A disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4) (ADAMTS4)

A disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4), also known as Aggrecanase-1, is a secreted zinc-dependent metalloproteinase that plays a pivotal role in the remodeling and degradation of the extracellular matrix [3, 5, 20]. Its primary biological function is the cleavage of aggrecan, the major proteoglycan in articular cartilage responsible for its load-bearing properties [1, 12]. In pathological conditions like osteoarthritis and rheumatoid arthritis, ADAMTS4 is overexpressed, leading to accelerated cartilage destruction and joint failure [2, 8, 13]. Beyond joint health, it is involved in the degradation of brevican and versican in the brain and vasculature, contributing to conditions such as intervertebral disc degeneration, atherosclerosis, and Alzheimer's disease [7, 8, 15]. It has also been identified as a potential factor in tumor progression and metastasis due to its matrix-remodeling capabilities [2, 3]. Therapeutic efforts are centered on developing highly selective inhibitors, including small molecules like AGG-523 and monoclonal antibodies, to block its proteolytic activity [18, 23, 27]. A major challenge in drug development is achieving selectivity to avoid the musculoskeletal toxicity often associated with broad-spectrum metalloproteinase inhibitors [1, 9, 32]. Current research explores both active-site zinc chelation and exosite-targeted inhibition to preserve tissue integrity in degenerative diseases [9, 23].

Other names

Aggrecanase-1ADAMTS-4ADMP-1KIAA0688ADAM-TS 4

Inhibition of proteolytic activity through zinc chelation at the active site or binding to non-catalytic exosites to prevent substrate recognition and cleavage.