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Myostatin deficiency partially rescues the bone phenotype of osteogenesis imperfecta model mice

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Abstract

Summary

Mice with osteogenesis imperfecta (+/oim), a disorder of bone fragility, were bred to mice with muscle over growth to test whether increasing muscle mass genetically would improve bone quality and strength. The results demonstrate that femora from mice carrying both mutations have greater mechanical integrity than their +/oim littermates.

Introduction

Osteogenesis imperfecta is a heritable connective tissue disorder due primarily to mutations in the type I collagen genes resulting in skeletal deformity and fragility. Currently, there is no cure, and therapeutic strategies encompass the use of antiresorptive pharmaceuticals and surgical bracing, with limited success and significant potential for adverse effects. Bone, a mechanosensing organ, can respond to high mechanical loads by increasing new bone formation and altering bone geometry to withstand increased forces. Skeletal muscle is a major source of physiological loading on bone, and bone strength is proportional to muscle mass.

Methods

To test the hypothesis that congenic increases in muscle mass in the osteogenesis imperfecta murine model mouse (oim) will improve their compromised bone quality and strength, heterozygous (+/oim) mice were bred to mice deficient in myostatin (+/mstn), a negative regulator of muscle growth. The resulting adult offspring were evaluated for hindlimb muscle mass, and bone microarchitecture, physiochemistry, and biomechanical integrity.

Results

+/oim mice deficient in myostatin (+/mstn +/oim) were generated and demonstrated that myostatin deficiency increased body weight, muscle mass, and biomechanical strength in +/mstn +/oim mice as compared to +/oim mice. Additionally, myostatin deficiency altered the physiochemical properties of the +/oim bone but did not alter bone remodeling.

Conclusions

Myostatin deficiency partially improved the reduced femoral bone biomechanical strength of adult +/oim mice by increasing muscle mass with concomitant improvements in bone microarchitecture and physiochemical properties.

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Acknowledgments

We would like to thank the Biomolecular Imaging Center at the Harry S. Truman Memorial Veterans Hospital and the University of Missouri Comparative Orthopedics Laboratory for their contributions to this project as well as Dr. Mark Ellersieck for his invaluable assistance with statistical analyses. We would also like to thank the following funding sources: National Institutes of Health Grants AR055907 (SMC, BAG, AKO, CER, CLP) and T32RR007004 (BAG), National Space and Biomedical Research Institute Postdoctoral Fellowship NCC 9–58 (SMC), Leda J. Sears Trust Foundation Grant (SMC, BAG, CER, CLP), Phi Zeta Grant (BAG), University of Missouri Life Sciences Fellowship (AKO), University of Missouri Research Board Grant (MB, CLP), and University of Missouri Interdisciplinary Intercampus Research Program (CLP,YW, AKO). The funding sources were not involved in the designing, execution, analysis, reporting, or submission of this work for publication.

Conflicts of interest

Arin Kettle Oestreich, Stephanie Michelle Carleton, Xiaomei Yao, Bettina A. Gentry, Chad Edward Raw, Marybeth Brown, Ferris Michael Pfeiffer, Yong Wang, and Charlotte Longacre Phillips declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Biological Sciences, University of Missouri, Columbia, MO, 65211, USA

    A. K. Oestreich

  2. Department of Biochemistry, University of Missouri, Columbia, MO, 65211, USA

    S. M. Carleton, C. E. Raw & C. L. Phillips

  3. Department of Oral and Craniofacial Sciences, School of Dentistry, University of Missouri-Kansas City, Kansas City, MO, 64108, USA

    X. Yao & Y. Wang

  4. Department of Veterinary Pathobiology, University of Missouri, Columbia, MO, 65211, USA

    B. A. Gentry

  5. Department of Biomedical Sciences and Physical Therapy Program, University of Missouri, Columbia, MO, 65211, USA

    M. Brown

  6. Department of Orthopaedic Surgery and Bioengineering, University of Missouri, Columbia, MO, 65211, USA

    F. M. Pfeiffer

  7. Department of Child Health, University of Missouri, 117 Schweitzer Hall, Columbia, MO, 65211, USA

    C. L. Phillips

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  1. A. K. Oestreich
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  9. C. L. Phillips
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Correspondence to C. L. Phillips.

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Oestreich, A.K., Carleton, S.M., Yao, X. et al. Myostatin deficiency partially rescues the bone phenotype of osteogenesis imperfecta model mice. Osteoporos Int 27, 161–170 (2016). https://doi.org/10.1007/s00198-015-3226-7

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  • DOI: https://doi.org/10.1007/s00198-015-3226-7

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