成纤维细胞生长因子受体3fgfr3对骨形成的直接调控作用-the direct regulation of fibroblast growth factor receptor 3 fgfr 3 on bone formation.docxVIP

第三军医大学硕士学位论文 第三军医大学硕士学位论文 11 11 主要结论 1. 成骨细胞特异性表达 FGFR3 功能增强点突变小鼠体型变小，但生长板软骨未 见明显异常，提示成骨异常在 ACH 侏儒体型发生中有一定作用。 2. 成骨细胞特异性表达 FGFR3 功能增强点突变小鼠成年期骨形成增加，导致骨 量增多。 3. FGFR3 功能增强促进成骨细胞分化，抑制其矿化。 4. FGFR3 功能增强对成骨细胞的影响可能部分是通过 FGFR1、FGFR2 及 BMPRIA 的继发性改变所致。 5. FGFR3 功能增强导致小鼠骨皮质缺损愈合延迟。 关键词：FGFR3；骨形成；成骨细胞；破骨细胞；骨再生 PAGE PAGE 4 The role of FGFR3 in bone formation* Abstract Fibroblast growth factor receptors (FGFRs) are members of the receptor tyrosine kinase (RTK) family. There are now four known FGF receptors, FGFR-1 through FGFR-4, which share 55–72% overall amino acid identity. FGF/FGFRs signal pathway plays an important role in skeleton development and bone regeneration. Gain-of-function mutations or lose-of-function mutations of FGFR1,2,3 can cause a variety of human skeleton genetic disease, including craniosynostosis(CS), achondroplasia (ACH), CATSHL (camptodactyly, tall stature, scoliosis, and hearing loss) syndrome, and so on. Skeletal elements are formed through two distinct developmental processes: endochondral ossification, which also goes through two close related processes-- chondrogenesis and osteogenesis, and intramembranous ossification, in which mesenchymal cells differentiate into osteoblasts directly. Different FGFRs play distinct role in endochondral ossification and intramembranous ossification. A series of mutations in FGFR2 and a single missense mutation in FGFR1(P252R) can accelerate suture closure, leads to craniosynostosis syndromes; Gain-of-function mutations in FGFR3 can inhibit epiphyseal growth plate development, result in chondrodysplasia syndromes. It is therefore likely that intramembranous bone formation is controlled primarily by FGFR1 and FGFR2, while endochondral ossification is controlled primarily by FGFR3. Evidence suggests that FGFR3 is also involved in bone formation. FGFR3 shares high homology with FGFR1 and FGFR2 and can be activated by endogenous ligands FGF2, FGF18, which can promote osteogenesis, indicating that FGFR3 participate