Depression and musculoskeletal diseases: a framework of systemic mechanisms

Musculoskeletal disorders (MSDs) encompass a broad spectrum of conditions affecting bones, joints, and muscles, characterized by significant pain and functional impairment, and have become a major global health burden. In recent years, accumulating evidence has revealed complex bidirectional interactions between depression and musculoskeletal health. This review focuses on depression and delineates how it may influence the pathological progression of MSDs through multiple pathways, including neuroendocrine dysregulation, aberrant inflammatory responses, epigenetic modifications, dysregulated extracellular vesicle-mediated communication, abnormal neural activity along the brain–joint axis, and gut microbiota ecological imbalance. Collectively, depression is associated with an increased risk of MSDs and engages intricate interactions across multiple biological systems. Our study underscores that musculoskeletal disorders are by no means confined to isolated joints or local tissues, but rather represent complex diseases with prominent systemic features. Integrated management strategies combining psychosocial interventions, appropriate physical exercise, and dietary modification hold promise as potential multitargeted approaches for the comprehensive treatment of MSDs.