调控交感神经-Adrβ2-CLOCK通路以缓解骨性终板空洞所致下腰痛的机制研究

下腰痛临床极为常见，与感觉神经长入终板关系密切。申请人首次报道，修复骨性终板空洞缓解腰椎不稳模型所致下腰痛，确切机制不明。骨性终板空洞形成主要归因于终板成骨-破骨失衡。我们近期发现抑制交感神经-Adrβ2增高椎体骨量，目前未见Adrβ2表达于终板的报道，调控Adrβ2能否为改善终板成骨-破骨失衡带来新思路？预实验发现终板退变时循环血和终板去甲肾上腺素浓度升高、终板交感神经纤维和Adrβ2显著增加。交感神经激活可致CLOCK病理性表达；亦可激活Adrβ2-CLOCK通路调控骨代谢。据此假设：交感神经激活Adrβ2-CLOCK通路抑制骨性终板成骨活性，增强破骨活性，促进骨性终板空洞形成，吸引感觉神经长入，引发下腰痛。本项目拟通过临床样本和体内、外实验明确交感神经激活Adrβ2-CLOCK通路引起终板成骨-破骨失衡导致骨性终板空洞的确切机制，为有效防治感觉神经长入终板所致下腰痛提供新思路。

Low back pain is a very common disease in clinical and is closely related to sensory nerve innervation into the endplate. The applicant firstly reported that repairing porous endplate cavities alleviates low back pain caused by lumbar instability models in mice, but the specific mechanism still unknown. The formation of porous endplate cavities is mainly due to an imbalance of osteogenesis and osteoclastogenesis in the endplate. We have recently shown that inhibition of sympathetic -Adrβ2 increases vertebral bone mass; There has been no report on the expression of ADR β2 in the endplate so far. Could regulation of Adrβ2 bring a new idea for improving the imbalance of osteogenesis and osteoclastogenesis in the endplate? Preliminary experiments showed that the concentrations of norepinephrine, sympathetic nerve fibers, and Adrβ2 in the endplate significantly increased during endplate degeneration. Sympathetic nerve activation can induce pathological expression of CLOCK. The activation of the Adrβ2-CLOCK pathway could regulate bone metabolism. We hypothesized that the sympathetic nerve activates the Adrβ2-CLOCK pathway to inhibit the osteogenesis of the bone endplate, enhance the osteoclastogenesis, promote the formation of the bone endplate cavity, attract the sensory nerve innervation, induce low back pain. Through clinical samples, in vivo and in vitro experiments, this project aims to clarify the specific mechanism of the porous endplate cavity caused by the imbalance of endplate osteogenesis and osteoclastogenesis caused by sympathetic nerve activation Adrβ2-CLOCK pathway, therefore provide a new idea for the effective prevention and treatment for low back pain caused by sensory nerve innervated into the endplate.