Proteomic mediators of the association between anxiety–depression symptoms and degenerative joint disease: a prospective cohort study in the UK Biobank

Degenerative joint disease (DJD) is a major cause of pain and disability. The prospective associations of anxiety and depression symptoms with DJD and its underlying mechanisms remain unclear. This prospective cohort study included 366,833 UK Biobank participants who were free of DJD at baseline, of whom 31,789 had plasma proteomic data. Baseline anxiety–depression symptoms were assessed using the Patient Health Questionnaire-4 (PHQ-4). Multivariable Cox regression and restricted cubic spline analyses were used to examine associations with DJD and its major subtypes. In the proteomic subset, multivariable linear regression and Cox proportional hazards regression were used to identify candidate proteins, followed by exploratory mediation and functional enrichment analyses to investigate potential biological pathways. During a median follow-up of 4,868 days, 68,772 DJD cases were identified. Higher PHQ-4 total score and anxiety–depression symptoms were associated with higher risks of DJD and its major subtypes, with evidence of nonlinear dose–response relationships. Proteomic analyses identified 230 anxiety–depression-associated proteins. Mediation analyses identified 33, 36, 9, and 23 significant mediating proteins for DJD, osteoarthritis (OA), intervertebral disc degeneration (IVDD), and degenerative spinal disease (DSD), respectively. Four proteins—CD302, GDF15, IL15, and RBFOX3—were shared across all four outcomes. Functional enrichment analyses mainly implicated immune-inflammatory pathways and extracellular matrix remodeling. Anxiety–depression symptoms were associated with elevated risks of DJD and its major subtypes. Inflammatory and extracellular matrix-related proteomic pathways may partly underlie these associations.