Abnormal Stress Reduced miR-330 Supplementation Alleviates Osteoarthritis Progression by Suppressing Osteochondral Catabolism.

Abstract

Abnormal mechanical stress plays a crucial role in the progression of osteoarthritis (OA). Key factors regulating mechanical response remain to be explored. This study harvested synovium fluids from 96 temporomandibular disorders (TMD) patients and revealed that miR-330 was significantly reduced under abnormal mechanical stress. Similarly, the expression of miR-330 is also decreased in cartilage and subchondral bone tissue from OA clinical specimens and animal models. Global knockout of miR-330 aggravated osteoarthritis development in both temporomandibular joint and knee joint. Conditional knockout of miR-330 in either chondrocytes or osteoclasts exhibited a similar phenotype in both knee and TMJ mechanical instable animal models, suggesting the importance of miR-330 in both types of cells. Further molecular mechanism exploration unveiled that miR-330 can regulate the catabolism of chondrocytes and osteoclasts via suppressing CTGF, FGFR1, and EPOR as well as key inflammatory cytokines such as IL-1β and TNF-α. More importantly, intra-articular supplement of miR-330 exerts a therapeutic effect by mitigating the detrimental impacts of abnormal mechanical stress, where inhibition of chondrocytes apoptosis, osteoclasts activation, and inflammation were further confirmed via single-cell RNA sequencing analysis. In conclusion, this study for the first time revealed that miR-330 is a mechanical responsive, osteoarthritis protective micro RNA. We provide evidence that miR-330 has potential diagnostic and therapeutic value for both temporomandibular and knee OA.