The Role of Metals and Trace Elements in the Pathogenesis of Osteoarthritis and Other Rheumatic Diseases.

Osteoarthritis (OA) and other rheumatic diseases are among the leading causes of chronic pain, disability, and reduced quality of life worldwide. Increasing evidence indicates that disturbances in metal homeostasis contribute to the pathogenesis of these disorders through their effects on oxidative stress, immune regulation, cartilage metabolism, bone remodeling, and extracellular matrix degradation. This review summarizes current knowledge regarding the role of essential metals and trace elements, including zinc, iron, copper, magnesium, selenium, and manganese, as well as toxic metals such as cadmium, lead, mercury, and arsenic, with primary emphasis on their involvement in the development and progression of osteoarthritis. Other rheumatic diseases are discussed briefly to provide a comparative perspective. Particular attention is given to the molecular mechanisms underlying metal-mediated pathology, including oxidative stress, ferroptosis, mitochondrial dysfunction, activation of intracellular signaling pathways, and inflammasome activation. The diagnostic and therapeutic potential of metal-related biomarkers, metalomics, and targeted interventions aimed at restoring metal homeostasis are also discussed. Furthermore, current limitations of available studies and emerging research directions, including single-cell technologies, spatial transcriptomics, multi-omics approaches, and personalized medicine, are highlighted. A better understanding of metal homeostasis may improve the identification of novel biomarkers and therapeutic targets, ultimately contributing to more precise diagnosis and individualized treatment strategies for osteoarthritis and other rheumatic diseases.