Abstract
BACKGROUND: Cartilage has limited potential for self-regeneration, and damage results in structural, molecular, and functional aberrations, leading to osteoarthritis (OA). Traumatic knee injuries can also lead to cartilage degeneration and post-traumatic OA (PTOA). This study aimed to explore whether lysyl oxidase-like 2 (LOXL2) deletion aggravate PTOA and overexpression alleviate inflammation and pain at mechanical as well as molecular levels. METHODS: Modified medial meniscectomy was performed on C57BL/6J mice knee followed by aggrecan promotes specific deletion of Loxl2 in cartilage. Transcriptomic aberrations were studied using RNA-seq and qPCR, and biomechanics and allodynia was evaluated using treadmill exhaustion and von Frey nociception test after adenovirus-delivered LOXL2 intra-articular treatment. RESULTS: LOXL2 was found to be downregulated in mouse knee PTOA. Loxl2 deletion in knee cartilage, shows OA-like molecular changes, and aggravates PTOA. Transcriptomics analysis revealed the upregulation of cartilage degeneration factors, signatures of inflammatory M1 macrophages, and pain. These Loxl2 deleted PTOA mice have a molecular resemblance to the human knee OA pathogenic gene signature. Interestingly, LOXL2 treatment alleviates knee joint function, reduces M1 macrophage infiltration, restores biomechanic capabilities, and reduces mechanical allodynia by relieving knee joint disability and pain. CONCLUSION: LOXL2 deletion enhances the severity of PTOA, similar to human OA, whereas overexpression mitigates these effects by reducing inflammation and pain, offering LOXL2 as a therapeutic option in OA. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: LOXL2 modulates inflammation, pain, and degeneration, showing strong translational potential as a disease-modifying therapy for human PTOA.