The proposal will investigate regulation of extracellular networks by ADAMTS10, a secreted metalloprotease mutated in recessive Weill-Marchesani syndrome (WMS), a rare inherited connective tissue disorder. Despite its rarity, WMS is of considerable biomedical significance because its clinical picture is the opposite of Marfan syndrome (MFS), a more common disorder caused by fibrillin-1 mutations. In contrast to MFS, WMS is characterized by short stature, brachydactyly, thick skin, stiff joints and aortic stenosis but like MFS, there is dislocation of the lens. Dominant WMS is clinically indistinguishable from recessive WMS, but is caused by mutations in fibrillin-1, providing a strong genetic link to MFS. Like fibrillin-1, preliminary studies show robust ADAMTS10 gene expression in the skeleton, hand and foot mesenchyme, lung, skin, major blood vessels and heart valves, suggesting a broad role in connective tissue regulation. We show that ADAMTS10 binds specifically and with high affinity to fibrillin-1 in vitro and that it is localized to microfibrils in situ. Preliminary studies of AdamtslO null mice have identified a phenotype in the skeleton and lungs that contrasts with mouse models of fibrillin deficiency. This genetic association and the preliminary studies have led us to hypothesize that ADAMTS10 and fibrillin- 1 are linked in a connective tissue regulatory network. To define the physiological role of ADAMTS10 and better understand this regulatory network, funding is requested for two Specific Aims: 1. To determine the consequences of AdamtslO inactivation in mice and cells and to investigate whether partial or total AdamtslO deficiency will influence mouse models of fibrillin deficiency. 2. To define the mechanistic basis for the genetic relationship of ADAMTS10 with fibrillins and to determine the role of ADAMTS10 in fibrillin networks. Relevance to public health: The proposal offers an opportunity to solve the mechanism of Weill-Marchesani syndrome and obtain a novel perspective on Marfan syndrome. An understanding of how ADAMTS10 integrates with fibrillin networks may have long-term potential for disease modification in Marfan syndrome.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Arthritis, Connective Tissue and Skin Study Section (ACTS)
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Tseng, Hung H
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Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
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Hubmacher, Dirk; Wang, Lauren W; Mecham, Robert P et al. (2015) Adamtsl2 deletion results in bronchial fibrillin microfibril accumulation and bronchial epithelial dysplasia--a novel mouse model providing insights into geleophysic dysplasia. Dis Model Mech 8:487-99
Hubmacher, Dirk; Apte, Suneel S (2013) The biology of the extracellular matrix: novel insights. Curr Opin Rheumatol 25:65-70
Gabriel, Luis A R; Wang, Lauren W; Bader, Hannah et al. (2012) ADAMTSL4, a secreted glycoprotein widely distributed in the eye, binds fibrillin-1 microfibrils and accelerates microfibril biogenesis. Invest Ophthalmol Vis Sci 53:461-9
Bader, Hannah L; Wang, Lauren W; Ho, Jason C et al. (2012) A disintegrin-like and metalloprotease domain containing thrombospondin type 1 motif-like 5 (ADAMTSL5) is a novel fibrillin-1-, fibrillin-2-, and heparin-binding member of the ADAMTS superfamily containing a netrin-like module. Matrix Biol 31:398-411
Wylie, James D; Ho, Jason C; Singh, Shweta et al. (2012) Adamts5 (aggrecanase-2) is widely expressed in the mouse musculoskeletal system and is induced in specific regions of knee joint explants by inflammatory cytokines. J Orthop Res 30:226-33
Le Goff, Carine; Mahaut, Clémentine; Wang, Lauren W et al. (2011) Mutations in the TGF? binding-protein-like domain 5 of FBN1 are responsible for acromicric and geleophysic dysplasias. Am J Hum Genet 89:7-14
Kutz, Wendy E; Wang, Lauren W; Bader, Hannah L et al. (2011) ADAMTS10 protein interacts with fibrillin-1 and promotes its deposition in extracellular matrix of cultured fibroblasts. J Biol Chem 286:17156-67
Hattori, Noriko; Carrino, David A; Lauer, Mark E et al. (2011) Pericellular versican regulates the fibroblast-myofibroblast transition: a role for ADAMTS5 protease-mediated proteolysis. J Biol Chem 286:34298-310
Hubmacher, Dirk; Apte, Suneel S (2011) Genetic and functional linkage between ADAMTS superfamily proteins and fibrillin-1: a novel mechanism influencing microfibril assembly and function. Cell Mol Life Sci 68:3137-48
Dupuis, Loren E; McCulloch, Daniel R; McGarity, Jessica D et al. (2011) Altered versican cleavage in ADAMTS5 deficient mice; a novel etiology of myxomatous valve disease. Dev Biol 357:152-64

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