title: Adamtsl2 deletion results in bronchial fibrillin microfibril accumulation and bronchial epithelial dysplasia--a novel mouse model providing insights into geleophysic dysplasia.
abstract: Mutations in the secreted glycoprotein ADAMTSL2 cause recessive geleophysic dysplasia (GD) in humans and Musladin-Lueke syndrome (MLS) in dogs. GD is a severe, often lethal, condition presenting with short stature, brachydactyly, stiff skin, joint contractures, tracheal-bronchial stenosis and cardiac valve anomalies, whereas MLS is non-lethal and characterized by short stature and severe skin fibrosis. Although most mutations in fibrillin-1 (FBN1) cause Marfan syndrome (MFS), a microfibril disorder leading to transforming growth factor-β (TGFβ) dysregulation, domain-specific FBN1 mutations result in dominant GD. ADAMTSL2 has been previously shown to bind FBN1 and latent TGFβ-binding protein-1 (LTBP1). Here, we investigated mice with targeted Adamtsl2 inactivation as a new model for GD (Adamtsl2(-/-) mice). An intragenic lacZ reporter in these mice showed that ADAMTSL2 was produced exclusively by bronchial smooth muscle cells during embryonic lung development. Adamtsl2(-/-) mice, which died at birth, had severe bronchial epithelial dysplasia with abnormal glycogen-rich inclusions in bronchial epithelium resembling the cellular anomalies described previously in GD. An increase in microfibrils in the bronchial wall was associated with increased FBN2 and microfibril-associated glycoprotein-1 (MAGP1) staining, whereas LTBP1 staining was increased in bronchial epithelium. ADAMTSL2 was shown to bind directly to FBN2 with an affinity comparable to FBN1. The observed extracellular matrix (ECM) alterations were associated with increased bronchial epithelial TGFβ signaling at 17.5 days of gestation; however, treatment with TGFβ-neutralizing antibody did not correct the epithelial dysplasia. These investigations reveal a new function of ADAMTSL2 in modulating microfibril formation, and a previously unsuspected association with FBN2. Our studies suggest that the bronchial epithelial dysplasia accompanying microfibril dysregulation in Adamtsl2(-/-) mice cannot be reversed by TGFβ neutralization, and thus might be mediated by other mechanisms.
authors.affiliation: Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA hubmacd@ccf.org aptes@ccf.org.
authors.forename: Dirk
authors.initials: D
authors.lastname: Hubmacher
authors.affiliation: Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Lauren W
authors.initials: LW
authors.lastname: Wang
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Mecham
authors.affiliation: Department of Anatomy and Cell Biology and Faculty of Dentistry, McGill University, 3640 University Street, Montreal, Quebec, Canada H3A 0C7.
authors.forename: Dieter P
authors.initials: DP
authors.lastname: Reinhardt
authors.affiliation: Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA hubmacd@ccf.org aptes@ccf.org.
authors.forename: Suneel S
authors.initials: SS
authors.lastname: Apte
mesh_terms: D000071096:ADAMTS Proteins; D000818:Animals; D000831:Animals, Newborn; D001848:Bone Diseases, Developmental / Q000378:metabolism / Q000473:pathology*; D001980:Bronchi / Q000473:pathology* / Q000648:ultrastructure; D060833:Cellular Microenvironment; D004195:Disease Models, Animal; D004848:Epithelium / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D005109:Extracellular Matrix / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D000071838:Fibrillin-1; D000071840:Fibrillin-2; D000071837:Fibrillins; D017353:Gene Deletion; D006003:Glycogen / Q000378:metabolism; D017880:Limb Deformities, Congenital / Q000378:metabolism / Q000473:pathology*; D008810:Mice, Inbred C57BL; D020894:Microfibrils / Q000378:metabolism*; D008840:Microfilament Proteins / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D054392:Adipokines
chemical_list: D000071096:ADAMTS Proteins; D016326:Extracellular Matrix Proteins; D000071838:Fibrillin-1; D000071840:Fibrillin-2; D000071837:Fibrillins; D006003:Glycogen; D008840:Microfilament Proteins; D016212:Transforming Growth Factor beta; C525084:Adamtsl2 protein, mouse; C000605722:FBN1 protein, human; D054392:Adipokines; C000605723:FBN2 protein, human; C000605724:Fbn1 protein, mouse; C000605728:Fbn2 protein, mouse
keywords: ADAMTS-like protein; Connective tissue disorder; Extracellular matrix; Fibrillin microfibril; Lung development