ADAMTSL6β Protein Rescues Fibrillin-1 Microfibril Disorder in a Marfan Syndrome Mouse Model through the Promotion of Fibrillin-1 Assembly

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. ADAMTSL6 beta (A disintegrin-like metalloprotease domain with thrombospondin type I motifs-like 6 beta) 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 ADAMTSL6 beta plays an essential role in the development and regeneration of connective tissues. ADAMTSL6 beta 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 ADAMTSL6 beta attenuates the overactivation of TGF-beta signals associated with the increased release of active TGF-beta from disrupted fibrillin-1 microfibrils within periodontal ligaments. Our current data thus demonstrate the essential contribution of ADAMTSL6 beta to fibrillin-1 microfibril formation. These findings also suggest a new therapeutic strategy for the treatment of MFS through ADAMTSL6 beta-mediated fibrillin-1 microfibril assembly.