CRISPR-Cas9-mediated loss of function of β-catenin attenuates intervertebral disc degeneration

Intervertebral disc degeneration is a very common medical condition causing pain and disability, and it cannot be reversed by available treatment options. Here we report that targeting β-catenin, a pivotal factor associated with disc degeneration, ameliorates disc degeneration in a mouse model of disc injury. Degenerative changes in the disc in response to disc injury include decompression of nucleus pulposus (NP), replacement of notochordal cells in the NP by chondrocyte-like cells, and disorganization of annulus fibrosus (AF). Importantly, downregulation of β-catenin through intradiscal injection of CRISPR-Cas9-expressing adeno-associated virus significantly mitigated all these pathological changes, by preserving notochordal cells and attenuating chondro-osteogenesis in the NP, as well as maintaining the AF structure. Moreover, β-catenin loss-of-function decelerated the rapid induction of catabolic reactions in disc matrix and attenuated pain-related neural events during disc degeneration. Thus, our data demonstrate that targeting β-catenin in disc cells through CRISPR-Cas9 has multifaceted therapeutic effects on disc degeneration, and we suggest that β-catenin plays a fundamental role in the remodeling and degenerative processes of the disc. In addition, this study proposes that CRISPR-Cas9 is a useful tool for identifying new drug targets and developing therapeutic strategies for disc degeneration. [Display omitted] Upregulation of β-catenin is induced in a mouse model of disc degeneration. We administered adeno-associated virus expressing CRISPR-Cas9 in the injured discs to target the β-catenin-encoding gene. We found that loss-of-function of β-catenin ameliorates disc degeneration by maintaining notochord cells and reducing degenerative changes involving anabolic, catabolic, and pain-inducing responses.