Transgenic mouse model of the mild dominant form of osteogenesis imperfecta

Bonadio, Jeffrey<sup>1,2</sup>; Saunders, Thomas L.<sup>1</sup>; Tsai, Eugene<sup>3</sup>; Goldstein, Steven A.<sup>3</sup>; Morris-Wiman, Joyce<sup>4</sup>; Brinkley, Linda<sup>4</sup>; Dolan, David F.<sup>5</sup>; Altschuler, Richard A.<sup>5</sup>; Hawkins, Jr, Joseph E.<sup>5</sup>; Bateman, John F.<sup>6</sup>; Mascara, Thomas<sup>6</sup>; Jaenisch, Rudolf<sup>7</sup>

Affiliations

¹Howard Hughes Medical Institute, The University of Michigan, Ann Arbor, MI 48109-0650

²Department of Pathology, The University of Michigan, Ann Arbor, MI 48109-0650

³Department of Surgery, The University of Michigan, Ann Arbor, MI 48109-0650

⁴Department of Anatomy and Cell Biology, The University of Michigan, Ann Arbor, MI 48109-0650

⁵Kresge Hearing Research Institute, The University of Michigan, Ann Arbor, MI 48109-0650

⁶Department of Pediatrics, University of Melbourne, Parkville, Victoria, 3052, Australia

⁷Department of Biology, Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Nine Cambridge Center, Cambridge, MA 02142

Abstract

Osteogenesis imperfecta type I is a mild, dominantly inherited, connective tissue disorder characterized by bone fragility. Mutations in type I collagen account for all known cases. In Mov-13 mice, integration of a murine retrovirus within the first intron of the alpha 1(I) collagen gene results in a null allele blocked at the level of transcription. This study demonstrates that mutant mice heterozygous for the null allele are a model of osteogenesis imperfecta type I. A defect in type I collagen production is associated with dominant-acting morphological and functional defects in mineralized and nonmineralized connective tissue and with progressive hearing loss. The model provides an opportunity to investigate the effect of a reduced amount of type I collagen on the structure and integrity of extracellular matrix. It also may represent a system in which therapeutic strategies to strengthen connective tissue can be developed.

Links

DOI: 10.1073/pnas.87.18.7145

PubMed: 2402497

WoS: A1990DZ45300046

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Cited By (24)

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1998	Akhter MP, Cullen DM, Pedersen EA, Kimmel DB, Recker RR. Bone response to in vivo mechanical loading in two breeds of mice. Calcif Tiss Int. November 1998;63(5):442-449.
1997	Jepsen KJ, Schaffler MB, Kuhn JL, Goulet RW, Bonadio J, Goldstein SA. Type I collagen mutation alters the strength and fatigue behavior of Mov13 cortical tissue. J Biomech. November–December 1997;30(11-12):1141-1147.
1999	Derwin KA, Soslowsky LJ. A quantitative investigation of structure-function relationships in a tendon fascicle model. J Biomech Eng. December 1999;121(6):598-604.
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1999	Brodt MD, Ellis CB, Silva MJ. Growing C57Bl/6 mice increase whole bone mechanical properties by increasing geometric and material properties. J Bone Miner Res. December 1999;14(12):2159-2166.
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2022	Schindeler A, Lee LR, O'Donohue AK, Ginn SL, Munns CF. Curative cell and gene therapy for osteogenesis imperfecta. J Bone Miner Res. May 2022;37(5):826-836.
1993	Bonadio J, Jepsen KJ, Mansoura MK, Jaenisch R, Kuhn JL, Goldstein SA. A murine skeletal adaptation that significantly increases cortical bone mechanical properties: implications for human skeletal fragility. J Clin Invest. October 1993;92(4):1697-1705.
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