ADAMTS designates a family of 19 secreted enzymes, whose the first member ADAMTS1 was described in 1997. The ADAMTS family has a role in extracellular matrix degradation and turn over and has previously been involved in various human biological processes, including connective tissue structure, cancer, coagulation, arthritis, angiogenesis and cell migration. More recently, the ADAMTS(L) family has been described, sharing the same ancillary domain but distinct by the absence of any enzyme activity. Mutations in ADAMTS13, ADAMTS2, ADAMTS10, ADAMTS17, ADAMTSL2 and ADAMTSL4 have been identified in distinct human genetic disorders ranging from thrombotic thrombocytopenic purpura to acromelic dysplasia. The aim of our review was to emphasize the role of this family in the extracellular matrix based on human phenotypes so far identified in relation with ADAMTS(L) mutations.

Mutations in ADAMTS2, a procollagen amino-propeptidase, cause severe skin fragility, designated as dermatosparaxis in animals, and a subtype of the Ehlers-Danlos syndrome (dermatosparactic type or VIIC) in humans. Not all collagen-rich tissues are affected to the same degree, which suggests compensation by the ADAMTS2 homologs ADAMTS3 and ADAMTS14. In situ hybridization of Adamts2, Adamts3 and Adamts14, and of the genes encoding the major fibrillar collagens, Col1a1, Col2a1 and Col3a1, during mouse embryogenesis, demonstrated distinct tissue-specific, overlapping expression patterns of the protease and substrate genes. Adamts3, but not Adamts2 or Adamts14, was co-expressed with Col2a1 in cartilage throughout development, and with Col1a1 in bone and musculotendinous tissues. ADAMTS3 induced procollagen I processing in dermatosparactic fibroblasts, suggesting a role in procollagen I processing during musculoskeletal development. Adamts2, but not Adamts3 or Adamts14, was co-expressed with Col3a1 in many tissues including the lungs and aorta, and Adamts2^-/- mice showed widespread defects in procollagen III processing. Adamts2^-/- mice had abnormal lungs, characterized by a decreased parenchymal density. However, the aorta and collagen fibrils in the aortic wall appeared normal. Although Adamts14 lacked developmental tissue-specific expression, it was co-expressed with Adamts2 in mature dermis, which possibly explains the presence of some processed skin procollagen in dermatosparaxis. The data show how evolutionarily related proteases with similar substrate preferences may have distinct biological roles owing to tissue-specific gene expression, and provide insights into collagen biosynthesis and the pathobiology of dermatosparaxis.