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CRISPR-Cas9-mediated loss of function of β-catenin attenuates intervertebral disc degeneration
Yunshan Fan1, Lan Zhao1, Yumei Lai1
1Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL 60612, USA.
Abstract:
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.
Insights
Targeting beta-catenin in disc cells with CRISPR-Cas9 reversed disc degeneration in mice. This approach preserved notochordal cells, maintained disc structure, and reduced pain, offering a potential new therapy for this common condition.
Area of Science:
- Biomedical research
- Regenerative medicine
- Molecular biology
Background:
- Intervertebral disc degeneration is a prevalent cause of pain and disability.
- Current treatments cannot reverse disc degeneration.
- Beta-catenin is a key factor implicated in disc degeneration.
Purpose of the Study:
- To investigate the therapeutic potential of targeting beta-catenin in disc degeneration.
- To evaluate the efficacy of CRISPR-Cas9 gene editing in ameliorating disc degeneration.
- To understand the role of beta-catenin in disc cellular and matrix remodeling.
Main Methods:
- Utilized a mouse model of intervertebral disc injury.
- Administered CRISPR-Cas9-expressing adeno-associated virus via intradiscal injection to downregulate beta-catenin.
- Assessed pathological changes including nucleus pulposus decompression, cell replacement, annulus fibrosus disorganization, and pain-related neural events.
Main Results:
- Downregulation of beta-catenin significantly mitigated disc degeneration.
- Preserved notochordal cells and attenuated chondro-osteogenesis in the nucleus pulposus.
- Maintained annulus fibrosus structure and decelerated catabolic matrix reactions.
- Reduced pain-related neural events associated with disc degeneration.
Conclusions:
- Targeting beta-catenin in disc cells via CRISPR-Cas9 demonstrates multifaceted therapeutic effects on disc degeneration.
- Beta-catenin plays a fundamental role in disc remodeling and degeneration.
- CRISPR-Cas9 is a viable tool for identifying drug targets and developing therapies for disc degeneration.
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