[Is osteoarthritis merely a local "wear and tear" or a systemic disease? :exploration of the pathogenesis and therapeutic strategies for osteoarthritis].

Osteoarthritis (OA) has traditionally been characterized as a purely biomechanically driven, localized degenerative disease of the articular cartilage. However, the "local wear-and-tear" theory cannot fully explain clinical phenomena such as the high incidence of OA in non-weight-bearing joints and the inconsistency between symptoms and imaging findings, which has prompted researchers to propose a new hypothesis that OA represents a systemic disease. Based on advances in the understanding of OA, from localized cartilage degradation to a heterogeneous whole-joint disorder, this review summarizes the roles of mechanical stress-and joint trauma-related phenotypes, as well as systemic driving factors including metabolic syndrome, endocrine disorders, gut dysbiosis, senescence and genetic susceptibility in the initiation and progression of OA. It is further elaborated that the remodeling of the local microenvironment, involving the infrapatellar fat pad, synovium and subchondral bone, acts as a hub mediating the transition from distinct pathogenic phenotypes to irreversible cartilage degradation. In addition, potential phenotype-based disease-modifying therapeutic strategies, including mechanical intervention, metabolic regulation, anti-inflammatory therapy and targeted treatment for local microenvironment, are summarized. This review holds the view that OA is neither simply a local wear-and-tear disorder nor a pure systemic disease; instead, it is a whole-joint disease with different phenotypes driven by local mechanical injury and/or systemic metabolic-inflammatory imbalance. Future efforts should optimize patient screening and therapeutic decision-making based on phenotypic stratification, so as to advance the precise diagnosis and treatment of OA as well as the clinical translation of disease-modifying OA drugs.