硼酸盐生物活性玻璃对双膦酸盐相关性颌骨坏死的修复作用及机制研究

With the global escalation of the aging process, osteoporosis patients increase year by year. Bisphosphonates (BPs), the effective drug for the treatment of osteoporosis, is widely used in clinic. A serious skeletal complication, bisphosphonate-related osteonecrosis of the jaw (BRONJ), associated with the long-term oral or intravenous use of BPs is subsequently appeared. There is no effective treatment for such a complication to date. In BRONJ, normal bone turnover is severely suppressed by BP-induced inhibition of osteoclast differentiation and function. But there is no effective treatment to remove BPs adsorbed on crystals from bone. In our previous studies, we focused on dissociating bound BPs from mineralized bone. Computational chemistry and in vitro cell experiments were done. We found that borate bioactive glass (BBG) with the potential to induce osteogenesis and angiogenesis sequestrates BPs from bisphosphonate-bound apatite occurs in the presence of the borate-containing ionic cocktail and reverses BP-induced inhibition of osteoclastogenesis, stimulation of osteoclasts apoptosis and reduction of osteoclast resorptive activity. The aim of this project is to study the repair and mechanism of BBG on BRONJ depending on those results. First, the method to construct rat BRONJ model in a short term was screened out. BBG was employed to repair the jaw lesions. The effect of BBG on the repair of BRONJ was tested. Then, repaired BRONJ tissue in situ and in vitro cell experiments were done to explore the mechanism of BBG on BRONJ repairing through the aspects of osteogenic differentiation, vascular regeneration and functional recovery of osteoclasts. The results of this study will help to make use of BBG from “bench to bedside”. At the meantime, it will set a new direction for the clinical application of BBG in the treatment of BRONJ.

随着全球人口老龄化的加剧，骨质疏松患者逐年增多，双膦酸盐（BPs）作为治疗骨质疏松的有效药物广泛应用于临床，但随之也出现了严重并发症——双膦酸盐相关性颌骨坏死（BRONJ）。现有治疗方法治标不治本，不能有效清除颌骨晶体中吸附的BPs，使其持续性抑制破骨细胞功能。课题组前期研究以清除晶体中BPs为切入点，进行计算机模拟和体外细胞实验发现，具有诱导成骨和软组织修复潜力的硼酸盐生物活性玻璃（BBG）能够促使BPs脱离晶体，且与其反应后恢复破骨细胞的功能。本项目拟以此为理论基础展开深入研究。首先成功构建大鼠BRONJ原位模型，用BBG修复颌骨病变，检测BBG对BRONJ的修复作用。再通过原位组织体外实验和体外细胞实验，从成骨分化，血管再生和破骨功能恢复等方面，探索BBG对BRONJ修复作用的机制。本研究可为BBG从实验室研究向临床应用的转化提供更可靠的理论依据，同时为根治BRONJ开辟新的方向。

随着全球人口老龄化的加剧，骨质疏松患者逐年增多，双膦酸盐（BPs）作为治疗骨质疏松的有效药物广泛应用于临床，但随之也出现了严重并发症——双膦酸盐相关性颌骨坏死（BRONJ）。现有治疗方法治标不治本，不能有效清除颌骨晶体中吸附的BPs，使其持续性抑制破骨细胞功能。课题组前期研究以清除晶体中BPs为切入点，进行计算机模拟和体外细胞实验发现，具有诱导成骨和软组织修复潜力的硼酸盐生物活性玻璃（BBG）能够促使BPs脱离晶体，且与其反应后恢复破骨细胞的功能。本项目以此为理论基础展开深入研究。使用4周龄雌性SD大鼠为模型动物，腹腔注射唑来膦酸（125 μg/kg）每周两次联合腹腔注射地塞米松（5 mg/kg）每周一次，4周后拔除右下颌第一磨牙，8周后成功构建BRONJ模型。将BBG置于大鼠BRONJ拔牙窝内，8周后拔牙窝愈合，骨陷窝形成，破骨功能恢复，成骨、成血管功能恢复，BBG可以促进BRONJ的修复。并发现BBG通过上调BMSCs成骨相关基因的表达（Runx2、Ocn、Opn、Bmp-2、Alp）逆转N-BPs对BMSCs增殖、分化和成骨功能的抑制。同时通过上调HUVECs成血管相关基因的表达（VEGF、KDR、CD31 、HIF-α）逆转 N-BPs对HUVECs增殖和成血管功能的抑制，并减少N-BPs诱导的细胞凋亡。证实BBG通过影响破骨细胞、成骨细胞、血管生成促进大鼠BRONJ的修复。本研究可为BBG从实验室研究向临床应用的转化提供更可靠的理论依据，同时为根治BRONJ开辟新的方向。