Roles of metabolic dysregulation in osteoarthritis.

Osteoarthritis (OA) is increasingly recognized not merely as a mechanically driven degenerative disorder, but as a complex whole-joint disease shaped by profound metabolic dysregulation. Beyond cartilage wear, OA involves coordinated pathological changes in subchondral bone, synovium, and periarticular tissues, with metabolic syndrome emerging as a major systemic driver of disease initiation and progression. This review summarizes current advances in the understanding of metabolic disturbances in OA, with a particular focus on lipid, glucose, bone, and calcium-phosphate metabolism. In lipid metabolism, adipokines such as leptin, cholesterol accumulation, peroxisome proliferator-activated receptor signaling, and altered polyunsaturated fatty acid balance contribute to chronic low-grade inflammation, chondrocyte catabolism, and cartilage degradation. In glucose metabolism, hyperglycemia, insulin resistance, and advanced glycation end products aggravate oxidative stress, inflammatory signaling, and extracellular matrix destruction, thereby accelerating structural joint damage. Bone metabolic remodeling, including dysregulation of the OPG/RANKL/RANK axis, osteocalcin signaling, hyaluronic acid turnover, CTX-II release, and matrix metalloproteinase activation, further disrupts the balance between bone formation and resorption and amplifies cartilage degeneration. In parallel, calcium-phosphate metabolism influences OA progression through calcitonin, parathyroid hormone, and vitamin D-dependent regulation of osteochondral homeostasis. Collectively, these findings indicate that OA is driven by dynamic crosstalk among systemic metabolism, inflammatory mediators, chondrocyte dysfunction, and subchondral bone remodeling. A deeper understanding of these interconnected metabolic pathways not only refines the pathogenic framework of OA but also identifies potential therapeutic opportunities, including metabolic modulation, biomarker-guided stratification, and multi-target intervention strategies aimed at slowing disease progression and improving patient outcomes.