Sonic Hedgehog Is An Important Regulator Of Intervertebral Disc Homeostasis And Rejuvenation

Intervertebral disc degeneration and associated neurological symptoms constitute a global health burden, yet no cure is currently available (1,2). Each disc consists of a central nucleus pulposus, surrounded by annulus fibrosus, and end plates connecting it to the growth plates of adjacent vertebral bodies. The notochord-descendant nucleus pulposus continues to express sonic hedgehog, which regulates the proliferation and differentiation of all components of neonatal mouse discs (3-7). Sonic hedgehog expression and function decline with age and are associated with disc pathologies, including terminal differentiation of nucleus pulposus cells to chondrocyte-like phenotype (7,8). Here, we used fate-mapping and conditional genetic mouse models to test the role of sonic hedgehog in the homeostasis of aging discs. We found that loss of NP-derived Shh is sufficient to accelerate multiple features of age-associated disc degeneration, including reduced NP cell number, altered matrix turnover, and induction of inflammatory, angiogenic and neurotrophic programs. Age-related disc pathologies were more prevalent in the lumbosacral discs of mice, like in humans (8-13). Also, like mice, the expression of sonic hedgehog and its targets by human nucleus pulposus cells declines with age and pathological degeneration. Moreover, pharmacologic Hedgehog activation partially restored anabolic gene expression and reduced catabolic, inflammatory and neurotrophic mediators in degenerated human NP explants ex vivo. These findings indicate that Sonic hedgehog, a developmental signal retained in the adult NP, is functionally active and required for disc homeostasis during aging and supports activation of hedgehog signaling as a candidate disease-modifying pathway for intervertebral disc pathologies.