SMOC2 promotes aggressive behavior of fibroblast-like synoviocytes in rheumatoid arthritis through transcriptional and post-transcriptional regulating MYO1C.
SMOC2 promotes aggressive behavior of fibroblast-like synoviocytes in rheumatoid arthritis through transcriptional and post-transcriptional regulating MYO1C.
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SMOC2通过转录和转录后调节MYO1C促进类风湿性关节炎中成纤维细胞样滑膜细胞的攻击行为
DOI：
10.1038/s41419-022-05479-0
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发表时间：
2022-12-13
影响因子：
9
通讯作者：
Xu, Hanshi
中科院分区：
文献类型：
--
作者：
Liu, Di;Li, Ruiru;Xu, Siqi;Shi, Maohua;Kuang, Yu;Wang, Jingnan;Shen, Chuyu;Qiu, Qian;Liang, Liuqin;Xiao, Youjun;Xu, Hanshi
成纤维细胞样滑膜细胞（FLS）在类风湿性关节炎（RA）滑膜炎症和骨质侵蚀中起关键作用，但其激活和侵袭的机制尚不清楚。迫切需要鉴定选择性靶向FLS的内源性蛋白。在这里，我们系统地确定，分泌模块化钙结合蛋白2（SMOC 2），在RA FLS和滑膜组织中显着增加。SMOC 2基因敲低特异性调节细胞骨架重塑，降低RA FLS的迁移和侵袭。从机制上讲，在SMOC 2表达减少的RA FLS中，细胞因子相关基因显著下调，尤其是运动蛋白肌球蛋白1c（MYO 1C）。SMOC 2通过SRY相关的高迁移率族蛋白4（SOX 4）和AlkB同源物5（ALKHB 5）介导的m6 A修饰通过转录和转录后调节来控制MYO 1C的表达。此外，关节内Ad-shRNA-SMOC 2治疗减轻了胶原诱导性关节炎（CIA）大鼠的滑膜炎症以及骨和软骨侵蚀。我们的研究结果表明，增加SMOC 2表达FLS可能有助于滑膜侵略和关节破坏类风湿关节炎。SMOC 2可能是抗RA的潜在靶点。SMOC 2介导的RA FLS中滑膜迁移和侵袭的调节。在RA FLS中，SMOC 2显著增加，通过SOX 4介导的转录调节和ALKBH 5介导的m6 A修饰导致MYO 1C水平增加，从而引起细胞骨架重塑并促进RA FLS迁移和侵袭。图由Figdraw绘制。
Fibroblast-like synoviocytes (FLSs), play a key role in perpetuating synovial inflammation and bone erosion in rheumatoid arthritis (RA), however, the underlying mechanism(s) of RA FLSs activation and aggression remain unclear. Identifying endogenous proteins that selectively target FLSs is urgently needed. Here, we systematically identified that secreted modular calcium-binding protein 2 (SMOC2), was significantly increased in RA FLSs and synovial tissues. SMOC2 knockdown specifically regulated cytoskeleton remodeling and decreased the migration and invasion of RA FLSs. Mechanistically, cytoskeleton-related genes were significantly downregulated in RA FLSs with reduced SMOC2 expression, especially the motor protein myosin1c (MYO1C). SMOC2 controlled MYO1C expression by SRY-related high-mobility group box 4 (SOX4) and AlkB homolog 5 (ALKHB5) mediated-m6A modification through transcriptional and post-transcriptional regulation. Furthermore, intra-articular Ad-shRNA-SMOC2 treatment attenuated synovial inflammation as well as bone and cartilage erosion in rats with collagen-induced arthritis (CIA). Our findings suggest that increased SMOC2 expression in FLSs may contribute to synovial aggression and joint destruction in RA. SMOC2 may serve as a potential target against RA. SMOC2-mediated regulation of the synovial migration and invasion in RA FLSs. In RA FLSs, SMOC2 is significantly increased, leading to the increased level of MYO1C via SOX4-mediated transcriptional regulation and ALKBH5-mediated m6A modification, thereby causing cytoskeleton remodeling and promoting RA FLSs migration and invasion. The Figure was drawn by Figdraw.
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DOI：
10.1002/art.40504
发表时间：
2018-07
期刊：
Arthritis & rheumatology (Hoboken, N.J.)
影响因子：
--
作者：
Falconer J;Murphy AN;Young SP;Clark AR;Tiziani S;Guma M;Buckley CD
通讯作者：
Buckley CD
DOI：
10.1002/art.40386
发表时间：
2018-03
期刊：
Arthritis & rheumatology (Hoboken, N.J.)
影响因子：
--
作者：
Bhattaram P;Muschler G;Wixler V;Lefebvre V
通讯作者：
Lefebvre V
影响因子：
8
作者：
Gerarduzzi, Casimiro;Kumar, Ramya K.;Vaidya, Vishal S.
通讯作者：
Vaidya, Vishal S.
影响因子：
4.6
作者：
Morkmued, Supawich;Clauss, Francois;Niederreither, Karen
通讯作者：
Niederreither, Karen
影响因子：
8
作者：
Shvab, A.;Haase, G.;Ben-Ze'ev, A.
通讯作者：
Ben-Ze'ev, A.