ADAMTSL6β Protein Rescues Fibrillin-1 Microfibril Disorder in a Marfan Syndrome Mouse Model through the Promotion of Fibrillin-1 Assembly*
ADAMTSL6β Protein Rescues Fibrillin-1 Microfibril Disorder in a Marfan Syndrome Mouse Model through the Promotion of Fibrillin-1 Assembly*
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DOI：
10.1074/jbc.m111.243451
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发表时间：
2011-08
期刊：
影响因子：
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通讯作者：
M. Saito;Misaki Kurokawa;Masahito Oda;M. Oshima;Ko Tsutsui;Kazutaka Kosaka;K. Nakao;M. Ogawa;Ri-ichiroh Manabe;Naoto Suda;Ganburged Ganjargal;Yasunobu Hada;T. Noguchi;T. Teranaka;K. Sekiguchi;T. Yoneda;T. Tsuji
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文献类型：
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作者：
M. Saito;Misaki Kurokawa;Masahito Oda;M. Oshima;Ko Tsutsui;Kazutaka Kosaka;K. Nakao;M. Ogawa;Ri-ichiroh Manabe;Naoto Suda;Ganburged Ganjargal;Yasunobu Hada;T. Noguchi;T. Teranaka;K. Sekiguchi;T. Yoneda;T. Tsuji
背景：马凡氏综合征的病理是由于结缔组织中的微纤维形成不足引起的。结果：重组ADAMTSL 6 β直接给药可成功改善马凡氏综合征的临床表现。结论：本研究证明了微纤维再生在预防马凡综合征中的重要性。意义：我们目前的数据支持一个新的概念，即使用ADAMTSL 6 β的微纤维再生对于改善马凡综合征至关重要。马凡氏综合征（MFS）是一种结缔组织的系统性疾病，其由不充分的β-l微纤维形成引起，并且可引起心脏并发症、肺气肿、眼透镜脱位和严重的牙周病。ADAMTSL 6 β（A disintegrin-like metalloprotease domain with thrombospondin type I motifs-like 6β）是一种微纤维相关的细胞外基质蛋白，在各种结缔组织中表达，参与了β 1微纤维的组装。我们在这里报告，ADAMTSL 6 β在结缔组织的发育和再生中起着至关重要的作用。在MFS小鼠模型中，ADAMTSL 6 β表达通过促进Escherin-1微纤维组装来挽救牙周膜损伤后的微纤维障碍。此外，在给予ADAMTSL 6 β后，MFS小鼠中增强的TGF-β组装减弱了TGF-β信号的过度活化，该信号与牙周韧带内破坏的TGF-β微纤维中活性TGF-β的释放增加有关。因此，我们目前的数据证明了ADAMTSL 6 β对Escherin-1微纤维形成的重要贡献。这些发现也提示了通过ADAMTSL 6 β介导的MFS-1微纤维组装治疗MFS的新治疗策略。
Background: The pathology of Marfan syndrome is caused by insufficient fibrillin-1 microfibril formation in connective tissues. Results: Successful improvement of Marfan syndrome manifestations are induced by the direct administration of recombinant ADAMTSL6β. Conclusion: This study demonstrated critical importance of microfibril regeneration in preventing Marfan syndrome. Significance: Our current data support a new concept that the regeneration of microfibrils using ADAMTSL6β is essential for improving Marfan syndrome. 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.