Leptin: A Potential Adipokine Bridging Systemic Endotoxemia and Sex-Divergent Temporomandibular Joint Osteoarthritis Development

Abstract

Background: Temporomandibular joint (TMJ) osteoarthritis (OA) is a degenerative disease affecting the whole synovial joint, with a higher prevalence in women. Obesity is recognised as a risk factor for knee OA, but its association with TMJ degeneration remains controversial. Lipopolysaccharide (LPS), or endotoxin, has increasingly been proposed as a mediator of obesity-related knee OA. In parallel, adipose-derived leptin played a role in the development of metabolic OA. This study investigated whether chronic LPS exposure induces TMJ OA and whether leptin is involved in this process. Methods: Six-month-old female and male Wistar rats received continuous subcutaneous LPS infusion to induce TMJ OA. At 10 weeks, peripheral blood, white adipose tissue, and TMJs were harvested for biochemical, histological, micro-computed tomography and gene expression analyses. Primary TMJ chondrocytes isolated from healthy rats were used to investigate sex-specific cellular responses to leptin and LPS in vitro. Results: Chronic LPS exposure induced mild, sex-divergent TMJ changes. Compared to same-sex healthy controls, LPS-treated females showed a marginally worse Mankin score (P = 0.053) with greater cartilage glycosaminoglycan loss (P = 0.032), synovitis and subchondral bone deterioration, whereas LPS-treated males only showed worse cartilage surface fibrillation. Both sexes showed subcutaneous adipocyte hypertrophy in response to LPS. Only females progressed to adipose inflammation and plasma leptin elevation (P = 0.018), which correlated strongly with total Mankin score (Spearman rho=+0.773, P = 0.024). Leptin was detected in the joint on chondrocytes co-expressing leptin receptor (OB-R) and inducible nitric oxide synthase (iNOS). The percentage of cells positive for leptin, OB-R and iNOS was differentially abundant in LPS-treated females than in sex-matched controls and LPS-treated males. In vitro, at the same leptin dose, female chondrocytes exhibited lower metabolic activity and greater oxidative stress than male chondrocytes. Notably, leptin upregulated matrix metallopeptidase (MMP)-13 expression only in LPS-primed female chondrocytes. Conclusion: Chronic systemic LPS exposure induced sex-divergent TMJ osteoarthritic pathology, adipose dysfunction and altered leptin signalling. The tissue-level changes were associated with leptin-linked inflammatory cascades amplified in female chondrocytes. These findings suggest that leptin is involved in the pathogenesis of systemic endotoxin-triggered TMJ OA and may partly explain sex differences in OA development.