Leptin-Associated Sex Difference in TMJ OA Induced by Metabolic Endotoxemia

Temporomandibular joint (TMJ) osteoarthritis (OA) is a degenerative disease affecting cartilage, bone and synovium. Factors such as age, sex and obesity are associated with TMJ OA, however, the underling mechanisms, particularly the contribution of obesity, remain poorly understood. Unlike weight-bearing joints, TMJ pathology cannot be fully attributed to aberrant mechanical loading, suggesting a potential involvement of systemic metabolic factor. Evidence have linked metabolic endotoxemia, characterized by subclinical elevation of plasma lipopolysaccharide (LPS) level to low-grade systemic inflammation, adipose tissue dysfunction and adipokine dysregulation. Among adipokines, circulating leptin has been associated with OA progression, but its role in the onset and progression of TMJ OA, especially in a sex-specific context, is under studied.

In this study, we examined whether chronic systemic LPS could induce adipose tissue abnormalities and leptin signalling dysregulation, contributing to TMJ OA. The metabolic endotoxemia was induced in 6-month-old female and male Wistar rats via systemic LPS delivery for 6 weeks using subcutaneously implanted osmotic pumps. At the end of the study, the peripheral blood, subcutaneous and visceral white adipose tissue, and TMJs were harvested for various analyses.

We showed that LPS-treated female rats showed elevated circulating LPS and adipocyte hypertrophy in white adipose tissue. This was accompanied by increased plasma leptin concentrations. These changes were not observed in male rats. Histological evaluation of TMJ revealed pronounced osteoarthritic changes in TMJ, characterized by cartilage matrix loss, subchondral bone resorption, and synovial inflammation, in female but not male rats. Immunofluorescence staining discovered differences in the distribution and expression of nitric oxide and leptin receptor in cartilage between sexes. Correlation analysis suggested the involvement of leptin in TMJ OA.

In conclusion, we demonstrated that systemic LPS promoted sex-specific TMJ OA through leptin-mediated inflammation, suggesting a potential systemic-to-local link between endotoxemia, adipose dysfunction, and TMJ OA pathogenesis in female.