补肾中药通过抑制RANKL-NF-κB正向通路消除抗骨吸收治疗所致新骨形成障碍的机制及应用研究

抑制破骨细胞介导的骨吸收是抗骨质疏松药物治疗的首选方案。然而，抗骨吸收治疗导致的新骨生成障碍，是当前治疗或新药研发的难点。抗骨质疏松补肾中药具有抗骨吸收而不阻碍新骨形成的优势，但作用机制不清。申请人基于破骨-成骨耦联机制及前期研究结果，推测补肾中药的治疗优势可能是通过抑制RANKL-NF-κB正向通路实现的。申请人前期已经发现一批抑制该通路的抗骨质疏松补肾中药及其活性单体，并初步评价了破骨、成骨分化活性。本项目将在此基础上：①评价这些补肾类中药抑制破骨细胞分化、促进成骨细胞分化并消除破骨抑制所致成骨分化障碍的效应，确定最优中药及单体；②基于最优中药及单体，研究抑制RANKL-NF-κB正向通路可以阻止破骨分化、消除成骨分化障碍和促进新骨形成的机制；③体内确认抗骨质疏松的疗效。该研究为“肾主骨”中医理论及补肾类中药防治骨质疏松提供科学依据，也为抗骨质疏松药物开发或临床治疗提供新的方向。

Inhibition of osteoclast-mediated bone resorption is the first choice for anti-osteoporosis therapy. However, these treatments hamper the stimulatory activity of osteoclasts on osteoblast differentiation, which is difficult to overcome when it comes to treatment or new drug research and development. Anti-osteoporosis kidney tonifying herbs or formulas had been reported to have advantage of anti-bone resorption without affecting new bone formation or promoting , but the mechanism of action is unclear. Based on the coupling mechanism of osteoclasis-osteogenesis and the results of previous studies, the applicant speculated that the therapeutic advantage of kidney-tonifying herbs might be realized by inhibiting the positive RANKL-NF-κB pathway. RANKL-NF-κB forward signaling pathway inhibition. This project plans to further investigate: ①To identify the most active kidney-tonifying herb and agent by evaluating the osteoclastogenesis inhibition, osteogenesis promotion and the elimination of osteogenesis supression caused by osteoclastogenesis inhibition. ② Study the mechanism of inhibiting RANKL-NF-κB pathway in preventing osteoclast differentiation, eliminating osteogenic differentiation disorder and promoting new bone formation; ③ In vivo experiment was conducted to evaluate the therapeutic effect on osteoporosis. This proposal will explain the mechanism of "kidney governing bones" and kidney-tonifying herbs treat osteoporosis, as well as provide new route for developing of anti-osteoporosis drugs or clinical treatment.