HOXB9在BMP2诱导骨再生中的调控作用及机制研究

It is still a challenge to repair large bone defects of the jaws in dentistry. Though recombinant protein rhBMP2 can improve quantities of bone regeneration, its clinical applications give rise to side effects such as bone hyperplasia and so on. HOX genes are known to play important roles in embryo development and stem cell differentiation. As being involved in bone development in a manner of temporospatial colinearity, HOX genes are thought to be able to regulate bone regeneration accurately. Our previous work demonstrated the expression of HOXB9 increased in the rhBMP2 induced bone regeneration. In differentiation of mesenchymal stem cells (MSCs), the expression of HOXB9 stepped up with the increasing of osteogenic markers. HOXB9 may regulate the ossification through inducing the mesenchymal-epithelial transition (MET) of MSCs. Ongoing study will focus on HOXB9 regulation in BMP2-induced bone regeneration for finding a strategy of “precise regeneration of jaw”. To cover this study, we will attempt to answer questions of how the HOXB9 regulates the ossification of MSCs temporospatially. As the MET induction of HOXB9 may involve in the ossification of MSCs, the molecular mechanisms and its regulatory site targeting MET induction are supposed to be explored. With the help of conditional knockout mice model, we will try to illustrate the role of HOXB9 in different stages of jaw development, and propose optimal strategies of BMP2-induced bone regeneration regulated by HOXB9. We look forward to providing a novel clinical therapy in precise bone regeneration of jaw.

大块颌骨缺损的精确修复是口腔医学中的难点。应用BMP2重组蛋白促进骨再生的同时可能造成过度成骨等副作用。HOX基因在胚胎发育和干细胞分化过程中从时空两个维度发挥作用，为精确骨再生提供了新的思路。我们前期研究发现，在rhBMP2成骨诱导过程中HOXB9表达水平上调；HOXB9的表达水平与成骨标志物同步上调；HOXB9可以通过诱导间充质细胞上皮化（MET）发挥调控作用。本研究拟聚焦颌骨缺损后精确修复这一关键问题，从探讨HOXB9在rhBMP2诱导骨再生中的作用入手，在干细胞水平研究HOXB9如何在时空两个维度发挥成骨调控作用，阐明HOXB9通过MET调节骨再生的分子机制，明确HOXB9分子表面的调控靶点。借助HOXB9条件性基因敲除小鼠，从发育角度研究HOXB9时空表达异常对骨发育的影响极其作用机制，探索如何通过调控HOXB9实现rhBMP2诱导的精确骨再生，期待为临床颌骨精确修复提供新方案。

大块颌骨缺损的精确修复是口腔医学中的难点。应用BMP2重组蛋白促进骨再生的同时可能造成过度成骨等副作用。HOX基因在胚胎发育和干细胞分化过程中从时空两个维度发挥作用，为精确骨再生提供了新的思路。本项目围绕阐明HOXB9在细胞内调控的信号通路；明确HOXB9下游PI3K-NFκB调控细胞再生的诱导机制；探索可能参与HOXB9调控成骨的天然化合物及促成骨材料表面涂层体系等方面，从 HOXB9 在骨再生和骨发育过程中的调控作用及精确成骨的策略方案入手开展研究，优化实验条件，阐明骨再生调控机制的一环，提高骨再生整合性。研究成果共计发表基金标注 SCI 论文 7 篇，国内统计源期刊论文 4 篇。授权发明专利 1 项。