Mesenchymal Clock Regulates TMJ Homeostasis and Lipid Metabolic Rhythms with Age

Osteoarthritis (OA) is the most prevalent degenerative disorder of the temporomandibular joint (TMJ), with aging as a major risk factor. Although circadian clocks are essential for maintaining tissue homeostasis and metabolic balance, the influence of aging on tissue-specific circadian regulation of TMJ homeostasis remains unclear. Here, using aged mice and transgenic mouse models, we demonstrated that the mesenchymal circadian clock is indispensable for preserving TMJ osteochondral integrity during aging. Loss of the core circadian regulator <i>Bmal1</i> in mesenchymal cells leads to progressive osteochondral abnormalities in TMJ condyles, including disrupted cartilage stratification, thinning of the cartilage layer, and abnormal subchondral bone architecture, resembling age-related TMJ degeneration. Mechanistically, BMAL1 directly regulates <i>Prg4</i> transcription, suppresses aberrant transforming growth factor β (TGF-β) signaling to maintain osteochondral homeostasis, and preserves the circadian rhythmicity of lipid metabolism. Notably, circadian-timed intra-articular administration of recombinant PRG4 at night, corresponding to its physiological expression peak, partially restores the cartilage integrity in both <i>Bmal1</i> mutant and aged mice. Collectively, our findings reveal a mesenchymal clock-driven PRG4-TGF-β signaling axis that integrates circadian regulation with osteochondral homeostasis while also linking lipid metabolism, establishing chronotherapeutic PRG4 supplementation as a potential strategy to mitigate age-associated TMJ degeneration.