1. Genetics and Genomics
  2. Medicine

Tendon and motor phenotypes in the Crtap-/- mouse model of recessive Osteogenesis Imperfecta

  1. Matthew William Grol  Is a corresponding author
  2. Nele A Haelterman
  3. Joohyun Lim
  4. Elda M Munivez
  5. Marilyn Archer
  6. David M Hudson
  7. Sara F Tufa
  8. Douglas R Keene
  9. Kevin Lei
  10. Dongsu Park
  11. Cole D Kuzawa
  12. Catherine G Ambrose
  13. David R Eyre
  14. Brendan H Lee  Is a corresponding author
  1. University of Western Ontario, Canada
  2. Baylor College of Medicine, United States
  3. University of Washington, United States
  4. Shriners Hospital for Children, United States
  5. The University of Texas Health Sciences Center at Houston, United States
https://doi.org/10.7554/eLife.63488
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Cite this article
  1. Matthew William Grol
  2. Nele A Haelterman
  3. Joohyun Lim
  4. Elda M Munivez
  5. Marilyn Archer
  6. David M Hudson
  7. Sara F Tufa
  8. Douglas R Keene
  9. Kevin Lei
  10. Dongsu Park
  11. Cole D Kuzawa
  12. Catherine G Ambrose
  13. David R Eyre
  14. Brendan H Lee
(2021)
Tendon and motor phenotypes in the Crtap-/- mouse model of recessive Osteogenesis Imperfecta
eLife 10:e63488.
https://doi.org/10.7554/eLife.63488
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Abstract

Osteogenesis imperfecta (OI) is characterized by short stature, skeletal deformities, low bone mass, and motor deficits. A subset of OI patients also present with joint hypermobility; however, the role of tendon dysfunction in OI pathogenesis is largely unknown. Using the Crtap-/- mouse model of severe, recessive OI, we found that mutant Achilles and patellar tendons were thinner and weaker with increased collagen cross-links and reduced collagen fibril size at 1- and 4-months compared to wildtype. Patellar tendons from Crtap-/- mice also had altered numbers of CD146+CD200+ and CD146-CD200+ progenitor-like cells at skeletal maturity. RNA-seq analysis of Achilles and patellar tendons from 1-month Crtap-/- mice revealed dysregulation in matrix and tendon marker gene expression concomitant with predicted alterations in TGF-b, inflammatory, and metabolic signaling. At 4-months, Crtap-/- mice showed increased aSMA, MMP2, and phospho-NFkB in the patellar tendon consistent with excess matrix remodeling and tissue inflammation. Finally, a series of behavioral tests showed severe motor impairments and reduced grip strength in 4-month Crtap-/- mice – a phenotype that correlates with the tendon pathology.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been provided for Figure 6 that include full lists of differentially expressed genes resulting from RNA-seq analysis of Achilles and patellar tendons from 1- month wild-type and Crtap-/- mice. For each, a list of predicted upstream regulators identified using Ingenuity Pathway Analysis is also included.

Article and author information

Author details

  1. Matthew William Grol

    Physiology and Pharmacology, University of Western Ontario, London, Canada
    For correspondence
    mgrol2@uwo.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6514-9066

  2. Nele A Haelterman

    Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Joohyun Lim

    Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9670-806X

  4. Elda M Munivez

    Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Marilyn Archer

    Orthopaedics and Sports Medicine, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. David M Hudson

    Orthopaedics and Sports Medicine, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Sara F Tufa

    Shriners Hospital for Children, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. Douglas R Keene

    Shriners Hospital for Children, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.

  9. Kevin Lei

    Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.

  10. Dongsu Park

    Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.

  11. Cole D Kuzawa

    Orthopaedic Surgery, The University of Texas Health Sciences Center at Houston, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.

  12. Catherine G Ambrose

    Orthopaedic Surgery, The University of Texas Health Sciences Center at Houston, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.

  13. David R Eyre

    Orthopaedics and Sports Medicine, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.

  14. Brendan H Lee

    Baylor College of Medicine, Houston, United States
    For correspondence
    blee@bcm.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8573-4211

Funding

Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD024064)

  • Brendan H Lee

Rolanette and Berdon Lawrence Bone Disease Program of Texas

  • Brendan H Lee

BCM Center for Skeletal Medicine and Biology

  • Brendan H Lee

Pamela and David Ott Center for Heritable Disorders of Connective Tissue

  • Brendan H Lee

National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR373318)

  • David R Eyre

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Cheryl Ackert-Bicknell, University of Colorado, United States

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved Institutional Animal Care and Use Committee (IACUC) protocols (#AN-1506) at Baylor College of Medicine.

Version history

  1. Received: September 25, 2020
  2. Accepted: May 24, 2021
  3. Accepted Manuscript published: May 26, 2021 (version 1)
  4. Version of Record published: June 8, 2021 (version 2)

Copyright

© 2021, Grol et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Matthew William Grol
  2. Nele A Haelterman
  3. Joohyun Lim
  4. Elda M Munivez
  5. Marilyn Archer
  6. David M Hudson
  7. Sara F Tufa
  8. Douglas R Keene
  9. Kevin Lei
  10. Dongsu Park
  11. Cole D Kuzawa
  12. Catherine G Ambrose
  13. David R Eyre
  14. Brendan H Lee
(2021)
Tendon and motor phenotypes in the Crtap-/- mouse model of recessive Osteogenesis Imperfecta
eLife 10:e63488.
https://doi.org/10.7554/eLife.63488

Share this article

https://doi.org/10.7554/eLife.63488

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