Multi-Omics Reveals Nonlinear Trajectories and Subtypes in TMJ Disease

Temporomandibular joint (TMJ) disease encompasses a disease continuum from disc displacement to osteoarthritis and perforation, yet patients with similar imaging often follow divergent clinical trajectories. Here, we performed integrated proteomic and metabolomic profiling of synovial fluid from patients across 5 imaging-defined stages (normal disc to advanced degeneration with perforation), quantifying 860 proteins ( n  = 91) and 1,027 metabolites ( n  = 62). Clinical symptoms did not differ significantly across stages, and unsupervised principal component analysis revealed substantial molecular overlap with no stage separation. Integrated multi-omics analysis revealed that complement activation, cholesterol metabolism, and glutathione-mediated oxidative stress were dynamically associated with disease progression. The imaging severity score (ISS) increased from stage 1 to stage 4 and declined at stage 5, revealing a nonlinear disease pattern. Proteomic and metabolomic modules correlated strongly with ISS ( r  = 0.60 and r  = −0.49), identifying phospholipid transfer protein (PLTP) and follistatin-like protein 1 (FSTL1) as exploratory candidate markers associated with disease severity. Given that anatomical staging failed to capture molecular heterogeneity, exploratory consensus clustering identified 3 molecular phenotypes complementary to anatomical staging: subtype 1 (extracellular matrix remodeling/mechanotransduction), subtype 2 (inflammatory-lipid metabolic), and subtype 3 (immune activated), each with distinct clinical profiles. Together, this study provides the first integrated multi-omics characterization of the TMJ disease continuum, revealing nonlinear progression with disc perforation as a potential transition point and supporting a complementary biology-informed framework for molecular stratification and future mechanism-based therapeutic research.