Abstract
BACKGROUND: Osteoarthritis (OA) is a prevalent degenerative joint disorder affecting over 240 million people worldwide, yet no disease-modifying therapies currently exist, with clinical management limited to symptomatic relief or joint replacement. Exosomes (Exos) from bone marrow mesenchymal stem cells (Exo(BMSC)) play positive role in the treatment of cartilage damage. Parathyroid hormone (PTH) (1-34) can enhance cartilage repair. Here, We found Exos from Exo(BMSC) reduces cartilage damage during treatment. Meanwhile, the Exos of PTH(1-34)-preconditioned BMSCs (Exo(PTH)) can alleviate OA better than Exo(BMSC). Through MicroRNA (miRNA) sequencing analysis, this study aims to reveal the effects and potential mechanism of miRNA (let-7a-5p) in Exo(PTH) to repair OA cartilage. METHODS: Differential centrifugation was used for isolating Exo(BMSC) and Exo(PTH). Extract bone marrow mesenchymal stem cells from rats and utilize the C28/I2 chondrocytes line, the OA model was established using lipopolysaccharide (LPS; 1 µg/mL) in vitro. OA was induced in rats with intra-articular injection with collagenase-2. By performing a miRNA array, RNA-seq, in addition to bioinformatic analysis, the miRNA and the potential regulatory mechanism were detected. We compared in vitro let-7a-5p effects on the ability of OA chondrocytes to proliferate, migrate, apoptosis, and form the extracellular matrix (ECM). Histological and immunohistochemical assessments were used for evaluating cartilage pathology in vivo. RESULTS: We extracted Exo(BMSC) and Exo(PTH) and established the OA model in vitro. Compared with Exo(BMSC) group, Exo(PTH) group has a stronger effect on promoting the proliferation and migration of chondrocytes. Exo(BMSC) and Exo(PTH) can inhibit the apoptosis of chondrocytes, but there was no significant difference between the two groups. The two most significant differences in groups Exo(BMSC) and Exo(PTH) are let-7a-5p. Let-7a-5p promotes OA chondrocytes proliferation and migration by inhibiting the expression of IL-6 in vitro experiments. For in vivo experiments, let-7a-5p delays the progression of OA. CONCLUSION: Our study shows that Exo(PTH) may improve the regulatory inflammatory responses to delays the progression of OA by shuttling let-7a-5p. Let-7a-5p promoted chondrocytes migration and proliferation to suppress OA pathology by inhibiting IL-6/STAT3 pathway.