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


Autoři: Zhaoyang Liu aff001;  Garrett W. D. Easson aff003;  Jingjing Zhao aff004;  Nadja Makki aff004;  Nadav Ahituv aff004;  Matthew J. Hilton aff006;  Simon Y. Tang aff003;  Ryan S. Gray aff001
Působiště autorů: Department of Nutrional Sciences, University of Texas at Austin, Austin, Texas, United States of America aff001;  Department of Pediatrics, Dell Pediatric Research Institute, University of Texas at Austin Dell Medical School, Austin, Texas, United States of America aff002;  Department of Orthopedics, Washington University School of Medicine, Saint Louis, Missouri, United States of America aff003;  Department of Bioengineering and Therapeutic Sciences and Institute for Human Genetics, University of California San Francisco, San Francisco, California, United States of America aff004;  Department of Anatomy and Cell Biology, University of Florida, College of Medicine, Gainesville, Florida, United States of America aff005;  Department of Orthopedic Surgery and Cell Biology, Duke University School of Medicine, Durham, North Carolina, United States of America aff006
Vyšlo v časopise: Dysregulation of STAT3 signaling is associated with endplate-oriented herniations of the intervertebral disc in Adgrg6 mutant mice. PLoS Genet 15(10): e32767. doi:10.1371/journal.pgen.1008096
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008096

Souhrn

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.

Klíčová slova:

Cartilage – Collagens – Fibrosis – Gene expression – Growth plate – Mouse models – STAT signaling – Stiffness


Zdroje

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