Diabetes-Related Metabolic Osteoarthritis: Advanced Glycation-Collagen Axis, Cartilage Stiffening, and...

Diabetes mellitus, particularly type 2 diabetes, has been associated in some studies with increased osteoarthritis (OA) risk, greater symptom burden, and structural progression; however, epidemiological evidence remains heterogeneous, and the extent to which diabetes independently contributes to OA after accounting for obesity, adiposity, physical inactivity, and other metabolic confounders remains debated. In metabolically susceptible patients, chronic hyperglycemia, insulin resistance, carbonyl stress, and low-grade inflammation may contribute to disruption of the joint microenvironment. One proposed mechanism involves the accumulation of advanced glycation end products (AGEs), which can cross-link with type I/II collagen and may increase extracellular matrix crosslinking and stiffness. Through these biochemical and biomechanical effects, the AGE-collagen axis may influence chondrocyte mechanotransduction, inflammatory signaling, matrix turnover, and cell survival, thereby providing a plausible but not yet fully validated link between systemic metabolic dysfunction and OA-relevant structural degeneration. Recent advances in biomaterials may offer experimental and translational strategies to modulate the glycated, inflamed, and mechanically altered joint microenvironment. These approaches include stiffness-tunable and stimuli-responsive hydrogels, nanocarriers designed to deliver anti-AGE agents or AGE-cleaving enzymes, osteochondral gradient scaffolds that mimic native tissue transitions, and immunomodulatory materials that may attenuate local inflammation. At present, these interventions should be viewed primarily as preclinical or early translational strategies rather than established disease-modifying therapies. This review discusses the potential molecular and biomechanical implications of the AGE-collagen axis in diabetes-related OA, critically evaluates emerging biomaterials-based therapeutic approaches, and highlights preclinical evaluation models and outcome measures. Finally, we outline key translational challenges-including targeted delivery, long-term safety of degradation products, metabolic heterogeneity, patient stratification, and integration with systemic therapies-and propose methodological frameworks to support the future development of clinically testable biomaterials interventions.