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

Published online

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Liu, Z; Easson, GWD; Zhao, J; Makki, N; Ahituv, N; Hilton, MJ; Tang, SY; Gray, RS

Published Date

  • October 2019

Published In

Volume / Issue

  • 15 / 10

Start / End Page

  • e1008096 -

PubMed ID

  • 31652254

Pubmed Central ID

  • 31652254

Electronic International Standard Serial Number (EISSN)

  • 1553-7404

Digital Object Identifier (DOI)

  • 10.1371/journal.pgen.1008096

Language

  • eng

Conference Location

  • United States