Let-7a-5p derived from parathyroid hormone (1-34)-preconditioned BMSCs exosomes delays the progression of osteoarthritis by promoting chondrocyte proliferation and migration.

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.