基于Piezo1对血管/破骨/成骨的三元调控探讨活血通络法对激素性股骨头坏死的骨修复机制

Osteonecrosis of femoral head(ONFH) is a series of pathological changes with the main characteristics of the collapse of the femoral head which caused by the disturbances of blood supply resulted from the application of steroid or other causes. How to prevent the collapse of the femoral head and promote the repair of necrotic bone is the key factor. We found that blood stasis syndrome penetrated into the pathological process of steroid-induced ONFH(SIONFH). Magnetic resonance quantitative analysis showed that the blood flow of microcirculation in the femoral head of SIONFH is significantly higher than the normal one. Blood supply of SIONFH increased in the necrotic regions as well as the expression of mechanical induction protein Piezo1 which promotes angiogenesis increased significantly. Both these finding suggest the mechanism of bone repair reaction may exist in the femoral head which include the progress of ischemia, necrosis repair, the decline of the bearing capacity of the femoral head, collapse, the high expression of Piezo1, promoting angiogenesis, resorption of necrotic bone and osteogenesis. Based on the three-pronged regulatory effect of Piezo1 on angiogenesis, osteoclastogenesis and osteogenesis, we propose innovative view that the promoting blood circulation method may activating the three-pronged regulation channel via enhance the expression of Piezo1 at early stage to prevent and cure the early collapse and to retain the hip function.

股骨头坏死（ONFH）是应用激素等原因导致股骨头血供障碍而引起的以塌陷为主要特征的一系列病理改变。如何防止股骨头塌陷并促进坏死骨修复是关键因素。前期研究发现：①“血瘀证”贯穿激素性ONFH整个病理过程；②磁共振定量分析提示激素性ONFH股骨头内微循环灌注血流量明显高于正常股骨头；③激素性ONFH患者坏死骨吸收区域内血供显著增加，促进血管形成的力学感应蛋白Piezo1表达显著升高，提示股骨头内可能存在“缺血-坏死-修复-股骨头承载能力下降-塌陷-Piezo1高表达-促进血管形成-促进坏死骨吸收-促进新骨形成”的骨修复连锁反应机制。课题组尝试从Piezo1对血管形成、破骨与成骨的三元调控探讨活血通络法是否可以通过早期提高Piezo1表达激活三元调控通道来防治早期ONFH塌陷，保留髋关节功能。

股骨头坏死（ONFH）是应用激素等原因导致股骨头血供障碍而引起的以塌陷为主要特征的一系列病理改变。本课题尝试从Piezo1对血管形成、破骨与成骨的三元调控探讨活血通络法是否可以通过早期提高Piezo1表达激活三元调控通道来防治早期ONFH塌陷，保留髋关节功能。本项目发现激素组患者股骨头骨组织的坏死区、硬化区和正常区Piezo1蛋白的表达均高于酒精组患者；免疫组化结果提示激素性股骨头坏死组坏死区、硬化区和正常区阳性表达较酒精组更明显；Piezo1可能是感应股骨头坏死塌陷的力学敏感蛋白，并参与成骨的过程；激素性与酒精性股骨头坏死骨组织中 Piezo1的差异表达可能与两者不同的骨形成修复特点有关。在第二部分超表达或沉默表达 Piezo1 对成血管/破骨/成骨活性的影响及活血通络方的干预研究中，发现Piezo1蛋白在破骨细胞分化过程中明显增加，表明Piezo1在小鼠BMM中有表达，并且与破骨细胞分化密切相关，为创新性发现；Piezo1作为机械敏感蛋白与成骨分化密切相关，而TAZ也被证明参与调节成骨分化，但Piezo1调控人骨髓间充质干细胞成骨分化时TAZ是否参与其中目前尚不明确，故研究其具体机制对防止股骨头坏死具有重要意义。结果显示Piezo1能够促进人骨髓间充质干细胞的成骨分化，沉默Piezo1后人骨髓间充质干细胞的成骨能力明显降低。同时，沉默Piezo1后TAZ的表达也明显降低。这为Piezo1在干细胞方面以及股骨头坏死治疗方面的研究提供思路。后期可考虑继续深入挖掘相关机制，以及开展体内、临床研究。