Department of Orthopedic Surgery, First Affiliated Hospital of Soochow University, Suzhou, P.R. China.
Orthopedic Institute, Suzhou Medical College, Soochow University, Suzhou, P.R. China.
Bone Res. 2024 May 30;12(1):34. doi: 10.1038/s41413-024-00331-x.
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. 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.
退变终板呈奶酪样形态和感觉神经支配，导致腰痛，并随后在老年人群中诱导椎间盘退变。然而，奶酪样形态的起源和发展机制尚不清楚。在本研究中，我们报告了腰椎不稳定引起的软骨终板重塑是导致这种病理变化的原因。异常应力下终板软骨细胞的转录组测序显示，Hippo 信号通路对于这个过程是关键的。在腰椎不稳定（LSI）手术后，软骨终板中 Hippo 信号的激活或关键基因 Yap1 的敲除阻断了奶酪样形态的改变和椎间盘退变，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，在异常力学应力下，终板软骨细胞中破骨细胞分化相关基因集的表达上调，这一过程在 Hippo 信号通路激活后发生。在发现的破骨细胞分化基因集中，CCL3 在异常应激下从软骨细胞中大量释放，其功能是募集和促进破骨细胞形成，从而促进软骨终板重塑。Yap1 的过表达通过阻断其启动子抑制了 CCL3 的转录，从而使终板从重塑转变为奶酪样形态。最后，通过在病变部位局部注射携带 Yap1 过表达质粒的 AAV5，可以成功挽救 LSI 诱导的软骨终板重塑。这些发现表明，软骨终板中 Hippo 信号诱导的破骨细胞基因集的激活是管理不稳定引起的腰痛和腰椎退变的一个潜在新靶点。
