Intervertebral disc (IVD) degeneration (IVDD) is the main cause of low back pain with major social and economic burdens; however, its underlying molecular mechanisms remain poorly defined. Here we show that the focal adhesion protein Kindlin-2 is highly expressed in the nucleus pulposus (NP), but not in the anulus fibrosus and the cartilaginous endplates, in the IVD tissues. Expression of Kindlin-2 is drastically decreased in NP cells in aged mice and severe IVDD patients. Inducible deletion of Kindlin-2 in NP cells in adult mice causes spontaneous and striking IVDD-like phenotypes in lumbar IVDs and largely accelerates progression of coccygeal IVDD in the presence of abnormal mechanical stress. Kindlin-2 loss activates Nlrp3 inflammasome and stimulates expression of IL-1β in NP cells, which in turn downregulates Kindlin-2. This vicious cycle promotes extracellular matrix (ECM) catabolism and NP cell apoptosis. Furthermore, abnormal mechanical stress reduces expression of Kindlin-2, which exacerbates Nlrp3 inflammasome activation, cell apoptosis, and ECM catabolism in NP cells caused by Kindlin-2 deficiency. In vivo blocking Nlrp3 inflammasome activation prevents IVDD progression induced by Kindlin-2 loss and abnormal mechanical stress. Of translational significance, adeno-associated virus-mediated overexpression of Kindlin-2 inhibits ECM catabolism and cell apoptosis in primary human NP cells in vitro and alleviates coccygeal IVDD progression caused by mechanical stress in rat. Collectively, we establish critical roles of Kindlin-2 in inhibiting Nlrp3 inflammasome activation and maintaining integrity of the IVD homeostasis and define a novel target for the prevention and treatment of IVDD.

椎间盘（IVD）退行性变（IVDD）是导致腰痛的主要原因，给社会和经济造成重大负担；然而，其潜在的分子机制仍不清楚。在这里，我们显示粘着斑蛋白 Kindlin-2 在髓核 (NP) 中高表达，但在 IVD 组织中的纤维环和软骨终板中没有。Kindlin-2 在老年小鼠和严重 IVDD 患者的 NP 细胞中的表达急剧下降。成年小鼠 NP 细胞中 Kindlin-2 的可诱导缺失导致腰椎 IVD 中自发且显着的 IVDD 样表型，并在存在异常机械应力的情况下大大加速尾骨 IVDD 的进展。Kindlin-2 缺失激活 Nlrp3 炎性体并刺激 NP 细胞中 IL-1β 的表达，进而下调 Kindlin-2。这种恶性循环促进细胞外基质 (ECM) 分解代谢和 NP 细胞凋亡。此外，异常机械应力会降低 Kindlin-2 的表达，从而加剧 Kindlin-2 缺乏引起的 NP 细胞中 Nlrp3 炎性体激活、细胞凋亡和 ECM 分解代谢。体内阻断 Nlrp3 炎性体激活可防止 Kindlin-2 丢失和异常机械应力诱导的 IVDD 进展。具有转化意义的是，腺相关病毒介导的 Kindlin-2 过表达在体外抑制原代人 NP 细胞中的 ECM 分解代谢和细胞凋亡，并减轻大鼠机械应力引起的尾骨 IVDD 进展。集体，