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

View ORCID ProfileZhaoyang Liu, Amro A. Hussien, Yunjia Wang, Terry Heckmann, Roberto Gonzalez, Courtney M. Karner, Jess G. Snedeker, View ORCID ProfileRyan S. Gray
doi: https://doi.org/10.1101/2021.02.22.432353
Zhaoyang Liu
1Department of Pediatrics, Dell Pediatric Research Institute, 1400 Barbara Jordan Blvd, The University of Texas at Austin, Dell Medical School, Austin, TX 78723, USA
2Department of Nutritional Sciences, 200 W 24th Street, The University of Texas at Austin, Austin, TX 78712, USA
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Amro A. Hussien
3Department of Orthopedics, Balgrist University Hospital, University of Zurich, 8008 Zurich, Switzerland
4Institute for Biomechanics, ETH Zurich, 8092 Zurich, Switzerland
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Yunjia Wang
1Department of Pediatrics, Dell Pediatric Research Institute, 1400 Barbara Jordan Blvd, The University of Texas at Austin, Dell Medical School, Austin, TX 78723, USA
5Department of Spine Surgery and Orthopaedics, No 87 Xiangya Road, Xiangya Hospital, Central South University, Changsha 410008, China
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Terry Heckmann
1Department of Pediatrics, Dell Pediatric Research Institute, 1400 Barbara Jordan Blvd, The University of Texas at Austin, Dell Medical School, Austin, TX 78723, USA
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Roberto Gonzalez
1Department of Pediatrics, Dell Pediatric Research Institute, 1400 Barbara Jordan Blvd, The University of Texas at Austin, Dell Medical School, Austin, TX 78723, USA
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Courtney M. Karner
6Department of Internal Medicine, Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, 5323 Harry Hines Blvd, University of Texas Southwestern Medical Center, Dallas, TX 75390
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Jess G. Snedeker
3Department of Orthopedics, Balgrist University Hospital, University of Zurich, 8008 Zurich, Switzerland
4Institute for Biomechanics, ETH Zurich, 8092 Zurich, Switzerland
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Ryan S. Gray
1Department of Pediatrics, Dell Pediatric Research Institute, 1400 Barbara Jordan Blvd, The University of Texas at Austin, Dell Medical School, Austin, TX 78723, USA
2Department of Nutritional Sciences, 200 W 24th Street, The University of Texas at Austin, Austin, TX 78712, USA
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  • For correspondence: ryan.gray@austin.utexas.edu
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Summary

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 (e.g., ligaments and tendons), are essential for maintenance of spinal alignment. We show that the G-coupled protein receptor Adgrg6, previously implicated in human AIS association studies, is required in these tissues to maintain typical spine morphology. We show that Adgrg6 regulates biomechanical properties of tendon and stimulates CREB signaling governing gene expression in cartilaginous tissues of the spine. Treatment with an cAMP agonist was able to mirror aspects of receptor function in culture defining core pathways for regulation of these axial connective tissues. As ADGRG6 is a key gene involved in human AIS, these findings open up novel therapeutic opportunities for human scoliosis.

Highlights

  • Knockout mice lacking Adgrg6 function in the tendons and ligaments of the spine develop perinatal-onset thoracic scoliosis.

  • Loss of Adgrg6 function in cartilaginous tissues of the discs contribute to the incidence and severity of scoliosis.

  • The loss of Adgrg6 function in spine tissues provide a model of construct validity for human adolescent idiopathic scoliosis

  • Fine tuning of the biomechanical properties of dense connective tissues is essential for maintaining spine alignment.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • All authors have read and approved the final submitted manuscript.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted February 22, 2021.
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A G protein-coupled receptor is required in cartilaginous and dense connective tissues to maintain spine alignment
Zhaoyang Liu, Amro A. Hussien, Yunjia Wang, Terry Heckmann, Roberto Gonzalez, Courtney M. Karner, Jess G. Snedeker, Ryan S. Gray
bioRxiv 2021.02.22.432353; doi: https://doi.org/10.1101/2021.02.22.432353
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A G protein-coupled receptor is required in cartilaginous and dense connective tissues to maintain spine alignment
Zhaoyang Liu, Amro A. Hussien, Yunjia Wang, Terry Heckmann, Roberto Gonzalez, Courtney M. Karner, Jess G. Snedeker, Ryan S. Gray
bioRxiv 2021.02.22.432353; doi: https://doi.org/10.1101/2021.02.22.432353

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