Osteocyte-derived extracellular vesicles mediate the bone-to-cartilage crosstalk and promote osteoarthritis progression [only osteocyte-enriched subchondral bone]

Osteoarthritis (OA) is the most common degenerative joint disease. During its initiation and early progression a disruption in subchondral bone (SCB) remodeling, induced by excessive and cumulative mechanical loading, occurs before cartilage degeneration. While it is known that osteocytes in the SCB are mainly responsible for mechanosensing, their role in the early phases of OA are still unclear. Here, we found that mechanical stress induces SCB osteocytes to secrete extracellular vesicles (EVs) that accelerate cartilage metabolic dysregulation. By gain- and loss-of function experiments we show that such EVs via miR-23b-3p promote cartilage catabolism while inhibiting their anabolism. Mechanistically, miR-23b-3p inhibits mitophagy by targeting OTUD4 to promote this metabolic skewing. Further, by inhibiting miR-23b-3p in either osteocytes or chondrocytes we could alleviate cartilage degeneration and OA progression in a mouse model. Together, our findings show that SCB osteocytes communicate with chondrocytes via EVs and that targeting a key EV-derived miRNA can ameliorate OA progression.