[en] A disintegrin and metalloproteinase with thrombospondin motifs 2 (ADAMTS2) is a member of the ADAMTS zinc metalloproteinase family, best known for its role as a procollagen I N-proteinase in the maturation of fibrillar collagens. Biallelic defects in the ADAMTS2 gene, resulting in a loss of ADAMTS2 enzyme activity and consequent retention of N-propeptides in type I procollagen molecules, lead to the rare monogenic disease Ehlers-Danlos syndrome dermatosparaxis type (dEDS) in humans, and dermatosparaxis in animals, conditions that are hallmarked by extreme fragility of the skin and other soft connective tissues. Recent studies have expanded the substrate repertoire of ADAMTS2 considerably, revealing its potential implication in several biological processes, including angiogenesis, lymphangiogenesis, neurodevelopment, immunity, and spermatogenesis. There is also emerging evidence for a role for ADAMTS2 in complex disorders, including cancer and cardiovascular and neurodegenerative disease. These findings may not only provide answers to hitherto unsolved questions in dermatosparaxis but also unveil a therapeutic and/or biomarker potential of ADAMTS2 in many diseases. This narrative review provides an in-depth overview of the discovery, structure, regulation, and enzymatic role of ADAMTS2, its role in fibrillar collagen maturation and in dEDS pathogenesis, as well as its newly discovered substrates and its potential role in complex disorders.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Vanlerberghe, Ruben ; Center for Medical Genetics, Ghent University Hospital, Department of Biomolecular Medicine, Ghent University, Ghent 9000, Belgium
Colige, Alain ; Université de Liège - ULiège > GIGA > GIGA Cancer - Connective Tissue Biology
Malfait, Anne-Marie ; Division of Rheumatology, Department of Internal Medicine, Rush University Medical College, and Chicago Center on Musculoskeletal Pain, Chicago, IL 60612, United States
Syx, Delfien; Center for Medical Genetics, Ghent University Hospital, Department of Biomolecular Medicine, Ghent University, Ghent 9000, Belgium
Malfait, Fransiska ; Center for Medical Genetics, Ghent University Hospital, Department of Biomolecular Medicine, Ghent University, Ghent 9000, Belgium
UGent - Ghent University NIAMS - National Institute of Arthritis and Musculoskeletal and Skin Diseases FWO - Research Foundation Flanders Rheumatology Research Foundation NIH - National Institutes of Health EDS - Ehlers-Danlos Society F.R.S.-FNRS - Fund for Scientific Research ULiège - University of Liège
Funding text :
This work was supported by the Research Foundation Flanders (FWO), Belgium (No. 1842318N, 3G041519 to F.M.; 12Q5920N to D.S.); Ghent University (No. GOA019-21); The Ehlers-Danlos Society (to D.S. and F.M.); the National Institutes of Health [National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)] (USA) (No. R01AR060364, R01AR064251, P30AR079206 to A.M.M.; 1R21AR085242-01 to A.M.M., D.S., and F.M.). A.M.M. is supported by the Klaus E. Kuettner, PhD, Chair of Osteoarthritis Research. A.C. is a \u201CSenior Research Associate\u201D of the Fonds de la Recherche Scientifique - Fonds National de la Recherche Scientifique (FRS-FNRS, Belgium), and his work is supported by grants from the FRS-FNRS (No. FC96394, J.0034.24), the Fonds Sp\u00E9ciaux de la Recherche (Universit\u00E9 de Li\u00E8ge), and the Fondation Hospitalo-Universitaire L\u00E9on Fr\u00E9d\u00E9ricq (Universit\u00E9 of Li\u00E8ge, Belgium).
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