ADAMTS4

ADAMTS4 (A Disintegrin and Metalloproteinase with Thrombospondin Motifs 4), also known as aggrecanase-1, is a secreted zinc-dependent protease involved in extracellular matrix (ECM) remodeling. It cleaves proteoglycans such as aggrecan and versican, regulating tissue integrity and cellular signaling. Its activity is tightly modulated by endogenous inhibitors like TIMP-3. ADAMTS4 operates through the TGF-β and NF-κB pathways, influencing inflammatory responses and tissue repair. Dysregulation contributes to pathological ECM degradation, notably in osteoarthritis, where it accelerates cartilage destruction. It is also implicated in rheumatoid arthritis, atherosclerosis, and neurodegenerative disorders like Alzheimer’s disease due to its role in processing amyloid precursor protein (APP).
Current drug development targets ADAMTS4 inhibition to mitigate ECM degradation. Small-molecule inhibitors (e.g., TAPI-2) and monoclonal antibodies are under preclinical investigation, with osteoarthritis as a primary focus. Recent studies highlight its crosstalk with ADAMTS5, suggesting dual inhibition strategies for enhanced efficacy. Biomarker research explores ADAMTS4 levels in synovial fluid as a prognostic indicator for joint diseases. Challenges remain in achieving tissue-specific targeting to avoid off-effects on related metalloproteinases. Emerging therapeutic approaches include CRISPR-based gene editing and miRNA regulators to modulate its expression in chronic inflammatory conditions.