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First published online March 23, 2006
doi: 10.1242/10.1242/dev.02308

Development 133, 1587-1596 (2006)
Published by The Company of Biologists 2006
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Regulation of procollagen amino-propeptide processing during mouse embryogenesis by specialization of homologous ADAMTS proteases: insights on collagen biosynthesis and dermatosparaxis

Carine Le Goff1, Robert P. T. Somerville1, Frederic Kesteloot2, Kimerly Powell1, David E. Birk3, Alain C. Colige2 and Suneel S. Apte1,*

1 Department of Biomedical Engineering and Orthopaedic Research Center, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
2 Laboratory of Connective Tissues Biology, Center of Biomedical Integrative Genoproteomics, University of Liège, 4000 Sart Tilman, Belgium.
3 Department of Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.

* Author for correspondence (e-mail: aptes{at}ccf.org)

Accepted 2 February 2006

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.

Key words: ADAMTS, Metalloprotease, Procollagen, Dermatosparaxis, Ehlers-Danlos syndrome


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