Cuproptosis and Orthopedic Diseases: Molecular Mechanisms of Copper Metabolic Imbalance in the Skeletal System and Clinical Translation Prospects.

Copper, an essential trace element, serves as a critical cofactor for enzymes governing energy metabolism, antioxidant defense, and connective tissue synthesis. The narrow margin between physiological requirement and toxicity necessitates precise homeostatic control, as both deficiency and excess compromise bone cell viability. Dysregulated copper metabolism has emerged as a pathogenic driver in orthopedic disorders, prompting investigation of cuproptosis-a distinctive form of mitochondrial cell death triggered by copper overload. The development of numerous diseases may occur when copper levels are abnormal in the body. A newly proposed form of cell death, known as cuproptosis, is distinct from necroptosis, apoptosis, autophagy, ferroptosis, and pyroptosis due to its cause: an excessive accumulation of intracellular copper. In the TCA cycle, copper binds to lipoylated proteins, which induces their aggregation, proteotoxic stress, the loss of Fe-S cluster proteins, and ultimately results in cell death. This process highlights the intricate relationship between metal homeostasis and cellular metabolism illustrating excess copper can induce cellular toxicity through biochemical mechanisms. Ever since cuproptosis was introduced, increasing research has highlighted its crucial involvement in the occurrence, development and management of many orthopedic disorders. The skeletal system presents unique features that make it particularly relevant for cuproptosis research: (i) bone tissue undergoes continuous remodeling with high metabolic demands, making it highly sensitive to mitochondrial dysfunction; (ii) osteoblasts, osteoclasts, and chondrocytes rely heavily on TCA cycle activity for energy production and differentiation; (iii) copper-containing biomaterials have been widely used in orthopedics for their dual osteogenic and antimicrobial properties, yet their mechanisms remained unclear until the discovery of cuproptosis; and (iv) the hypoxic microenvironment in bone marrow and inflammatory joints creates conditions favorable for copper accumulation and lipoylated protein aggregation. These distinctive characteristics position orthopedic diseases as an ideal model system for investigating cuproptosis pathophysiology and its therapeutic applications. In the review, we summarize copper homeostasis, copper ions' role in the major cells of bone metabolism, and the interconnections of cuproptosis in osteosarcoma, osteoarthritis, rheumatoid arthritis, osteoporosis, osteomyelitis, spinal disorders, implant infections, and wound repair. We hope to provide novel diagnostic and therapeutic ideas for these diseases by modulating copper homeostasis and targeting cuproptosis.