Human umbilical cord mesenchymal stem cell-derived exosomal miR-199a-3p inhibits the MAPK4/NF-κB signaling pathway to relieve osteoarthritis

Background: There is currently no effective treatment for osteoarthritis (OA), which is the most common joint disorder leading to disability. Although human umbilical cord mesenchymal stem cells (hUC-MSCs) are promising OA treatments, their use is limited by the condition itself, and understanding of the underlying mechanisms of OA is lacking.

Aim: To explore the specific molecular mechanism by which hUC-MSC-derived exosomal miR-199a-3p improves OA.

Methods: Sodium iodoacetate was injected into rat articulations to construct an animal model of OA. Interleukin (IL)-1β was used to induce human chondrocytes (CHON-001) to construct an OA chondrocyte model. Exosomes in hUC-MSCs were isolated using Ribo^™ Exosome Isolation Reagent. Real-time reverse transcriptase-polymerase chain reaction and western blotting were used to detect the expression of related genes and proteins, and damage to CHON-001 cells and rat articular cartilage tissue was evaluated by enzyme-linked immunosorbent assay, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-nick end labelling staining and hematoxylin and eosin staining.

Results: hUC-MSC-derived exosomes (hUC-MSC-Exos) inhibited the expression of IL-1β-induced inflammatory cytokines, namely, IL-6, IL-8 and tumor necrosis factor-α. hUC-MSC-Exos also improved the viability but inhibited the Apoptosis of CHON-001 cells, improved the pathological condition of articular cartilage tissue and alleviated the development of OA in vivo. Mechanistically, hUC-MSC-Exos downregulated the expression of mitogen-activated protein kinase 4 by delivering miR-199a-3p, thereby inhibiting the activation of the nuclear factor-kappaB signaling pathway, alleviating IL-1β-induced chondrocyte inflammation and Apoptosis, and ultimately improving the development of OA.

Conclusion: hUC-MSC-derived exosomal miR-199a-3p alleviates OA by inhibiting the mitogen-activated protein kinase 4/nuclear factor-kappaB signaling pathway. The present findings suggest that miR-199a-3p delivery by hUC-MSC-Exos may be a novel strategy for the treatment of OA.

Exosomes; Human umbilical cord mesenchymal stem cells; MiR-199a-3p; Mitogen-activated protein kinase 4; Nuclear factor-kappaB; Osteoarthritis.