TY - JOUR
T1 - Induced ablation of Bmp1 and Tll1 produces osteogenesis imperfecta in mice
AU - Muir, Alison M.
AU - Ren, Yinshi
AU - Butz, Delana Hopkins
AU - Davis, Nicholas A.
AU - Blank, Robert D.
AU - Birk, David E.
AU - Lee, Se Jin
AU - Rowe, David
AU - Feng, Jian Q.
AU - Greenspan, Daniel S.
N1 - Funding Information:
This work was supported by grants AR60636 and AR59685 (to S.-J.L.), AR54753 (to R.D.B.), AR44745 (to D.E.B.), DE018486 (to J.F.), and AR53815 and AR47746 (to D.S.G.) from the National Institutes of Health.
PY - 2014/6/15
Y1 - 2014/6/15
N2 - 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 floxedBmp1 and Tll1 alleles to induce postnatal, simultaneous ablation of the two genes, thus avoiding barriers ofBmp1-/- andTll1-/- lethality andissues 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,andbymarkedinduction ofcanonicalWntsignaling.Thenovel animalmodelpresented 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.
AB - 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 floxedBmp1 and Tll1 alleles to induce postnatal, simultaneous ablation of the two genes, thus avoiding barriers ofBmp1-/- andTll1-/- lethality andissues 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,andbymarkedinduction ofcanonicalWntsignaling.Thenovel animalmodelpresented 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.
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U2 - 10.1093/hmg/ddu013
DO - 10.1093/hmg/ddu013
M3 - Article
C2 - 24419319
AN - SCOPUS:84901299739
SN - 0964-6906
VL - 23
SP - 3085
EP - 3101
JO - Human molecular genetics
JF - Human molecular genetics
IS - 12
ER -