Induced ablation of Bmp1 and Tll1 produces osteogenesis imperfecta in mice

Alison M. Muir, Yinshi Ren, Delana Hopkins Butz, Nicholas A. Davis, Robert D. Blank, David E. Birk, Se Jin Lee, David Rowe, Jian Q. Feng, Daniel S. Greenspan

Research output: Contribution to journalArticle

25 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)3085-3101
Number of pages17
JournalHuman molecular genetics
Volume23
Issue number12
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

Fingerprint

Osteogenesis Imperfecta
Bone and Bones
Osteocytes
Procollagen
Peptide Hydrolases
Collagen
Mutation
Genes
Osteomalacia
Spontaneous Fractures
Proteins
Bone Remodeling
Dentin
Alleles

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Muir, A. M., Ren, Y., Butz, D. H., Davis, N. A., Blank, R. D., Birk, D. E., ... Greenspan, D. S. (2014). Induced ablation of Bmp1 and Tll1 produces osteogenesis imperfecta in mice. Human molecular genetics, 23(12), 3085-3101. https://doi.org/10.1093/hmg/ddu013

Induced ablation of Bmp1 and Tll1 produces osteogenesis imperfecta in mice. / Muir, Alison M.; Ren, Yinshi; Butz, Delana Hopkins; Davis, Nicholas A.; Blank, Robert D.; Birk, David E.; Lee, Se Jin; Rowe, David; Feng, Jian Q.; Greenspan, Daniel S.

In: Human molecular genetics, Vol. 23, No. 12, 01.01.2014, p. 3085-3101.

Research output: Contribution to journalArticle

Muir, AM, Ren, Y, Butz, DH, Davis, NA, Blank, RD, Birk, DE, Lee, SJ, Rowe, D, Feng, JQ & Greenspan, DS 2014, 'Induced ablation of Bmp1 and Tll1 produces osteogenesis imperfecta in mice', Human molecular genetics, vol. 23, no. 12, pp. 3085-3101. https://doi.org/10.1093/hmg/ddu013
Muir, Alison M. ; Ren, Yinshi ; Butz, Delana Hopkins ; Davis, Nicholas A. ; Blank, Robert D. ; Birk, David E. ; Lee, Se Jin ; Rowe, David ; Feng, Jian Q. ; Greenspan, Daniel S. / Induced ablation of Bmp1 and Tll1 produces osteogenesis imperfecta in mice. In: Human molecular genetics. 2014 ; Vol. 23, No. 12. pp. 3085-3101.
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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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