of Adamts4, Adamts5, and RANKL, and elevated the production of IL-6, granulocyte colony-stimulating factor, CXCL1, and CCL2. Socs3(Δ/Δcol2) mice developed exacerbated inflammation and joint damage in response to gp130 cytokine injections, and these histopathologic features were also observed in mice with inflammatory monarthritis.
The results of this study highlight a key role for SOCS-3 in regulating chondrocyte responses during inflammatory arthritis. Within the gp130 cytokine family, OSM is a potent stimulus of chondrocyte responses, while IL-6 probably signals via trans-signaling. The gp130 cytokine-driven production of RANKL in chondrocytes may link chondrocyte activation and bone remodeling during inflammatory arthritis. Thus, these findings suggest that the inhibition of OSM might reduce the development and severity of structural joint damage during inflammatory arthritis.
研究 gp130 细胞因子家族对鼠类关节软骨的影响，并探讨信号转导和转录激活因子 3（SOCS-3）在鼠类软骨细胞中的潜在调节作用。
在野生型（WT）鼠软骨细胞中，通过流式细胞术测定基线受体表达水平和 gp130 细胞因子诱导的 JAK/STAT 信号，通过定量聚合酶链反应评估 SOCS-3 的表达。在体外通过 Col2a1 启动子驱动 Socs3 条件性缺失的软骨细胞和 CD4+T 细胞依赖性炎症性单核关节炎小鼠中，研究内源性 SOCS-3 的作用。通过微计算机断层扫描分析小鼠关节中的骨侵蚀。
在 WT 小鼠的软骨细胞上，gp130 和抑瘤素 M（OSM）受体强烈表达，而跨膜白细胞介素 6（IL-6）受体的表达水平要低得多。与其他 gp130 细胞因子相比，OSM 是 JAK/STAT 途径和 SOCS-3 诱导的最有效激活剂。gp130 细胞因子处理 Socs3(Δ/Δcol2) 鼠软骨外植体和软骨细胞可延长 JAK/STAT 信号，增强软骨降解，增加 Adamts4、Adamts5 和 RANKL 的表达，并提高白细胞介素 6、粒细胞集落刺激因子、CXCL1 和 CCL2 的产生。Socs3(Δ/Δcol2) 小鼠对 gp130 细胞因子注射反应产生更严重的炎症和关节损伤，这些组织病理学特征也见于单核关节炎小鼠。
本研究结果强调了 SOCS-3 在调节炎症性关节炎期间软骨细胞反应中的关键作用。在 gp130 细胞因子家族中，OSM 是软骨细胞反应的有效刺激物，而白细胞介素 6 可能通过转信号传递。gp130 细胞因子驱动软骨细胞中 RANKL 的产生可能在炎症性关节炎期间连接软骨细胞激活和骨重塑。因此，这些发现表明抑制 OSM 可能减少炎症性关节炎期间结构关节损伤的发生和严重程度。
