Induced ablation of Bmp1 and Tll1 produces osteogenesis imperfecta in mice. Hum Mol Genet 2014 Jun 15;23(12):3085-101
Date
01/15/2014Pubmed ID
24419319Pubmed Central ID
PMC4030766DOI
10.1093/hmg/ddu013Scopus ID
2-s2.0-84901299739 (requires institutional sign-in at Scopus site) 63 CitationsAbstract
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.
Author List
Muir AM, Ren Y, Butz DH, Davis NA, Blank RD, Birk DE, Lee SJ, Rowe D, Feng JQ, Greenspan DSAuthor
Robert D. Blank PhD, MD Emeritus Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBone Morphogenetic Protein 1
Disease Models, Animal
Femur
Gene Knockdown Techniques
Humans
Mice
Mice, Inbred C57BL
Mutation
Osteogenesis Imperfecta
Tolloid-Like Metalloproteinases
