Background
As one of the most common disabling diseases in the musculoskeletal system, osteoarthritis (OA) is characterized with cartilage matrix degeneration and chondrocyte apoptosis. Endoplasmic reticulum (ER) stress is well known for participate in chondrocyte apoptosis and cartilage degeneration in OA progression. microRNAs (miRNAs) could function in cartilage homeostasis, yet limited is known regarding whether miRNA could modulate ER stress in chondrocytes. Here, we reported that exosomal microRNA-486-5p from adipose derived stem cells (ADSCs) could alleviate chondrocyte apoptosis and osteoarthritis by attenuating ER stress
Methods
ER stress markers and inflammatory cytokines were analyzed in OA knee joint by immunohistochemistry and immunofluorescence staining. IL-1β induced apoptosis of chondrocytes was analyzed using flow cytometry. ER stress markers and inflammatory cytokines of IL-1β induced chondrocytes were analyzed by immunofluorescence staining, western blot and ELISA. miR-486-5p mimic overexpressed ADSCs and their exosomes were validated and used to treat IL-1β induced chondrocytes together with miR-486-5p mimic. Different administrative methods of miR-486-5p mimic were tracked both in vitro and in vivo, and further used to treat OA model mice. OA progression of mice was analyzed by H&E, safranin O/fast green, immunofluorescence and immunohistochemistry staining.
Results
We validated the increased inflammation and ER stress in OA synovium and cartilage, and the IL-1β induced chondrocyte apoptosis was through the ER stress activation. Administration of exogenous miR-486-5p could not only inhibit the ER stress, but also alleviate chondrocytes apoptosis and promote matrix regeneration. In comparison with direct administration of miR-486-5p and miR-486-5p overexpressing ADSCs, exosomes seem to be a better delivery vehicle for miRNA in modulating chondrocyte homeostasis. Our immunofluorescence and IVIS imaging data further validated the better delivery ability of exosomes through tracking the uptake of miR486-5p in chondrocytes and the diffusion of miR-486-5p in the knee joint with different transportation methods. Exosomal microRNA-486-5p also showed a better effect on alleviating mice OA.
Conclusion
Our data demonstrated that exosomes are better delivery vehicle for miR-486-5p on alleviating chondrocyte apoptosis and osteoarthritis. This study provides evidence to this efficient strategy of exosomal miRNA delivery and to the miRNA-based therapy for OA.