激素性股骨头坏死中内源性干细胞成骨-成脂分化命运及补肾中药干预机制研究

Steroid-induced necrosis of femoral head (SANFH) is a common and intractable disease in the orthopedics field. Abnormal proliferation and differentiation of Mesenchymal stem cell (MSCs) are the critical factors for the development of SANFH. According to the latest study of “kidney hidden essence dominating bone”, Bu-shen Chinese medicine can activate MSCs and regulate the homeostasis of microenvironment, which is a potential mechanism of its intervention in the progression of SANFH. Our previous study found that Bu-shen Chinese medicine can activate Wnt/β-catenin signaling pathway to affect bone metabolism. So we speculate that Bu-shen Chinese medicine can mediate Wnt/β-catenin signaling to regulate the proliferation and differentiation of stem cells to affect the course of SANFH. In this study, stem cell specific tdTomato transgenic mice are used to establish SANFH mouse model and endogenous MSCs are tracked to observe the proliferation and osteogenetic-adipogenic differentiation. Meanwhile, the effects of Wnt/β-catenin signaling pathway in proliferation and osteogenic-adipogenic differentiation of MSCs is explored using stem cell specific β-catenin knockdown technology and siRNA. This study will further reveal the pathogenesis of SANFH and provide experimental evidence for the modern interpretation of “kidney hidden essence dominating bone” and treatment of Bu-shen Chinese medicine.

激素性股骨头坏死（SANFH）是骨科领域常见难治性疾病，干细胞增殖异常及成骨-成脂分化失衡是导致SANFH的关键因素。根据“肾藏精主骨”的最新研究结果，补肾中药能够激活干细胞和调节微环境稳态，是干预SANFH进展的潜在机制。前期研究发现补肾中药能够激活Wnt信号通路影响机体骨组织代谢。因此，我们提出假说补肾中药能够介导Wnt/β-catenin信号调控干细胞增殖分化影响SANFH进程。本研究拟借助细胞谱系示踪技术建立干细胞特异性的tdTomato转基因小鼠，构建SANFH模型，对股骨头内源性干细胞定向示踪，观察其增殖及分化情况。同时结合干细胞特异性β-catenin基因敲除技术及siRNA技术，探讨SANFH中Wnt/β-catenin信号通路对干细胞增殖及成骨-成脂分化的调控作用。研究结果将进一步揭示SANFH发病机制，为“肾藏精主骨”理论的现代诠释及补肾中药治疗SANFH提供实验依据。

糖皮质激素诱导的股骨头坏死（SANFH）是一种常见的致残性关节疾病，其特征是骨损伤和结构塌陷。SANFH的确切发病机制仍然未知。在糖皮质激素诱导的SANFH模型鼠的坏死股骨头中观察到异常的成骨和脂肪生成合并β-catenin降低。β-catenin信号传导的激活有效缓解了SANFH模型鼠的这些坏死变化，并恢复了糖皮质激素过多引起的骨髓干/祖细胞（BMSC）的成骨/成脂分化失衡。Col2+骨祖细胞贡献了BMSC的很大一部分，Col2+骨祖细胞中β-catenin的条件敲除导致SANFH样表型，甚至包括成年小鼠股骨头塌陷。总体而言，我们发现β-catenin抑制导致Col2+骨祖细胞的成骨/脂肪分化不平衡是SANFH发病的重要环节。根据“肾藏精主骨”的最新研究结果，补肾中药能够激活干细胞和调节微环境稳态，是干预SANFH进展的潜在机制。研究发现补肾中药能够激活Wnt/β-catenin信号调控干细胞增殖分化影响SANFH病程。