A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) (ADAMTS)

The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) family consists of 19 secreted zinc-metalloproteinases that play pivotal roles in extracellular matrix (ECM) assembly and degradation [PMID: 25703314]. ADAMTS-4 and ADAMTS-5, known as aggrecanases, are the primary enzymes responsible for aggrecan cleavage in osteoarthritis, leading to permanent cartilage loss [PMID: 30107311]. ADAMTS-7 and ADAMTS-12 are also linked to cartilage degradation and have emerged as significant factors in cardiovascular diseases, particularly atherosclerosis and vascular calcification [PMID: 21737367]. These enzymes function by cleaving specific ECM components like aggrecan, versican, and cartilage oligomeric matrix protein (COMP), leading to tissue structural failure in disease states [PMID: 24033732]. Therapeutic intervention focuses on the development of selective inhibitors to prevent pathological proteolysis while sparing other family members involved in normal physiology [PMID: 33091198]. Early clinical attempts with broad-spectrum matrix metalloproteinase inhibitors failed due to dose-limiting musculoskeletal toxicity [PMID: 12065010]. Current drug candidates include highly specific small molecules like GLPG1972 and monoclonal antibodies such as CRB0017, which target the catalytic or ancillary domains of specific ADAMTS isoforms [PMID: 28234157]. Monitoring efficacy in clinical trials often involves measuring neoepitope biomarkers like ARGS-aggrecan fragments in synovial fluid or serum [PMID: 26373290].

Other names

AggrecanaseProcollagen N-endopeptidaseADAM-TSADAMTS-4ADAMTS-5ADAMTS-7ADAMTS-12

Inhibition of the catalytic zinc-dependent metalloproteinase domain or ancillary exosite domains to prevent the cleavage of extracellular matrix proteins such as aggrecan, versican, and cartilage oligomeric matrix protein (COMP) [PMID: 33091198].