以FGF23为靶点增强慢性肾病患者牙种植体骨整合的研究

Chronic kidney disease (CKD) has become a worldwide public health problem with its growing prevalence. FGF23 is recognized as the newest marker for early diagnostics of CKD, as its level increases significantly at the very early stage of CKD. FGF23 inhibits the maturation and mineralization of osteoblasts, and is independently associated with the decreased the bone quality in CKD patients. Our previous research showed that CKD impairs the osseointegration of titanium implants, and therefore we would like to further investigate the pathologic role of FGF23 in this process. In this project, we are going to dissect the mechanism of FGF23 in regulating osteogenic differentiation using CKD-derived BMSCs. We will also neutralize the high FGF23 levels in CKD mice or specifically knockout the FGF23/Klotho signal from osteoblasts, so as to reveal the role of FGF23 in osseointegration of titanium implants in these mice. Finally, we are going to analyze the relationship between the FGF23 levels and osseointegration of dental implants in hemodialysis patients, which will help us to verify if FGF23 could be a biomarker to predict the prognosis of implant treatment in CKD patients, and to explore potential treatment methods for enhancing the outcome. The results of this project will significantly improve the oral health and life quality of CKD patients.

慢性肾病已成为严重危害人类健康的全球性公共问题。FGF23是最新发现的早期检测慢性肾病的分子标志，能抑制成骨细胞的成熟和矿化，其浓度异常升高是造成肾病患者骨质异常的关键因素。课题组前期发现慢性肾病引起种植体早期骨结合率和结合强度下降，影响了种植体的早期愈合，因而假设FGF23在骨整合过程发挥了关键作用。本课题拟通过体外增强和阻断FGF23，研究其对慢性肾病小鼠来源骨髓基质细胞在钛表面成骨向分化的影响和机理；同时通过注射中和抗体清除小鼠体内高浓度FGF23，以及利用基因敲除小鼠，特异性敲除FGF23/Klotho，以揭示FGF23对肾病小鼠钛种植体骨整合的影响；最后通过临床实验，分析肾衰透析患者FGF23浓度与种植体骨整合的相关性，为明确判断慢性患者牙种植预后的分子标志，探索提高临床效果的干预措施奠定基础。研究结果对增强肾病患者牙种植修复效果，改善口腔状况，提高生存和生活质量具有重要意义。

慢性肾病是危害人类健康的重大公共卫生问题，对牙种植体早期骨结合有负面影响。本课题以FGF23作为切入点，按照原定计划实施，课题进展顺利，研究发现：（1）肾病条件下高浓度的FGF23影响种植体骨结合和骨缺损的修复；（2）中和体内高浓度的FGF23可以逆转慢性肾病-骨代谢紊乱，并提高种植体骨结合；（3）明确了慢性肾病对患者余留牙区骨质骨量的影响和种植治疗的手术条件，建立了慢性肾病患者的口腔种植治疗临床新策略。研究结果对改善慢性肾病条件下牙种植骨结合提供了理论基础，对提高患者的口腔种植治疗效果有重要意义。课题共标注发表SCI论文15篇，包括Nat Commnun等杂志。课题负责人获得四川省青年科技奖等奖励，参与课题的研究生获得美国骨矿化研究学会青年学者奖等奖项；在此基础上，课题负责人成功获得国家自然科学基金优秀青年基金和面上项目资助，入选长江青年学者（公示）和“万人计划”领军人才（公示），并担任四川省科技创新团队负责人。