The ADAMTS8 paradox: Context-dependent mechanisms linking tumor suppression and cardiovascular remodeling

ADAMTS8 is a secreted metalloproteinase with unexpectedly divergent roles in cancer and cardiovascular disease. In solid tumors, it is frequently silenced and exhibits tumor-suppressive and anti-angiogenic properties. In contrast, in pulmonary arterial hypertension and cardiac fibrosis, it is induced under pathological stress and contributes to vascular and fibrotic remodeling. This functional opposition suggests that ADAMTS8 cannot be understood as a protease with a single invariant role, but rather as a context-dependent regulator whose activity is shaped by the extracellular environment. In this review, we integrate current evidence on the structural and biochemical properties of ADAMTS8, including its domain organization, autoproteolysis, substrate selectivity, and sensitivity to TIMP-2. We discuss osteopontin as a key substrate and propose a unified model in which differential substrate processing, matrix-derived mechanical cues, and receptor-context differences together determine disease-specific signaling outputs. This framework helps explain why ADAMTS8 often acts to restrain angiogenic and oncogenic signaling in tumors yet favors pro-remodeling responses in cardiovascular pathology. Understanding this context dependence may inform future efforts to exploit ADAMTS8 as a biomarker and therapeutic target in a disease-selective manner.