异常应力激活OA软骨下骨TGF-β/Smads信号通路诱导成神经分化和疼痛敏化的机制及补肾活血中药的干预研究

疼痛是骨关节炎（OA）最突出的症状。软骨下骨在OA发病中的作用越来越受到重视。前期研究发现，OA患者和小鼠样本中，软骨下骨应力集中区骨细胞（力学传感器）分泌的RANKL上调、破骨细胞活跃、TGF-β信号激活、神经纤维标志蛋白和疼痛敏化蛋白TRPV1都明显上调。补肾活血方能有效缓解OA疼痛，调控TGF-β信号和干细胞迁移增殖。由此项目组提出科学假说：软骨下骨的骨细胞感受异常应力分泌RANKL，导致破骨细胞骨吸收亢进，骨基质中TGF-β1被释放，激活TGF-β信号，诱导MSCs分化为感觉神经细胞，并敏化初级感觉神经元TRPV1引发OA疼痛。补肾活血方可能参与调控这过程而发挥缓解OA疼痛的作用。项目组拟借助转基因和敲基因技术体内靶标软骨下骨的骨细胞、MSCs和感觉神经细胞，观察异常应力如何驱动软骨下骨的骨细胞-MSCs-感觉神经细胞发生变化，TGF-β信号如何参与调控，补肾活血方如何发挥作用。

Knee pain is the most prominent symptom of osteoarthritis (OA) and the cause of disability. More and more attention has been paid to the role of subchondral bone in the pathogenesis of OA. Previous studies found that RANKL was up-regulated, osteoclasts were active, TGF-β signal was activated in bone matrix, nerve fiber marker protein and pain sensitization protein TRPV1 were significantly up-regulated in both OA clinical samples and mouse samples. In previous studies, bushen huoxue herbs can effectively relieve OA pain, regulate TGF-β signal and stem cell migration and proliferation. Therefore, our team proposed a scientific hypothesis: the abnormal stress secretion of RANKL by osteocytes in subchondral bone causes hyperfunction of osteoclasts, releases TGF-β1 in bone matrix, activates TGF-β signal, induces differentiation of MSCs into sensory nerve cells, and sensitized primary sensory neurons TRPV1 to cause OA pain. The prescription of tonifying kidney and activating blood may play a role in alleviating OA pain by participating in the regulation of this process. Our team intends to use transgenic and gene knockout techniques to target osteocytes, MSCs and sensory nerve cells in subchondral bone in vivo, to observe how abnormal stress drives changes in osteocytes-MSCs-sensory nerve cells in subchondral bone, how TGF-β signals are involved in regulation, and how the prescription for tonifying kidney and activating blood plays a role.