Mesenchymal Circadian Clock Regulates TMJ Osteochondral Homeostasis During Aging

The prevalence of temporomandibular joint osteoarthritis (TMJ-OA) increases with aging. However, research focused on age-related mechanisms is rare. In this work, we elucidated the role of the mesenchyme-specific circadian clock in regulating TMJ osteochondral homeostasis during aging. Here, utilizing a Prrx1-specific Bmal1 knockout mouse model, bulk RNA sequencing across 24-hour time points, single-cell RNA sequencing analysis, and functional assays, we identified that the Prrx1+ cell population is crucial for maintaining TMJ equilibrium during aging, with the Bmal1-mediated circadian clock serving as a key homeostatic regulator in TMJ degeneration. Aging led to structural change in the TMJ condyle and impaired its metabolites circadian oscillation. Ablation of the mesenchymal circadian clock resulted in age-related TMJ-OA phenotype at middle age. Mechanistically, the core circadian regulator BMAL1 transcriptionally activates Prg4, suppresses Transforming Growth Factor Beta (TGF-β) activity, prevents excessive osteogenic activity, and governs the rhythmic oscillation of lipid metabolism. Furthermore, a circadian-based therapeutic intervention involving the intra-articular PRG4 administration at night effectively mitigated osteochondral ossification in both conditional knockout and aged mice. Collectively, our study uncovers the critical role of the mesenchymal circadian clock in preserving TMJ osteochondral homeostasis during aging, offering potential chronotherapeutic strategies for TMJ-OA.