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.
Highlights
Spine disorders are one of the most common health issues affecting human populations worldwide, causing a tremendous socio-economic burden
We demonstrate that conditional removal of ADGRG6 function in the intervertebral disc (IVD) results in endplate-oriented herniations in adult mice (Fig 1B, 1D and 1D’)
We found that adhesion G-protein coupled receptor G6 (Adgrg6) is highly expressed in the growth plate using immunohistochemistry-based in situ hybridization (S1A Fig), but we failed to detect expression in the cortical or trabecular bone in vertebrae of adult mice under these conditions
Summary
Spine disorders are one of the most common health issues affecting human populations worldwide, causing a tremendous socio-economic burden. More severe forms of disc degeneration can result in the herniation of the nucleus pulposus (i) laterally through the annulus fibrosis layer; or (ii) through the cartilaginous endplate into the vertebral body (endplate-oriented). Genetic susceptibility to disc degeneration has been shown to play a major role in disc degeneration [7], with the majority of these findings implicating extracellular matrix components of the disc, matrix metalloproteases, or pro-inflammatory cytokines [8]. Together these data suggest that dysregulation of anabolic and catabolic factors as well as inflammatory signaling may underlie many forms of disc degeneration in humans. The molecular regulators and initiating factors for these events remain to be defined
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