LOXL2 Deletion Triggers TMJ Osteoarthritis While Overexpression Protects Against NF-κβ-Induced Chondrocyte Apoptosis

Temporomandibular joint osteoarthritis (TMJ-OA) affects a significant proportion of the population worldwide. However, there has been no substantial progress in the development of FDA-approved drugs for treatment due to a lack of understanding of the specific factors regulating key TMJ-OA molecular mechanisms. Lysyl Oxidase Like-2 (LOXL2) promotes knee joint cartilage protection, and it is downregulated in TMJ-OA animal model. We evaluated the role of LOXL2 in TMJ cartilage, its molecular mechanism and gene networks using in vivo Loxl2 knockout mice ( Acan-Cre; Loxl2 ^flox/flox ) and ex vivo goat TMJ cartilage. Our results show that Loxl2 knockout in mice cartilage upregulates Il1b, Mmp9, Mmp13, Adamts4 , and Adamts5 , whereas it reduces the levels of aggrecan and proteoglycan. Loxl2 deleted TMJ cartilage show a higher enrichment of inflammatory response, TNFA signaling via NF-kB, extracellular matrix (ECM), and collagen degradation pathway network. Conversely, LOXL2 treatment reduces interleukin-1 beta (IL-1β)-induced expression of Mmp13 , protects mitochondrial function and ECM from degeneration. Importantly, LOXL2 attenuates IL-1β-induced chondrocyte apoptosis via phosphorylation of NF-κB and expression of pain-related gene PTGS2 (encodes COX2). Taken together, Loxl2 knockout mice exacerbate TMJ-OA through cartilage/ECM degradation, mitochondrial dysfunction, chondrocyte apoptosis, and inflammatory gene expression, whereas LOXL2 treatment mitigates these effects.