基于“破骨-成骨耦合”机理构建新型组织工程骨的研究

The development of Bone Tissue Engineering provides a potential strategy to treat critical-sized bone defects in the clinic. However, the conventional stem cell-based tissue-engineered bone faces with problems such as time- and cost-consuming construction procedure, inconsistent performance of bone regeneration, and safety concerns as to the multilineage differentiation of stem cells. These barriers strongly restrict the large-scale clinical application of Bone Tissue Engineering. With a deeper understanding of bone remodeling process and the mechanism of bone self-repair in the human body, it attracts increasing attention that bone resorption by osteoclasts virtually initiates and guides bone formation, which is named as the theory of “coupling of bone resorption and bone formation”. Although the molecular mechanism of this theory remains controversial, it is supported by increasing experimental data and provides us a potential strategy to develop novel tissue-engineered bone. Based on our previous studies on the theory of “coupling of bone resorption and bone formation”, this projects aims to construct osteoclast-based tissue engineered bone with monocytes, osteoclast-inducing cytokines, and conventional scaffolds. The capacity of osteoclast-based tissue-engineered bone to promote osteogenic process and to regenerate and repair bone will be evaluated by in vitro and in vivo studies. Also, we expect to figure out the mode of action of osteoclast-based tissue-engineered bone to initiate and to promote bone regeneration. The implement of this project would not only provide a new, low-cost, effective and safe approach to treat bone defects but also greatly contribute to a further understanding of the cellular and molecular mechanism of bone regeneration and repair. This knowledge would also provide novel molecular target and theoretical basis for further treatment of bone defects under pathological conditions.

骨组织工程技术的发展为临床治疗临界性骨缺损提供了新的可能。但由于传统的干细胞组织工程骨存在着构建时间长、成本高、成骨效果不稳定及干细胞多向分化等问题，骨组织工程技术至今仍未实现规模化临床应用。随着对机体骨重建周期及骨自发修复机制的深入理解，以破骨细胞介导的骨吸收启动并引导新骨形成这一“破骨-成骨耦合”机理逐渐成为研究热点。虽然具体分子机制仍存在着争议，但该机理得到了大量实验证据的支持，也为构建新型组织工程骨提供了新的思路。本项目基于对“破骨-成骨耦合”机理的前期探索，拟以单核细胞、破骨细胞诱导因子及常规支架材料构建破骨细胞组织工程骨。拟在体外及体内考察其成骨潜能与骨再生性能，并进一步探讨其启动或者参与骨修复的机理。该项目的实施不仅有望提供新型的低成本及高效安全的骨缺损治疗策略，更有助于进一步明确骨再生和骨修复的细胞与分子机制，为后续治疗病理条件下的骨缺损提供新的分子靶点和理论依据。

骨组织工程技术的发展为临床治疗临界性骨缺损提供了新的可能。但由于传统的干细胞组织工程骨存在着构建时间长、成本高、成骨效果不稳定及干细胞多向分化等问题，骨组织工程技术至今仍未实现规模化临床应用。随着对机体骨重建周期及骨自发修复机制的深入理解，以破骨细胞介导的骨吸收启动并引导新骨形成这一“破骨-成骨耦合”机理逐渐成为研究热点。虽然具体分子机制仍存在着争议，但该机理得到了大量实验证据的支持，也为构建新型组织工程骨提供了新的思路。.本项目基于对“破骨-成骨耦合”机理的前期探索，首创性地构建了基于破骨细胞的组织工程骨并评价了其修复骨缺损的效果及作用机理。体内实验发现破骨细胞组织骨可以显著促进骨组织的再生。细胞实验则证明负载的破骨细胞可以促进干细胞的迁移及成骨分化。更进一步的分子机理研究发现，破骨细胞分泌的含SPP1外泌体通过触发TGFβ1/SMAD3在促进干细胞成骨分化及后续骨再生中发挥了主要作用。这启发我们在后续研究应更深入地关注破骨细胞的同化作用以及利用该同化作用更有效地修复病理条件下骨缺损的可行性。总而言之，本项目的研究发现为目前骨组织工程技术提供了一种新型的低成本及更高效安全的骨缺损治疗策略。项目揭示的破骨细胞外泌体及其促成骨分化的机理有助于我们进一步明确骨再生和骨修复的细胞与分子机制，为后续治疗其它骨科疾病如骨质疏松、骨关节炎等提供新的分子靶点和理论依据。