Degenerated endplate appears with cheese-like morphology and sensory innervation, contributing to low back pain and subsequently inducing intervertebral disc degeneration in the aged population.¹ However, the origin and development mechanism of the cheese-like morphology remain unclear. Here in this study, we report lumbar instability induced cartilage endplate remodeling is responsible for this pathological change. Transcriptome sequencing of the endplate chondrocytes under abnormal stress revealed that the Hippo signaling was key for this process. Activation of Hippo signaling or knockout of the key gene Yap1 in the cartilage endplate severed the cheese-like morphological change and disc degeneration after lumbar spine instability (LSI) surgery, while blocking the Hippo signaling reversed this process. Meanwhile, transcriptome sequencing data also showed osteoclast differentiation related gene set expression was up regulated in the endplate chondrocytes under abnormal mechanical stress, which was activated after the Hippo signaling. Among the discovered osteoclast differentiation gene set, CCL3 was found to be largely released from the chondrocytes under abnormal stress, which functioned to recruit and promote osteoclasts formation for cartilage endplate remodeling. Over-expression of Yap1 inhibited CCL3 transcription by blocking its promoter, which then reversed the endplate from remodeling to the cheese-like morphology. Finally, LSI-induced cartilage endplate remodeling was successfully rescued by local injection of an AAV5 wrapped Yap1 over-expression plasmid at the site. These findings suggest that the Hippo signaling induced osteoclast gene set activation in the cartilage endplate is a potential new target for the management of instability induced low back pain and lumbar degeneration.

退化的终板呈现奶酪样形态和感觉神经支配，导致老年人群腰痛并随后诱发椎间盘退变。 ¹然而，奶酪样形态的起源和发展机制仍不清楚。在这项研究中，我们报告了腰椎不稳定引起的软骨终板重塑是造成这种病理变化的原因。对异常应激下终板软骨细胞的转录组测序表明，Hippo 信号传导是这一过程的关键。激活Hippo信号或敲除软骨终板中的关键基因Yap1可以切断腰椎不稳定（LSI）手术后奶酪样的形态变化和椎间盘退变，而阻断Hippo信号则逆转了这一过程。同时，转录组测序数据还显示，在异常机械应力下，终板软骨细胞中破骨细胞分化相关基因组的表达上调，并在Hippo信号传导后被激活。在已发现的破骨细胞分化基因组中，CCL3被发现在异常应激下从软骨细胞中大量释放，其功能是招募和促进破骨细胞形成以进行软骨终板重塑。 Yap1 的过度表达通过阻断其启动子来抑制 CCL3 转录，从而逆转终板重塑为奶酪样形态。最后，通过在该位点局部注射 AAV5 包裹的 Yap1 过表达质粒，成功挽救了 LSI 诱导的软骨终板重塑。 这些发现表明，Hippo 信号诱导软骨终板中的破骨细胞基因组激活是治疗不稳定引起的腰痛和腰椎退变的潜在新靶点。