Effects of a home exercise program on symptoms and inflammatory markers in temporomandibular disorders

Temporomandibular disorders (TMD) encompass a range of conditions affecting the temporomandibular joint (TMJ) and masticatory muscles, presenting as pain in the jaw joint, periauricular region, and facial muscles [1].Etiology is multifactorial, involving arthritis, jaw injury, and bruxism (teeth grinding), which is itself frequently precipitated or exacerbated by psychological stress [2].First-line management includes self-care measures -avoiding extreme jaw movements, cold/warm compresses, and soft diets -while persistent symptoms may require pharmacological treatment (analgesics, anti-inflammatories, muscle relaxants), oral splints, physical therapy, counseling, or, in refractory cases, surgery.Inflammation is thought to play a pivotal role in TMD pathogenesis, but the mechanisms linking it to jaw joint pain remain poorly defined [3].Observational studies have repeatedly reported elevated traditional inflammatory markers (IL-1β, IL-6, IL-8, TNF-α, PGE2, MMP-9) in TMD patients, yet these associations cannot establish causality, and the peripheral immune and metabolomic profiles of TMD patients remain incompletely characterized.Mendelian randomization (MR), which uses genetic variants as instrumental variables to approximate the random allocation of risk factors, offers a means of inferring causality while reducing susceptibility to confounding and reverse causation [4-6].It is now widely applied in drug target discovery and repurposing.However, no MR study has yet integrated genome-wide association study (GWAS) data on immune cell traits and circulating metabolites to jointly evaluate their causal roles in TMD -representing a key gap this study addresses.Here, we leverage large-scale GWAS data within an MR framework to systematically identify metabolites and inflammatory factors potentially associated with TMD, and we separately test, in a randomized clinical trial, whether a structured home exercise program improves TMD-associated symptoms and inflammatory markers in patients with DDWR.The two study components are presented and interpreted separately; any relationship between the genetic findings and the clinical intervention is discussed as hypothesis-generating rather than directly demonstrated.Methods.Brief methods are summarized here; full details are provided in the Supplementary File. Mendelian randomization analysis.We performed a two-sample MR analysis using European-ancestry GWAS summary statistics for 1,400 circulating metabolites and 91 inflammatory factors as exposures (331,976 participants) and FinnGen release R11 as the TMD outcome (453,733