Long Noncoding RNA XIST Binding to Let-7c-5p Contributes to Rheumatoid Arthritis Through Its Effects on Proliferation and Differentiation of Osteoblasts <i>via </i>Regulation of STAT3

Abstract

Rheumatoid arthritis (RA), a chronic autoimmune disease, affects around 1% population worldwide, with the life quality of patients severely reduced. In this study, we test the hypothesis that silencing long non-coding RNA x-inactive specific transcript (lncRNA XIST) acts as a biomarker for RA treatment through its effects on proliferation and differentiation of osteoblasts via let-7c-5p-mediated signal transducer and activator of transcription 3 (STAT3). We collected RA and normal cartilage tissues for determination of lncRNA XIST, let-7c-5p, and STAT3, the relationship among which were verified through alternation of lncRNA XIST and let-7c-5p in osteoblasts. The regulatory effects of lncRNA XIST in RA were investigated via loss-of-function and gain-of-function experiments. After RA rat models were established, TNF-α, IL-2, IL-6, alkaline phosphatase (ALP), osteocalcin, TGF-β1, and IGF1 were measured, and the damage degree of cartilage tissues was observed. The findings indicated that lncRNA XIST and STAT3 were highly expressed and let-7c-5p was reciprocal in RA cartilage tissues. LncRNA XIST knockdown or upregulation of let-7c-5p decreased levels of TNF-α, IL-2 and IL-6 to suppress inflammatory response, increased levels of ALP, osteocalcin, TGF-β1, and IGF-1 to promote proliferation and differentiation, and ameliorated pathological state and damage degree of cartilage tissues. these findings indicate that lncRNA XIST may act as a molecular sponge to regulate let-7c-5p, and its downregulation could relieve RA due to promoting effects on proliferation and differentiation of osteoblasts by inhibiting STAT3, serving as a future therapeutic strategy for RA. Funding Statement: This study was supported by grants from National Natural Science Foundation of China (No. 81402936; No.81302576), Six Talent Peak Research Project in Jiangsu Province (No. 2015-WSN-105), the 333 Project of Jiangsu Province, Jiangsu Province Youth Medical Talent Project, Jiangsu Provincial Natural Science Foundation of China (No. BK20131234). Declaration of Interests: The authors declare that we have no conflicts of interest. Ethics Approval Statement: All animal experiments were performed in line with the Guide for the Care and Use of Laboratory Animal. This study was approved by the Ethics Committee of Clinical Medical College, Yangzhou University, while all patients had provided the signed forms of informed consent.