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

ObjectiveTemporomandibular joint (TMJ) osteoarthritis (OA) is a degenerative disease affecting the whole synovial joint, with a higher prevalence in women. While obesity is recognised as a risk factor for knee OA, its association with TMJ degeneration remains controversial. Recently, metabolic endotoxemia, characterised by a subclinical elevation of circulating lipopolysaccharide (LPS), has been proposed as a key mediator of obesity. It was thought to accelerate OA progression in knee joints by triggering low-grade systemic inflammation. However, the contribution of endotoxemia to TMJ OA is unclear. This study investigated whether chronic LPS exposure induces TMJ OA and whether its interplay with adipose tissue is involved in this process, particularly in a sex-specific context. MethodsMetabolic endotoxemia was induced in 6-month-old female and male Wistar rats by continuous subcutaneous infusion of LPS for 4 - 6 weeks using osmotic pumps. Ten weeks after the start of LPS infusion, peripheral blood, subcutaneous and visceral white adipose tissue, and TMJs were harvested for biochemical, histological, micro-computed tomography and gene expression analyses. Primary TMJ chondrocytes isolated from healthy female and male rats were further used to assess sex-specific responses to leptin and LPS in vitro. ResultsChronic LPS exposure induced pronounced OA-like changes in female TMJs, including cartilage matrix loss, subchondral bone resorption and mild synovial inflammation, whereas male joints were minimally affected. In female cartilage, immunofluorescence analyses showed an increased proportion of cells co-expressing leptin, leptin receptor and inducible nitric oxide synthase, supporting local activation of leptin-associated inflammatory pathways. In contrast, LPS immunosignal was not detected in cartilage. Systemically, LPS-treated female rats exhibited elevated circulating LPS and leptin concentrations, together with adipocyte hypertrophy and inflammatory changes in subcutaneous adipose tissue, whereas these changes were not evident in males. In vitro, leptin induced stronger metabolic and inflammatory responses in female chondrocytes, including reduced intracellular lipid content and metabolic activity, increased nitric oxide production, and upregulated catabolic gene expressions following LPS priming. ConclusionChronic systemic LPS exposure induced sex-specific TMJ OA associated with adipose tissue dysfunction and altered leptin signalling. These findings support a potential female-biased systemic-to-local adipose-cartilage link between endotoxemia and TMJ OA pathogenesis.