title: ADAMTSL6β protein rescues fibrillin-1 microfibril disorder in a Marfan syndrome mouse model through the promotion of fibrillin-1 assembly.
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.
authors: Department of Biological Science and Technology, Faculty of Industrial Science, Tokyo University of Science, Noda, Chiba 278-8510, Japan; Research Institute for Science and Technology, Tokyo University of Science, Noda, Chiba 278-8510, Japan. Electronic address: mssaito@rs.noda.tus.ac.jp.
authors: Masahiro
authors: M
authors: Saito
authors: Department of Biological Science and Technology, Faculty of Industrial Science, Tokyo University of Science, Noda, Chiba 278-8510, Japan.
authors: Misaki
authors: M
authors: Kurokawa
authors: Department of Biological Science and Technology, Faculty of Industrial Science, Tokyo University of Science, Noda, Chiba 278-8510, Japan.
authors: Masahito
authors: M
authors: Oda
authors: Research Institute for Science and Technology, Tokyo University of Science, Noda, Chiba 278-8510, Japan.
authors: Masamitsu
authors: M
authors: Oshima
authors: Institute for Protein Research, Osaka University, Suita Osaka 565-0871, Japan.
authors: Ko
authors: K
authors: Tsutsui
authors: Division of Restorative Dentistry, Department of Oral Medicine, Kanagawa Dental College, Yokosuka Kanagawa 238-8580, Japan.
authors: Kazutaka
authors: K
authors: Kosaka
authors: Research Institute for Science and Technology, Tokyo University of Science, Noda, Chiba 278-8510, Japan.
authors: Kazuhisa
authors: K
authors: Nakao
authors: Research Institute for Science and Technology, Tokyo University of Science, Noda, Chiba 278-8510, Japan; Organ Technologies Inc., Tokyo, Japan.
authors: Miho
authors: M
authors: Ogawa
authors: RIKEN Genomic Sciences Center, RIKEN Yokohama Institute, Yokohama 230-0045, Japan.
authors: Ri-Ichiroh
authors: RI
authors: Manabe
authors: Maxillofacial Orthognathics, Graduate School, Tokyo Medical and Dental University, Tokyo 113-0034, Japan.
authors: Naoto
authors: N
authors: Suda
authors: Maxillofacial Orthognathics, Graduate School, Tokyo Medical and Dental University, Tokyo 113-0034, Japan.
authors: Ganburged
authors: G
authors: Ganjargal
authors: Department of Biological Science and Technology, Faculty of Industrial Science, Tokyo University of Science, Noda, Chiba 278-8510, Japan; Oral Implantology and Regenerative Dental Medicine, Graduate School, Tokyo Medical and Dental University, Tokyo 113-0034, Japan.
authors: Yasunobu
authors: Y
authors: Hada
authors: Department of Periodontology, School of Dentistry, Aichi-Gakuin University, Nisshin 470-0195, Japan.
authors: Toshihide
authors: T
authors: Noguchi
authors: Division of Restorative Dentistry, Department of Oral Medicine, Kanagawa Dental College, Yokosuka Kanagawa 238-8580, Japan.
authors: Toshio
authors: T
authors: Teranaka
authors: Institute for Protein Research, Osaka University, Suita Osaka 565-0871, Japan.
authors: Kiyotoshi
authors: K
authors: Sekiguchi
authors: Department of Molecular and Cellular Biochemistry, Graduate School of Dentistry, Osaka University, Suita Osaka 565-0871, Japan.
authors: Toshiyuki
authors: T
authors: Yoneda
authors: Department of Biological Science and Technology, Faculty of Industrial Science, Tokyo University of Science, Noda, Chiba 278-8510, Japan; Research Institute for Science and Technology, Tokyo University of Science, Noda, Chiba 278-8510, Japan; Organ Technologies Inc., Tokyo, Japan.
authors: Takashi
authors: T
authors: Tsuji
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000502:physiology; D000071838:Fibrillin-1; D000071837:Fibrillins; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008382:Marfan Syndrome / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020894:Microfibrils / Q000473:pathology; D008840:Microfilament Proteins / Q000737:chemistry*; D008957:Models, Genetic; D011994:Recombinant Proteins / Q000737:chemistry; D014070:Tooth / Q000196:embryology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014945:Wound Healing; D054392:Adipokines
chemical_list: D016326:Extracellular Matrix Proteins; D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C000605722:FBN1 protein, human; D054392:Adipokines; C000605724:Fbn1 protein, mouse