Sex-dependent mechanisms of temporomandibular joint osteoarthritis.

Temporomandibular joint osteoarthritis (TMJ OA) is a prevalent degenerative disease characterized by chronic pain and impaired jaw function. Similarly to other OA affected limb joints, TMJ OA has shown increased prevalence across several demographic and biological factors. These risk factors include sex, with female patients reporting twice the incidence rate and suffering from greater symptom severity compared to male patients. However, due to a lack of relevant preclinical models, there is limited knowledge related to how sex differences impact TMJ OA pathophysiology. With increasing attention in women's health, we aim to understand the molecular mechanisms underlying sexually-dimorphic TMJ OA pathogenesis. Using the burn-synovectomy mouse model to induce TMJ OA, which mimics the elevated inflammatory cytokines associated with chronic stressors and local TMJ derangement, we observed more severe cartilage and subchondral bone abnormalities in females consistent with findings in patients. Single-cell RNA sequencing (scRNA-seq) and histology revealed that females had an increased inflammatory response, both in terms of immune cell abundance as well as in their inflammatory gene signature, compared to male animals. Additional analyses also showed that female mice downregulated major morphogenetic pathways, such as WNT, BMP TGF-β, and FGF, within osteochondral cell populations, while simultaneously increasing expression of extracellular matrix remodeling enzymes. These results demonstrate the sexual-dimorphisms in disease initiation and progression leading to the differentially observed TMJ OA phenotypes. The data herein may explain the incident tendency and symptom severity in female patients and suggest sex-dependent treatment strategies for future patient care.