Department of Rheumatology and Immunology, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, P.R. China.
Biomater Sci. 2020 Jun 21;8(12):3430-3442. doi: 10.1039/c9bm01761e. Epub 2020 May 14.
The pathogenesis of rheumatoid arthritis (RA) is related to the inhibition of osteoblast differentiation. Exosomes secreted from RA fibroblast-like synoviocytes (RA-FLSs-exos) are associated with the pathogenesis of RA and microRNAs (miRNAs) being crucial for RA progression. Accordingly, the aim of the present study is to elucidate the effect of RA-FLS-derived exosomes on osteoblast differentiation and further identify exosomal cargos responsible for this effect. RA-FLSs were isolated from a RA patient and osteoblasts from the donor bone. Isolated RA-FLSs-exos were co-cultured with osteoblasts. Osteoblast differentiation was evaluated by ALP quantification assays, Alizarin Red S staining, and determining markers of osteoblast activity (Osx, OC, Col1a1 and Dlx2). Collagen induced arthritis (CIA)-induced mouse models were established. RA-FLSs-exo could be phagocytosed by osteoblasts. Elevating the expression of miR-486-5p in RA-FLSs-exo promoted osteoblast differentiation. miR-486-5p targeted Tob1 and activated the BMP/Smad signaling pathway in osteoblasts. In addition, RA-FLSs-exo containing miR-486-5p facilitated osteoblast differentiation by activating the BMP/Smad signaling pathway and repressing Tob1. Moreover, RA-FLSs-exo containing miR-486-5p alleviated the disease severity of RA by decreasing Tob1 expression in CIA-induced mice. To sum up, RA-FLSs-exo carrying miR-486-5p serve as a promoter for osteoblast differentiation in RA, ultimately highlighting a promising competitive new target for RA treatment.
类风湿关节炎（RA）的发病机制与成骨细胞分化抑制有关。RA 成纤维样滑膜细胞（RA-FLS）来源的外泌体与 RA 的发病机制有关，微小 RNA（miRNA）在 RA 进展中起关键作用。因此，本研究旨在阐明 RA-FLS 衍生的外泌体对成骨细胞分化的影响，并进一步鉴定负责这种作用的外泌体载体。RA-FLS 从 RA 患者中分离，成骨细胞从供骨中分离。分离的 RA-FLS 来源的外泌体与成骨细胞共培养。通过碱性磷酸酶（ALP）定量测定、茜素红 S 染色和测定成骨细胞活性标志物（Osx、OC、Col1a1 和 Dlx2）来评估成骨细胞分化。建立胶原诱导关节炎（CIA）诱导的小鼠模型。RA-FLS 来源的外泌体可被成骨细胞吞噬。RA-FLS 来源的外泌体中 miR-486-5p 的表达升高促进成骨细胞分化。miR-486-5p 靶向 Tob1 并在成骨细胞中激活 BMP/Smad 信号通路。此外，含 miR-486-5p 的 RA-FLS 来源的外泌体通过激活 BMP/Smad 信号通路和抑制 Tob1 促进成骨细胞分化。此外，含 miR-486-5p 的 RA-FLS 来源的外泌体通过降低 CIA 诱导的小鼠 Tob1 表达减轻 RA 的疾病严重程度。总之，携带 miR-486-5p 的 RA-FLS 来源的外泌体作为 RA 中成骨细胞分化的促进剂，最终突出了 RA 治疗的一个有前途的竞争新靶点。
