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

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


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Disease Models, Animal
  • Disease Progression
  • Growth Plate
  • Humans
  • Intervertebral Disc / growth & development
  • Intervertebral Disc / pathology
  • Intervertebral Disc Degeneration / genetics*
  • Intervertebral Disc Degeneration / physiopathology
  • Intervertebral Disc Displacement / genetics*
  • Intervertebral Disc Displacement / physiopathology
  • Mice
  • Mutation
  • Receptors, G-Protein-Coupled / genetics*
  • STAT3 Transcription Factor / genetics*
  • Signal Transduction


  • Gpr126 protein, mouse
  • Receptors, G-Protein-Coupled
  • STAT3 Transcription Factor
  • Stat3 protein, mouse