LOXL2 protects temporomandibular joint from mitochondrial dysfunction, apoptosis and osteoarthritis like progression

Temporomandibular joint (TMJ) osteoarthritis (OA) affects a significant population, and there are no FDA-approved drugs for its treatment. Our previous studies showed that lysyl oxidase-like-2 (LOXL2) has anabolic effects on cartilage; however, whether LOXL2 plays a role in relieving TMJ-OA remains unknown. The goal of this study was to comprehensively investigate LOXL2 mechanism in TMJ protection, with an emphasis on transcriptomic network analysis, mitochondria, and apoptosis during TMJ-OA. We showed that the TMJ is transcriptionally unique compared to the knee, with elevated Loxl2 expression and cartilage-degenerative genes, potentially indicating its different mechanisms of action. Aggrecan promoter-specific homozygous deletion of Loxl2 in mice resulted in a cartilage-degeneration phenotype, mitochondrial dysfunction, NF-κβ-mediated chondrocyte apoptosis, and inflammatory immune response leading to TMJ-OA-like conditions. IL-1β is known to induce osteoarthritis via NF-κβ. With regard to translation, adenoviral-Loxl2 transduction in ex-vivo goat cartilage reduced the IL-1β-mediated degenerative effects. Importantly, LOXL2 preserved IL-1β–induced mitochondrial dysfunction, p62-mediated mitophagy, apoptosis, and extracellular matrix degeneration. Overall, we identified the protective role of LOXL2 during natural TMJ-OA-like progression and established LOXL2 as a potential candidate gene therapy candidate for future therapeutics.