ADAMTSL6β protein rescues fibrillin-1 microfibril disorder in a Marfan syndrome mouse model through the promotion of fibrillin-1 assembly

Masahiro Saito, Misaki Kurokawa, Masahito Oda, Masamitsu Oshima, Ko Tsutsui, Kazutaka Kosaka, Kazuhisa Nakao, Miho Ogawa, Ri Ichiroh Manabe, Naoto Suda, Ganburged Ganjargal, Yasunobu Hada, Toshihide Noguchi, Toshio Teranaka, Kiyotoshi Sekiguchi, Toshiyuki Yoneda, Takashi Tsuji

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Marfan syndrome (MFS) is a systemic disorder of the connective tissues caused by insufficient fibrillin-1 microfibril formation and can cause cardiac complications, emphysema, ocular lens dislocation, and severe periodontal disease. ADAMTSL6β (A disintegrin-like metalloprotease domain with thrombospondin type I motifs-like 6β) is a microfibril-associated extracellular matrix protein expressed in various connective tissues that has been implicated in fibrillin-1 microfibril assembly. We here report that ADAMTSL6β plays an essential role in the development and regeneration of connective tissues. ADAMTSL6β expression rescues microfibril disorder after periodontal ligament injury in an MFS mouse model through the promotion of fibrillin-1 microfibril assembly. In addition, improved fibrillin-1 assembly in MFS mice following the administration of ADAMTSL6β attenuates the overactivation of TGF-β signals associated with the increased release of active TGF-β from disrupted fibrillin-1 microfibrils within periodontal ligaments. Our current data thus demonstrate the essential contribution of ADAMTSL6β to fibrillin-1 microfibril formation. These findings also suggest a new therapeutic strategy for the treatment of MFS through ADAMTSL6β-mediated fibrillin-1 microfibril assembly.

Original languageEnglish
Pages (from-to)38602-38613
Number of pages12
JournalJournal of Biological Chemistry
Volume286
Issue number44
DOIs
Publication statusPublished - Nov 4 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Saito, M., Kurokawa, M., Oda, M., Oshima, M., Tsutsui, K., Kosaka, K., Nakao, K., Ogawa, M., Manabe, R. I., Suda, N., Ganjargal, G., Hada, Y., Noguchi, T., Teranaka, T., Sekiguchi, K., Yoneda, T., & Tsuji, T. (2011). ADAMTSL6β protein rescues fibrillin-1 microfibril disorder in a Marfan syndrome mouse model through the promotion of fibrillin-1 assembly. Journal of Biological Chemistry, 286(44), 38602-38613. https://doi.org/10.1074/jbc.M111.243451