miRNA调控CTSK促进种植体骨结合的机制研究

Dental implant has been one of the best options for replacing missing teeth. Nowadays, the risk factors of dental implant failure are including: 1, lack of alveolar bone mass; 2, low bone mineral density; 3, peri-implantitis; 4, diabetes and other abnormalities of bone metabolism. These risk factors are all related to bone resorption. Cathepsin K (CTSK), specifically expressed by osteoclasts, plays a central role in bone resorption. Our preliminary data shows that bone resorption and CTSK level significantly increased within 1 week after implantation. We’ve also found potential miRNA candidates targeting CTSK. We hypothesis that inhibition of CTSK may effectively block bone resorption, increase bone mineral density, and lessen the peri-implantitis-induced or diabetes-induced implant failure risk. Furthermore, we propose a novel approach to eliminate the implant failure risk via miRNA targeting CTSK. In this proposal, we plan to use multiple animal models and cell models to mimic clinical situations. We will study: 1, implant-osseointegration upon CTSK inhibition; 2, the mechanism of potential miRNA regulating CTSK; 3, implant-osseointegration upon novel miRNA administration; 4, potential biomarkers of CTSK and miRNA in peri-implant crevicular fluid in patients. Based on these work, we hope to explain the mechanism of miRNA regulating CTSK, to establish a new approach to prevent implant failure, and to contribute to the benefit of patients receiving dental implantation.

口腔种植已成为常规的缺失牙修复方法，然而种植失败仍是常见的临床问题。其与骨吸收有关的风险因素包括：1，移植骨吸收；2，骨密度过低；3，种植体周围炎；4，糖尿病等骨代谢异常疾病。 组织蛋白酶K（CTSK）是破骨细胞特异性表达的蛋白酶，在骨吸收中起着核心作用。前期研究表明，种植体植入后一周，其周围骨组织表现出CTSK上调和骨吸收。同时，我们找出了可能调节CTSK的miRNA。据此推测，抑制CTSK可有效抑制骨吸收；使用miRNA靶向CTSK，可减少骨吸收，用于种植并发症的治疗。我们将构建多种动物模型和细胞模型，研究以下问题：1，抑制CTSK对种植体骨结合的影响；2，寻找更多潜在的miRNA靶点及其调控CTSK的机制；3，miRNA调控种植体骨结合；4，在患者中检测种植体周围龈沟液中CTSK、miRNA的表达。通过上述研究，阐述miRNA对CTSK调控的机制，为进一步提高种植成功率奠定基础。

本项目采用股骨干骺端种植体植入的小鼠模型，致力于探讨种植体植入后骨结合过程的变化细节。骨结合过程中存在着复杂的分子调控机制。种植体植入后，其表面形成细胞外基质蛋白层，与骨微环境内的纤维蛋白凝块共同提供了破骨细胞、成骨细胞、间充质干细胞所需的生长因子和成骨空间，最终形成矿化的成熟骨组织。我们发现，破骨细胞的关键酶组织蛋白酶K（CTSK）在种植体植入后短期具有显著的升高，可能作为合理的调控破骨细胞的靶点。miRNA及其他多种调控方式可以调节这一靶点。我们发现，miRNA-96可能改变CTSK的表达，并改变种植体骨结合程度。我们还发现，寒冷刺激也可能通过改变破骨细胞糖代谢而改变CTSK的表达，从而改变种植体骨结合程度。这些工作提供了提高种植体骨结合的潜在治疗靶点，可能改善口腔种植患者的种植体骨结合成功率。