THBS2

Thrombospondin-2 (THBS2/TSP2) is a secreted homotrimeric matricellular glycoprotein (~145 kDa per monomer) that modulates cell-matrix interactions rather than serving as a core structural ECM component. THBS2 contains a modular domain architecture including an N-terminal heparin-binding domain, procollagen-like region, three type I thrombospondin repeats (TSRs), EGF-like repeats, seven type III calcium-binding repeats, and C-terminal globular domain with RGD cell attachment site. Primary functions include: (1) Potent endogenous angiogenesis inhibitor - the type I repeats bind CD36 receptor on endothelial cells triggering apoptosis and capillary regression via caspase-3 activation and mitochondrial membrane potential loss; (2) Regulator of ECM organization - modulates collagen fibrillogenesis by binding MMP-2 and facilitating its endocytic clearance via LRP1 receptor; (3) Mediator of cell-matrix adhesion - binds integrins including avb3 via RGD motif. THBS2-null mice exhibit disorganized collagen fibrils, elevated MMP-2 levels, connective tissue defects (skin fragility, lax tendons), and increased tissue vascularization. Heterozygous THBS2 pathogenic variants cause Ehlers-Danlos syndrome with vascular features (EDSCLL3) in humans via impaired MMP2 clearance. Localizes to interstitial ECM and basement membranes of connective tissues. Expression is low at baseline but induced during tissue remodeling, wound healing, and fibrosis. Recent studies implicate THBS2 in fibrogenesis via TLR4-FAK/TGF-beta signaling in hepatic stellate cells. Functions as an extracellular scaffold orchestrating cell-matrix communication, tissue architecture, and angiogenic balance.