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PLoS Genet. 2019 Oct 25;15(10):e1008096. doi: 10.1371/journal.pgen.1008096. eCollection 2019 Oct.

Dysregulation of STAT3 signaling is associated with endplate-oriented herniations of the intervertebral disc in Adgrg6 mutant mice.

Author information

1
Department of Nutritional Sciences, University of Texas at Austin, Austin, Texas, United States of America.
2
Department of Pediatrics, Dell Pediatric Research Institute, University of Texas at Austin Dell Medical School, Austin, Texas, United States of America.
3
Department of Orthopedics, Washington University School of Medicine, Saint Louis, Missouri, United States of America.
4
Department of Bioengineering and Therapeutic Sciences and Institute for Human Genetics, University of California San Francisco, San Francisco, California, United States of America.
5
Department of Anatomy and Cell Biology, University of Florida, College of Medicine, Gainesville, Florida, United States of America.
6
Department of Orthopedic Surgery and Cell Biology, Duke University School of Medicine, Durham, North Carolina, United States of America.

Abstract

Degenerative changes of the intervertebral disc (IVD) are a leading cause of disability affecting humans worldwide and has been attributed primarily to trauma and the accumulation of pathology during aging. While genetic defects have also been associated with disc degeneration, the precise mechanisms driving the initiation and progression of disease have remained elusive due to a paucity of genetic animal models. Here, we discuss a novel conditional mouse genetic model of endplate-oriented disc herniations in adult mice. Using conditional mouse genetics, we show increased mechanical stiffness and reveal dysregulation of typical gene expression profiles of the IVD in adhesion G-protein coupled receptor G6 (Adgrg6) mutant mice prior to the onset of endplate-oriented disc herniations in adult mice. We observed increased STAT3 activation prior to IVD defects and go on to demonstrate that treatment of Adgrg6 conditional mutant mice with a small molecule inhibitor of STAT3 activation ameliorates endplate-oriented herniations. These findings establish ADGRG6 and STAT3 as novel regulators of IVD endplate and growth plate integrity in the mouse, and implicate ADGRG6/STAT3 signaling as promising therapeutic targets for endplate-oriented disc degeneration.

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