CRISPR-Cas9-mediated loss of function of β-catenin attenuates intervertebral disc degeneration.
CRISPR-Cas9-mediated loss of function of β-catenin attenuates intervertebral disc degeneration.
复制标题
DOI：
10.1016/j.omtn.2022.03.024
复制
发表时间：
2022-06-14
期刊：
影响因子：
--
通讯作者：
Huang, Jian
中科院分区：
文献类型：
--
作者：
Fan, Yunshan;Zhao, Lan;Lai, Yumei;Lu, Ke;Huang, Jian
椎间盘退变是一种非常常见的疾病，会导致疼痛和残疾，并且无法通过现有的治疗方案逆转。在这里，我们报告了靶向β-连环蛋白，一个与椎间盘退变相关的关键因素，改善了椎间盘损伤小鼠模型的椎间盘退变。椎间盘损伤后的退行性改变包括髓核（NP）减压、髓核中的脊索细胞被软骨细胞样细胞替代以及纤维环（AF）解体。重要的是，通过椎间盘内注射表达CRISPR-Cas9的腺相关病毒下调β-连环蛋白，通过保留NP中的脊索细胞和减弱软骨-骨生成以及维持AF结构，显著减轻了所有这些病理变化。此外，β-连环蛋白功能丧失减缓了椎间盘基质中分解代谢反应的快速诱导，并减弱了椎间盘退变期间疼痛相关的神经事件。因此，我们的数据表明，通过CRISPR-Cas9靶向椎间盘细胞中的β-catenin对椎间盘退变具有多方面的治疗作用，我们认为β-catenin在椎间盘的重塑和退行性过程中起着重要作用。此外，这项研究还表明，CRISPR-Cas9是一种有用的工具，可用于识别新的药物靶点和开发椎间盘退变的治疗策略。椎间盘退变小鼠模型中诱导β-连环蛋白上调。我们在受损椎间盘中施用表达CRISPR-Cas9的腺相关病毒以靶向β-连环蛋白编码基因。我们发现β-连环蛋白功能丧失通过维持脊索细胞和减少涉及合成代谢、分解代谢和疼痛诱导反应的退行性变化来改善椎间盘退变。
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. 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.
登录
查看更多内容
影响因子：
5.3
作者：
Fan, Yunshan;Zhao, Lan;Huang, Jian
通讯作者：
Huang, Jian
影响因子：
--
作者：
Hiyama, Akihiko;Sakai, Daisuke;Risbud, Makarand V.;Tanaka, Masahiro;Arai, Fumiyuki;Abe, Koichiro;Mochida, Joji
通讯作者：
Mochida, Joji
影响因子：
14
作者：
Bowles RD;Setton LA
通讯作者：
Setton LA
影响因子：
--
作者：
Erwin, W. Mark;Ashman, Keith;Inman, Robert D.
通讯作者：
Inman, Robert D.
影响因子：
3
作者：
THOMPSON, JP;PEARCE, RH;BISHOP, PB
通讯作者：
BISHOP, PB