image: Image Caption: Schematic representation of the exon (A) and protein domain (B) structure of ADAMTS2. Image link: https://ars.els-cdn.com/content/image/1-s2.0-S2352304225001758-gr2_lrg.jpg
Credit: Genes & Diseases
ADAMTS2, a member of the ADAMTS zinc metalloproteinase family, is widely recognized for its pivotal role as a procollagen I N-proteinase. This enzyme plays a crucial part in the maturation of fibrillar collagens, which are essential for maintaining the structural integrity of connective tissues. Beyond its traditional role, recent discoveries have revealed that ADAMTS2 is involved in a diverse range of biological processes that extend well beyond collagen maturation.
One of the most significant findings about ADAMTS2 is its association with the Ehlers-Danlos syndrome dermatosparaxis type (dEDS). This rare genetic disorder is marked by extreme skin fragility due to defective collagen processing. The loss of ADAMTS2 enzyme activity leads to the retention of N-propeptides in type I procollagen molecules, resulting in weakened and disorganized collagen fibrils. This discovery has shed light on the molecular basis of dEDS and has highlighted the critical role of ADAMTS2 in collagen homeostasis.
However, ADAMTS2’s functions are not confined to collagen processing. The enzyme has emerged as a key player in angiogenesis, where it exhibits anti-angiogenic and anti-tumorigenic activities. By interacting with nucleolin on endothelial cell surfaces, ADAMTS2 can suppress cell proliferation, induce morphological changes, and promote anoikis-induced apoptosis. This anti-angiogenic function positions ADAMTS2 as a potential therapeutic target for controlling tumor growth and metastasis.
Furthermore, ADAMTS2 has been implicated in lymphangiogenesis through its ability to process pro-VEGFC into its active form, thereby promoting VEGFR3 signaling. This function highlights the enzyme’s contribution to maintaining lymphatic homeostasis and its potential relevance in pathological conditions where lymphangiogenesis plays a role.
Intriguingly, ADAMTS2 also plays a role in neurodevelopment by modulating the activity of Reelin, a glycoprotein essential for neuronal migration and synaptic plasticity. In the central nervous system, ADAMTS2-mediated cleavage of Reelin can lead to impaired neuronal function, which is linked to neurodegenerative diseases such as Alzheimer’s and schizophrenia. This suggests that ADAMTS2 may be a crucial factor in the pathophysiology of neuropsychiatric disorders.
ADAMTS2 also contributes to the regulation of the immune system. It influences the activity of several immune components, including immunoglobulins, complement proteins, and macrophage inhibitory factors. These interactions underscore the enzyme’s potential role in immune modulation and inflammatory responses.
Research has also highlighted the involvement of ADAMTS2 in cardiovascular diseases, where it appears to modulate cardiac hypertrophy and heart failure through interactions with the PI3K/AKT signaling pathway. This regulatory capacity points to its cardioprotective role under conditions of cardiac stress.
The multifunctional nature of ADAMTS2 suggests its potential as both a biomarker and a therapeutic target in a range of diseases. As research continues to unravel the complexities of this enzyme’s role, the potential to develop targeted therapies aimed at modulating ADAMTS2 activity offers promising prospects for treating conditions ranging from genetic disorders to cancer and cardiovascular diseases.
# # # # #
Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.
Scopus CiteScore: 8.4
Impact Factor: 9.4
# # # # # #
More information: https://www.keaipublishing.com/en/journals/genes-and-diseases/
Editorial Board: https://www.keaipublishing.com/en/journals/genes-and-diseases/editorial-board/
All issues and articles in press are available online in ScienceDirect (https://www.sciencedirect.com/journal/genes-and-diseases ).
Submissions to Genes & Disease may be made using Editorial Manager (https://www.editorialmanager.com/gendis/default.aspx ).
Print ISSN: 2352-4820
eISSN: 2352-3042
CN: 50-1221/R
Contact Us: editor@genesndiseases.com
X (formerly Twitter): @GenesNDiseases (https://x.com/GenesNDiseases )
# # # # # #
Reference
Ruben Vanlerberghe, Alain Colige, Anne-Marie Malfait, Delfien Syx, Fransiska Malfait, ADAMTS2: More than a procollagen N-proteinase, Genes & Diseases, Volume 12, Issue 6, 2025, 101686, https://doi.org/10.1016/j.gendis.2025.101686
Funding Information:
Research Foundation Flanders (FWO), Belgium 1842318N
Research Foundation Flanders (FWO), Belgium 3G041519
Research Foundation Flanders (FWO), Belgium 12Q5920N
Ghent University GOA019-21
The Ehlers-Danlos Society
National Institutes of Health [National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)] (USA) R01AR060364
National Institutes of Health [National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)] (USA) R01AR064251
National Institutes of Health [National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)] (USA) P30AR079206
National Institutes of Health [National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)] (USA) 1R21AR085242-01
Klaus E. Kuettner, PhD, Chair of Osteoarthritis Research
Fonds de la Recherche Scientifique - Fonds National de la Recherche Scientifique FRS-FNRS, Belgium FRS-FNRS FC96394
Fonds de la Recherche Scientifique - Fonds National de la Recherche Scientifique FRS-FNRS, Belgium FRS-FNRS J.0034.24
Fonds Spéciaux de la Recherche (Université de Liège)
Fondation Hospitalo-Universitaire Léon Frédéricq (Université of Liège, Belgium)