微泡强化声动效应抑制激素诱导早期股骨头坏死的应用基础研究

Hormone-related osteonecrosis of femoral head seriously affects human health. Major surgery is inevitable once articular surface of femoral head collapses. Current studies mainly focus on inhibition of progression of early-staged osteonecrosis. The mechanism behind necrosis progression is that the direct effect of hormones on bone tissue and vascular endothelial cells induces the imbalance between osteoclasts and osteoblasts. Our previous data indicated that the microbubble-enhanced bioaccoustic effect regulated the expression of molecules associated with the activity of osteoclasts and osteoblasts and contributed to restoration of the balance between osteoclasts and osteoblasts. Based upon the present viewpoint that the bioaccoustic effect can promote local blood supply and angiogenesis, we speculate that the microbubble-enhanced bioaccoustic effect may inhibit the progression of early-staged osteonecrosis through adjusting the expression of proteins associated with the activity of osteoclasts and osteoblasts. With the techniques of the cell co-culture system, the animal model of femoral head necrosis and the analysis platform of scattered sound spectrum and the means of molecular biology, histomorphometry, biomechanics and acoustics, we attempted to verify (1) the impact of the microbubble-enhanced bioaccoustic effect on the expression of molecules associated with the activity of osteoclasts and osteoblasts; (2) the optimized parameters and biocompatibility of ultrasound; (3) the molecular and accoustic mechanisms. The project is promising to provide a non-invasive, safe and novel concept for treatment of the early-staged femoral head necrosis.

激素相关股骨头坏死严重影响人类的健康，一旦关节面塌陷手术难以避免，故目前研究集中在如何抑制早期股骨头坏死的进展，激素对骨组织及血管内皮细胞的直接作用引起破骨成骨失衡是坏死进展的主要机制。我们发现，微泡增强声动效应可以调节成骨和破骨相关蛋白的表达，有助于恢复破骨成骨的平衡。结合"声动效应可以促进局部血供和血管生成"的观点，我们推测：微泡增强声动效应通过调控成骨破骨相关分子的表达，调节破骨成骨平衡，抑制早期股骨头坏死的进展。本项目拟采用细胞共育体系、股骨头坏死的动物模型及声谱散射分析平台，运用分子生物学、组织计量学、力学、声学等手段，拟从微泡强化声动效应的以下方面验证假设：（1）其对坏死局部成骨破骨相关分子的影响与规律；（2）其体内参数的优化及生物相容性；（3）其抑制坏死的初步分子生物学与声学机制。本项目有望为抑制早期股骨头坏死的进展提供一种无创、安全的新颖理念和相关基础。

股骨头无菌性坏死可导致髋关节残疾，严重影响正常生活。该疾病是由于股骨头血供中断或受损引起的骨细胞及骨髓成分死亡，继而引起股骨头结构改变、塌陷等病变。我们通过本项目发现，微泡强化超声可以调节成骨和破骨相关基因及蛋白的表达，同时可以促进局部血供和血管生成。结果显示：（1）微泡强化超声可使股骨头血管数量、骨矿化率及力学强度进一步提高；（2）微泡强化超声可抑制假体-骨界面内纤维膜的长入，使假体-骨界面的抗剪切强度得到显著的提高；（3）微泡强化超声一方面通过提高VEGF和BMP-2基因和蛋白的表达，进而促进血管生成，刺激成骨细胞的增殖、分化及相应功能；另一方面通过抑制ERK-c-Fos-NFATC1信号通路，抑制破骨细胞的分化及相关基因表达，最终调节局部破骨成骨平衡，一定程度抑制股骨头坏死的进展；（4）微泡可进一步提高超声对VEGF和BMP-2基因和蛋白表达的促进作用。本项目表明，微泡强化超声通过调节成骨、破骨相关基因及蛋白的蛋白，抑制股骨头坏死的进展，为临床上合理运用微泡强化超声防治股骨头坏死提供了基础依据。