A G protein-coupled receptor is required in cartilaginous and dense connective tissues to maintain spine alignment

  1. Zhaoyang Liu
  2. Amro A Hussien
  3. Yunjia Wang
  4. Terry Heckmann
  5. Roberto Gonzalez
  6. Courtney M Karner
  7. Jess G Snedeker
  8. Ryan S Gray  Is a corresponding author
  1. University of Texas at Austin, United States
  2. University of Zurich, Switzerland
  3. Central South University, China
  4. University of Texas at Austin - Dell Pediatrics Research Institute, United States
  5. University of Texas Southwestern Medical Center, United States
  6. ETH Zurich, Switzerland

Abstract

Adolescent idiopathic scoliosis (AIS) is the most common spine disorder affecting children worldwide, yet little is known about the pathogenesis of this disorder. Here, we demonstrate that genetic regulation of structural components of the axial skeleton, the intervertebral discs, and dense connective tissues (i.e., ligaments and tendons) are essential for the maintenance of spinal alignment. We show that the adhesion G protein-coupled receptor ADGRG6, previously implicated in human AIS association studies, is required in these tissues to maintain typical spine alignment in mice. Furthermore, we show that ADGRG6 regulates biomechanical properties of tendon and stimulates CREB signaling governing gene expression in cartilaginous tissues of the spine. Treatment with a cAMP agonist could mirror aspects of receptor function in culture, thus defining core pathways for regulating these axial cartilaginous and connective tissues. As ADGRG6 is a key gene involved in human AIS, these findings open up novel therapeutic opportunities for human scoliosis.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Zhaoyang Liu

    Nutritional Sciences/ Pediatrics, University of Texas at Austin, Austin, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8032-1167
  2. Amro A Hussien

    Department of Orthopedics, University of Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9324-9360
  3. Yunjia Wang

    Department of Spine Surgery and Orthopaedics, Central South University, Changsha, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Terry Heckmann

    Pediatrics, University of Texas at Austin - Dell Pediatrics Research Institute, Austin, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Roberto Gonzalez

    Pediatrics, University of Texas at Austin - Dell Pediatrics Research Institute, Austin, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Courtney M Karner

    Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0387-4486
  7. Jess G Snedeker

    Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  8. Ryan S Gray

    Nutritional Sciences/ Pediatrics, University of Texas at Austin - Dell Pediatrics Research Institute, Austin, United States
    For correspondence
    ryan.gray@austin.utexas.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9668-6497

Funding

NIH Office of the Director (R01AR072009)

  • Ryan S Gray

NIH Office of the Director (R01AR071967)

  • Courtney M Karner

NIH Office of the Director (R01AR076325)

  • Courtney M Karner

NIH Office of the Director (F32AR073648)

  • Zhaoyang Liu

Vontobel-Stiftung

  • Jess G Snedeker

NIH Office of the Director (K99AR077090)

  • Zhaoyang Liu

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 (AUP-2018-00276) of the University of Texas at Austin.

Copyright

© 2021, Liu 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. Zhaoyang Liu
  2. Amro A Hussien
  3. Yunjia Wang
  4. Terry Heckmann
  5. Roberto Gonzalez
  6. Courtney M Karner
  7. Jess G Snedeker
  8. Ryan S Gray
(2021)
A G protein-coupled receptor is required in cartilaginous and dense connective tissues to maintain spine alignment
eLife 10:e67781.
https://doi.org/10.7554/eLife.67781

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https://doi.org/10.7554/eLife.67781