Tendon and motor phenotypes in the Crtap-/- mouse model of recessive Osteogenesis Imperfecta
- University of Western Ontario, Canada
- Baylor College of Medicine, United States
- University of Washington, United States
- Shriners Hospital for Children, United States
- The University of Texas Health Sciences Center at Houston, United States
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
Matthew William Grol
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.
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.
Reviewing Editor
- Cheryl Ackert-Bicknell, University of Colorado, United States
Publication history
- Received: September 25, 2020
- Accepted: May 24, 2021
- Accepted Manuscript published: May 26, 2021 (version 1)
- 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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