Yuan Gongsheng, Yang Shu-Ting, Yang Shuying
Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
The Penn Center for Musculoskeletal Disorders, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Mol Ther Nucleic Acids. 2022 Dec 27;31:197-210. doi: 10.1016/j.omtn.2022.12.017. eCollection 2023 Mar 14.
Synovial fibroblasts are the active and aggressive drivers in the progression of arthritis, but the cellular and molecular mechanisms remain unknown. Here, our results showed that regulator of G protein signaling 12 (RGS12) maintained ciliogenesis in synovial fibroblasts, which is critical for the development of inflammatory arthritis. Deletion of RGS12 led to a significant decrease in ciliogenesis, adhesion, migration, and secretion of synovial fibroblasts. Mechanistically, RGS12 overexpression in synovial fibroblasts increased the length and number of cilia but decreased the protein level of kinesin family member 2A (KIF2A). The results of LC-MS analyses showed that RGS12 interacted with MYC binding protein 2 to enhance its ubiquitination activity, through which the KIF2A protein was degraded in synovial fibroblasts. Moreover, overexpression of KIF2A blocked the increases in cilia length and number. Mice with RGS12 deficiency or treatment of RGS12 shRNA nanoparticles significantly decreased the clinical score, paw swelling, synovitis, and cartilage destruction during inflammatory arthritis by inhibiting the activation of synovial fibroblasts. Therefore, this study provides evidence that RGS12 activates synovial fibroblasts' pathological function via promoting MCYBP2-mediated degradation of KIF2A and ciliogenesis. Our data suggest that RGS12 may be a potential drug target for the treatment of inflammatory arthritis.
滑膜成纤维细胞是关节炎进展过程中活跃且具有侵袭性的驱动因素，但其细胞和分子机制仍不清楚。在此，我们的结果表明，G蛋白信号调节因子12（RGS12）维持滑膜成纤维细胞的纤毛发生，这对炎性关节炎的发展至关重要。RGS12的缺失导致滑膜成纤维细胞的纤毛发生、黏附、迁移和分泌显著减少。从机制上讲，滑膜成纤维细胞中RGS12的过表达增加了纤毛的长度和数量，但降低了驱动蛋白家族成员2A（KIF2A）的蛋白水平。液相色谱-质谱分析结果表明，RGS12与MYC结合蛋白2相互作用以增强其泛素化活性，通过这种方式，KIF2A蛋白在滑膜成纤维细胞中被降解。此外，KIF2A的过表达阻止了纤毛长度和数量的增加。RGS12缺陷小鼠或RGS12短发夹RNA纳米颗粒治疗通过抑制滑膜成纤维细胞的激活，显著降低了炎性关节炎期间的临床评分、爪肿胀、滑膜炎和软骨破坏。因此，本研究提供了证据表明RGS12通过促进MCYBP2介导的KIF2A降解和纤毛发生来激活滑膜成纤维细胞的病理功能。我们的数据表明，RGS12可能是治疗炎性关节炎的潜在药物靶点。
