Department of Rheumatology and Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Department of Rheumatology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China.
JCI Insight. 2021 Dec 8;6(23):e146757. doi: 10.1172/jci.insight.146757.
Fibroblast-like synoviocytes (FLSs) play a key role in controlling synovial inflammation and joint destruction in rheumatoid arthritis (RA). The contribution of long noncoding RNAs (lncRNAs) to RA is largely unknown. Here, we show that the lncRNA LINK-A, located mainly in cytoplasm, has higher-than-normal expression in synovial tissues and FLSs from patients with RA. Synovial LINK-A expression was positively correlated with the severity of synovitis in patients with RA. LINK-A knockdown decreased migration, invasion, and expression and secretion of matrix metalloproteinases and proinflammatory cytokines in RA FLSs. Mechanistically, LINK-A controlled RA FLS inflammation and invasion through regulation of tyrosine protein kinase 6-mediated and leucine-rich repeat kinase 2-mediated HIF-1α. On the other hand, we also demonstrate that LINK-A could bind with microRNA 1262 as a sponge to control RA FLS aggression but not inflammation. Our findings suggest that increased level of LINK-A may contribute to FLS-mediated rheumatoid synovial inflammation and aggression. LINK-A might be a potential therapeutic target for RA.
成纤维样滑膜细胞（FLSs）在控制类风湿关节炎（RA）中的滑膜炎症和关节破坏中起着关键作用。长链非编码 RNA（lncRNA）在 RA 中的作用在很大程度上是未知的。在这里，我们表明，位于细胞质中的 lncRNA LINK-A 在 RA 患者的滑膜组织和 FLSs 中表达高于正常水平。滑膜 LINK-A 的表达与 RA 患者滑膜炎的严重程度呈正相关。LINK-A 敲低降低了 RA FLSs 的迁移、侵袭以及基质金属蛋白酶和促炎细胞因子的表达和分泌。在机制上，LINK-A 通过调节酪氨酸蛋白激酶 6 介导和富含亮氨酸重复激酶 2 介导的 HIF-1α 来控制 RA FLS 炎症和侵袭。另一方面，我们还证明 LINK-A 可以作为海绵与 microRNA 1262 结合，从而控制 RA FLS 的侵袭，但不能控制炎症。我们的研究结果表明，LINK-A 水平的升高可能导致 FLS 介导的类风湿性滑膜炎症和侵袭。LINK-A 可能是 RA 的一个潜在治疗靶点。
