Su Chen-Ming, Chiang Yi-Chun, Huang Chun-Yin, Hsu Chin-Jung, Fong Yi-Chin, Tang Chih-Hsin
Department of Biomedical Sciences Laboratory, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang, China 322100; Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan 40466;
Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan 40466;
J Immunol. 2015 Oct 1;195(7):3355-64. doi: 10.4049/jimmunol.1403191. Epub 2015 Aug 24.
Accumulating evidence indicates that subchondral bone might play an essential role in rheumatoid arthritis (RA). Osteopontin (OPN) induces the production of an important proinflammatory cytokine involved in the pathogenesis of RA. This study evaluated the activation of oncostatin M (OSM) by OPN in human primary osteoblasts to understand RA pathogenesis and characterized the intracellular signaling pathways involved in this activation. Quantitative PCR, ELISA, and Western blot results indicated that stimulation of human primary osteoblasts with OPN induces OSM expression through αvβ3 integrin/c-Src/platelet-derived growth factor receptor transactivation/MEK/ERK. Treatment of osteoblasts with OPN also increased c-Jun phosphorylation, AP-1 luciferase activity, and c-Jun binding to the AP-1 element on the OSM promoter, as demonstrated using chromatin immunoprecipitation assay. Moreover, inhibition of OPN expression using lentiviral-OPN short hairpin RNA resulted in the amelioration of articular swelling, cartilage erosion, and OSM expression in the ankle joint of mice with collagen-induced arthritis as shown using microcomputed tomography and immunohistochemistry staining. Our results imply that OSM expression in osteoblasts increases in response to OPN-induced inflammation in vitro. Finally, lentiviral-OPN short hairpin RNA ameliorates the inflammatory response and bone destruction in mice with collagen-induced arthritis. Therefore, OPN may be a potential therapeutic target for RA.
越来越多的证据表明，软骨下骨可能在类风湿关节炎（RA）中起重要作用。骨桥蛋白（OPN）可诱导一种参与RA发病机制的重要促炎细胞因子的产生。本研究评估了OPN在人原代成骨细胞中对抑瘤素M（OSM）的激活作用，以了解RA的发病机制，并对参与这种激活的细胞内信号通路进行了表征。定量PCR、ELISA和蛋白质印迹结果表明，用OPN刺激人原代成骨细胞可通过αvβ3整合素/c-Src/血小板衍生生长因子受体反式激活/MEK/ERK诱导OSM表达。用OPN处理成骨细胞还增加了c-Jun磷酸化、AP-1荧光素酶活性以及c-Jun与OSM启动子上AP-1元件的结合，染色质免疫沉淀分析证明了这一点。此外，使用慢病毒OPN短发夹RNA抑制OPN表达可改善胶原诱导性关节炎小鼠踝关节的关节肿胀、软骨侵蚀和OSM表达，微计算机断层扫描和免疫组织化学染色显示了这一点。我们的结果表明，体外成骨细胞中OSM的表达会因OPN诱导的炎症而增加。最后，慢病毒OPN短发夹RNA可改善胶原诱导性关节炎小鼠的炎症反应和骨质破坏。因此，OPN可能是RA的一个潜在治疗靶点。
