Endocrine‑metabolic imbalance drives osteoarthritis: From whole‑joint pathobiology to precision therapy (Review).

Osteoarthritis (OA) is a chronic degenerative joint disease closely associated with aging and metabolic dysfunction, characterized by cartilage degeneration, synovial inflammation, aberrant subchondral bone remodeling, pain and progressive functional impairment. Beyond mechanical loading, accumulating evidence indicates that OA is increasingly recognized as a whole‑joint disorder shaped by the interplay between local tissue damage and systemic endocrine‑metabolic imbalance. Endocrine factors, including sex hormones, thyroid hormone, melatonin, parathyroid hormone and vitamin D, together with metabolic disturbances, such as obesity, insulin resistance, dysregulated glucose and lipid metabolism and gut microbiota imbalances, can cooperatively remodel the joint microenvironment. Mechanistically, these alterations converge on immuno‑inflammatory amplification, mitochondrial dysfunction, oxidative stress, cellular senescence, metabolic reprogramming and regulated cell death, thereby promoting extracellular matrix degradation, persistent synovitis and uncoupled bone‑cartilage remodeling. The present review systematically summarizes the molecular basis of endocrine‑metabolic crosstalk in OA and discusses emerging therapeutic opportunities targeting hormonal signaling, metabolic pathways, circadian regulation, nutritional support and lifestyle interventions. Nevertheless, the reciprocal interactions among endocrine signals, systemic metabolic abnormalities and local joint pathology remain incompletely understood, and their translation into mechanism‑based clinical stratification remains at an early stage. Thus, targeting endocrine‑metabolic crosstalk may support mechanism‑based phenotyping and subtype‑informed precision therapy for OA, provided that candidate biomarkers and interventions are validated in prospective clinical studies.