Mechanical Suppression of Sonic Hedgehog Signaling by Nucleus Pulposus Cells Underlies Early Disc Degeneration in Mouse

Abstract

Sonic hedgehog (SHH) expression by nucleus pulposus (NP) cells is important for intervertebral disc development and maintenance. The lumbosacral disc, the most immobile region of the spine, lies adjacent to the sacrum and is most vulnerable to degeneration. We hypothesized that a lack of mobility represses SHH expression by NP cells, leading to degenerative changes in the intervertebral disc. To test this hypothesis, we employed a Shh-LacZ reporter mouse and a tail-loop surgical model of constant compression and immobility. Using a comprehensive level-by-level analysis, we first determined the coccygeal level most affected by geometric and histopathological changes. We next determined the effects of constant compression and immobility on the subset of SHH-expressing cells compared with sham controls. Multiplex qPCR analysis validated a decline in Shh and its target Gli1 expression by NP cells in the tail-looped discs that was associated with an increase in Piezo1 expression compared to sham controls. In summary, the findings support a model in which restricted mobility and sustained compression in lumbosacral discs accelerate pathology by prematurely silencing developmental signaling programs, such as SHH, required for NP homeostasis.