Mitochondrial dysfunction activates ADAMTS-5 expression via mt-dsRNA-PKR-Spi-1 axis in osteoarthritic chondrocytes

Osteoarthritis (OA) involves cartilage degradation by ADAMTS-5, but how ADAMTS-5 expression is activated remains unclear. A recent study found that mitochondrial double-strand RNA (mt-dsRNA) and its leakage into the cytosol activate protein kinase R (PKR), which facilitates OA progression. However, the mechanisms are yet to be clarified. In this study, we focused on how mt-dsRNAs and PKR signaling activate ADAMTS-5 expression in chondrocytes undergoing mitochondrial dysfunction. Our findings revealed that mitochondrial dysfunction triggered the leakage of mt-dsRNAs into the cytosol. These mt-dsRNAs activated PKR to initiate Spi-1-dependent ADAMTS-5 transcription. Increased levels of mt-dsRNAs and PKR activation in the cartilage from OA patients and mice corroborate our findings. More importantly, PKR conditional knockout from articular chondrocytes alleviates the pathological phenotypes of OA mice. Our research offers a deep understanding of OA driven by mitochondrial dysfunction in chondrocytes and proposes mt-dsRNAs-PKR as potential targets for OA drugs.