title: Induced ablation of Bmp1 and Tll1 produces osteogenesis imperfecta in mice.
abstract: Osteogenesis imperfecta (OI), or brittle bone disease, is most often caused by dominant mutations in the collagen I genes COL1A1/COL1A2, whereas rarer recessive OI is often caused by mutations in genes encoding collagen I-interacting proteins. Recently, mutations in the gene for the proteinase bone morphogenetic 1 (BMP1) were reported in two recessive OI families. BMP1 and the closely related proteinase mammalian tolloid-like 1 (mTLL1) are co-expressed in various tissues, including bone, and have overlapping activities that include biosynthetic processing of procollagen precursors into mature collagen monomers. However, early lethality of Bmp1- and Tll1-null mice has precluded use of such models for careful study of in vivo roles of their protein products. Here we employ novel mouse strains with floxed Bmp1 and Tll1 alleles to induce postnatal, simultaneous ablation of the two genes, thus avoiding barriers of Bmp1(-/-) and Tll1(-/-) lethality and issues of functional redundancy. Bones of the conditionally null mice are dramatically weakened and brittle, with spontaneous fractures-defining features of OI. Additional skeletal features include osteomalacia, thinned/porous cortical bone, reduced processing of procollagen and dentin matrix protein 1, remarkably high bone turnover and defective osteocyte maturation that is accompanied by decreased expression of the osteocyte marker and Wnt-signaling inhibitor sclerostin, and by marked induction of canonical Wnt signaling. The novel animal model presented here provides new opportunities for in-depth analyses of in vivo roles of BMP1-like proteinases in bone and other tissues, and for their roles, and for possible therapeutic interventions, in OI.
authors.affiliation: Department of Cell and Regenerative Biology, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA, Laboratory of Genetics, University of Wisconsin, Madison, WI, USA.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Muir
authors.affiliation: Department of Biomedical Sciences, Baylor College of Dentistry Texas A&M Health Science Center, Dallas, TX, USA.
authors.forename: Yinshi
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Department of Cell and Regenerative Biology, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA.
authors.forename: Delana Hopkins
authors.initials: DH
authors.lastname: Butz
authors.affiliation: Department of Cell and Regenerative Biology, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Davis
authors.affiliation: Geriatrics Research, Education, and Clinical Center, William S. Middleton Veterans Hospital, Madison, WI, USA, Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Blank
authors.affiliation: Department of Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Birk
authors.affiliation: Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA and.
authors.forename: Se-Jin
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Reconstructive Sciences, Biomaterials and Skeletal Development, School of Dental Medicine, University of Connecticut, Farmington, CT, USA.
authors.forename: David
authors.initials: D
authors.lastname: Rowe
authors.affiliation: Department of Biomedical Sciences, Baylor College of Dentistry Texas A&M Health Science Center, Dallas, TX, USA.
authors.forename: Jian Q
authors.initials: JQ
authors.lastname: Feng
authors.affiliation: Department of Cell and Regenerative Biology, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA, dsgreens@wisc.edu.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Greenspan
mesh_terms: D000818:Animals; D055395:Bone Morphogenetic Protein 1 / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005269:Femur / Q000473:pathology* / Q000648:ultrastructure; D055785:Gene Knockdown Techniques / Q000379:methods*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D010013:Osteogenesis Imperfecta / Q000235:genetics / Q000473:pathology*; D055394:Tolloid-Like Metalloproteinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D055394:Tolloid-Like Metalloproteinases; C484477:Tll1 protein, mouse; C525707:Bmp1 protein, mouse; D055395:Bone Morphogenetic Protein 1