FGFR1经调节成骨等骨骼相关细胞影响骨骼愈合机制的研究

Considering the similarity between bone development and bone regeneration, multiple molecules involved in in skeletal development may play a similar role in the process of fracture repair. The essential role of FGFR1 in skeletal development and its specific spatio-temporal expressions during fracture healing indicate the crucial roles of FGFR1 in fracture repair. FGFR1 is expressed in multiple types of cells involved in fracture healing including mesenchyme, chondrocytes, osteoblasts, osteocytes and Osteoclasts，suggesting that FGFs/FGFR1 signaling has multifunctional roles in fracture healing by regulating these cell lineages involved in fracture healing. The accurate roles of FGFR1 in those cells during bone regeneration need to be studied further，although We and others found that FGFR1 can regulate the proliferation or differentiation of them during skeleton development and homeostasis. We speculate that FGFR1 may regulate the fracture repair process by affectting these cells. We will use fracture and cortical bone defect models of mouse strains with cell-specific knockout or activation of FGFR1，along with in vitro molecular and cellular studies，to identify the role of FGFR1 in the bone regeneration . This study will clarify the role and mechanism of FGFR1 in the regulating of bone healing, and provid the experimental data for the development of FGFR1 signaling-based therapies promoting bone regeneration.

骨骼修复与发育过程相似，均涉及软骨内成骨和膜内成骨过程，参与骨骼发育过程的分子常在骨折修复过程中发挥相近作用。成纤维细胞生长因子受体1(FGFR1)在骨骼发育和稳态维持中有重要作用，并且在骨损伤修复过程中有特征性表达，提示FGFR1参与骨折愈合，但具体作用和机制不明。间充质细胞、成骨、骨细胞和破骨细胞是骨痂形成及后期骨痂重建过程的主要细胞，已发现FGFR1对上述细胞均有明确调控作用。我们推测FGFR1可经调控这些细胞活性来影响骨折修复过程。本课题拟通过对比研究在间充质细胞、成骨细胞、骨细胞和破骨细胞敲除或增强FGFR1小鼠的胫骨稳定骨折和打孔后愈合情况，明确FGFR1对骨损伤愈合的调控作用及与其在骨骼发育中作用的异同，并探讨FGFR1能否经其下游ERK1/2途径影响骨损伤修复过程，为从干预FGFR1信号角度寻找促进骨折愈合的生物措施提供实验依据。

骨骼修复与发育过程相似，均涉及软骨内成骨和膜内成骨过程，参与骨骼发育过程的分子常在骨折修复过程中发挥相近作用。成纤维细胞生长因子受体1(FGFR1)在骨骼发育和稳态维持中有重要作用，并且在骨损伤修复过程中有特征性表达，提示FGFR1参与骨折愈合，但具体作用和机制不明。间充质细胞、成骨、骨细胞和破骨细胞是骨痂形成及后期骨痂重建过程的主要细胞，已发现FGFR1对上述细胞均有明确调控作用。我们推测FGFR1可经调控这些细胞活性来影响骨折修复过程。本课题拟明确FGFR1对骨损伤愈合的调控作用及与其在骨骼发育中作用的异同，为从干预FGFR1信号角度寻找促进骨折愈合的生物措施提供实验依据。本项目通过研究，明确FGFR1在生长板损伤、颞下颌关节磨损等软骨损伤修复过程中的表达。在软骨细胞敲除Fgfr1引起软骨细胞肥大障碍、成骨受阻，而在软骨细胞、成骨细胞特异性激活Fgfr1点突变，导致骨骼发育迟缓、骨量减少。发现FGFR1可通过影响软骨细胞的自噬等过程参与软骨退变及损伤修复过程的调节；FGFR1条件性敲除小鼠出现不同程度的骨愈合，FGFR1可通过影响间充质、软骨等细胞功能参与骨损伤修复过程调节；初步发现FGFR1抗体可延缓软骨基质的丢失及软骨损伤的发生。