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

Abstract

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.

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

Core Tip: Osteoarthritis (OA), a debilitating joint disorder, currently lacks effective treatment options. This study reveals that exosomal miR-199a-3p derived from human umbilical cord mesenchymal stem cells offers a novel therapeutic strategy for OA. By targeting the mitogen-activated protein kinase 4/nuclear factor-kappaB signaling pathway, miR-199a-3p significantly reduces inflammation and inhibits apoptosis in chondrocytes. These findings highlight the potential of exosomal miR-199a-3p delivery as a promising approach for managing OA, providing a foundation for future clinical applications.