A Functional Shift of IGFBP3 in Osteoarthritis: From Cartilage Protection to Disease Promotion.

Osteoarthritis (OA) is a prevalent degenerative joint disease driven by complex interactions among mechanical stress, inflammation, and metabolic dysregulation. Insulin-like growth factor binding protein 3 (IGFBP3) has emerged as a key regulator of cartilage homeostasis, yet its role in OA remains controversial. Accumulating evidence indicates that IGFBP3 exerts both insulin-like growth factor 1 (IGF-1)-dependent and IGF-1-independent effects on chondrocytes, including modulation of proliferation, apoptosis, and nuclear signaling. However, existing studies report contradictory findings, showing both protective and inhibitory actions of IGFBP3, likely reflecting differences in disease stage, cellular microenvironment, and experimental models. Notably, diabetic OA represents a distinct pathological subtype. Emerging data suggest that metabolic conditions reshape IGF signaling and IGFBP3 function, highlighting important differences between primary OA and diabetic OA. IGFBP3 activity is further regulated by endocrine factors, extracellular matrix components, proteases, and epigenetic mechanisms, and mediates multicellular crosstalk among chondrocytes, synovial fibroblasts, macrophages, mesenchymal stem cells, and bone cells. This review integrates these divergent findings and proposes IGFBP3 as a molecular link between metabolic disturbance and joint degeneration, providing a novel framework for subtype-specific therapeutic targeting in OA.