Department of Orthopaedics, Yancheng City No. 1 People's Hospital, Yancheng, 224006, China.
Department of Gynecology and Obstetrics, Yancheng City No. 1 People's Hospital, Yancheng, 224006, China.
Mol Biol Rep. 2019 Feb;46(1):627-637. doi: 10.1007/s11033-018-4518-8. Epub 2018 Nov 27.
Osteoarthritis (OA) is a degenerative joint disease characterized by the degradation of joint cartilage, the formation of osteophyma at joint margins, and synovial changes. Whereas lesions of the joint cartilage were the key point of the research and treatment of osteoarthritis before, a recent study showed that the synovium plays a crucial role in the pathological progress of OA. The inflammatory environment in the joints of OA patients always results in the overactivation of fibroblast-like synoviocytes (FLSs), which produce a multitude of inflammatory factors and media, not only leading to the degradation and injury of the cartilage tissue and promoting the development of osteoarthritis but also resulting in synovial fibrosis and joint stiffness. Therefore, the synovium has attracted increasing attention in the research of OA, and the study of the mechanism of activation of FLSs and the fibrosis of joint synovium may shed new light on OA treatment. By using high-throughput screening, we have identified that hsa-miR338-3p is significantly downregulated in the synovial tissue and joint effusion from OA patients. A functional study showed that overexpression of hsa-miR338-3p in the FLSs inhibited the TGF-β1-induced overactivation of the TGF-β/Smad fibrosis regulation pathway by suppressing TRAP-1 expression and thus reducing the TGF-β1-induced activation of the FLSs and the expression of vimentin and collagen I, two fibrosis markers. Meanwhile, a mechanism study also showed that the upregulation of hsa-miR338-3p reduced Smad2/3 phosphorylation by suppressing TRAP-1 and thus inhibited the TGF-β/Smad pathway and TIMP1, a downstream protein. The present study, for the first time, illustrates the role of hsa-miR338-3p in synovial fibrosis in OA patients and the related mechanism, which is of importance to the treatment of OA and its complications by targeting the FLSs and synovial tissue. Hsa-miR338-3p not only has the potential to be a target for the gene therapy of OA but also has the potential to be a new marker for the diagnosis of clinical progression in OA patients.
骨关节炎（OA）是一种退行性关节疾病，其特征为关节软骨降解、关节边缘骨赘形成和滑膜变化。虽然关节软骨病变一直是骨关节炎研究和治疗的重点，但最近的一项研究表明，滑膜在 OA 的病理进展中起着至关重要的作用。OA 患者关节中的炎症环境总是导致成纤维样滑膜细胞（FLS）过度激活，这些细胞产生多种炎症因子和介质，不仅导致软骨组织降解和损伤，促进骨关节炎的发展，还导致滑膜纤维化和关节僵硬。因此，滑膜在 OA 的研究中引起了越来越多的关注，研究 FLS 的激活机制和关节滑膜纤维化可能为 OA 的治疗带来新的曙光。通过高通量筛选，我们发现 hsa-miR338-3p 在 OA 患者的滑膜组织和关节积液中显著下调。功能研究表明，在 FLSs 中过表达 hsa-miR338-3p 通过抑制 TRAP-1 表达抑制 TGF-β1 诱导的 TGF-β/Smad 纤维化调节通路的过度激活，从而减少 TGF-β1 诱导的 FLSs 激活以及波形蛋白和胶原 I（两种纤维化标志物）的表达。同时，机制研究还表明，hsa-miR338-3p 的上调通过抑制 TRAP-1 减少 Smad2/3 磷酸化，从而抑制 TGF-β/Smad 通路和 TIMP1（下游蛋白）。本研究首次阐明了 hsa-miR338-3p 在 OA 患者滑膜纤维化中的作用及其相关机制，这对于通过靶向 FLSs 和滑膜组织治疗 OA 及其并发症具有重要意义。hsa-miR338-3p 不仅具有成为 OA 基因治疗的靶标潜力，而且具有成为 OA 患者临床进展新诊断标志物的潜力。
