Coordination of chondrogenesis and osteogenesis by fibroblast growth factor 18
Coordination of chondrogenesis and osteogenesis by fibroblast growth factor 18
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DOI：
10.1101/gad.965602
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发表时间：
2002-04-01
影响因子：
10.5
通讯作者：
Ornitz, DM
中科院分区：
文献类型：
--
作者：
Liu, ZH;Xu, JS;Ornitz, DM
成纤维细胞生长因子受体功能突变的获得会导致软骨发育不良和颅缝早闭综合征。在骨骼发育过程中与成纤维细胞生长因子受体(FGFRs)相互作用的配体仍然不清楚，而且成纤维细胞生长因子信号调节软骨内、骨膜和膜内骨生长的机制也不清楚。在这里，我们表明Fgf18在软骨膜中表达，并且Fgf18靶向中断的纯合子小鼠表现出与缺乏FGFR3的小鼠相似的生长板表型，以及表达FGFR2的部位的骨化缺陷。缺乏Fgf18或FGFR3的小鼠表现出软骨细胞增殖区和肥大区扩大，软骨细胞增殖、分化和印度刺猬信号增加。这些数据表明，FGF18是FGFR3的生理配基。此外，缺乏Fgf18的小鼠表现出延迟的骨化和成骨标志物的表达减少，这些表型在缺乏FGFR3的小鼠中看不到。这些数据表明，FGF18通过另一种FGFR信号调节成骨细胞的生长。信号转导多个FGFRs定位FGF18，以协调生长板中的软骨生成与皮质和松质骨中的成骨。
Gain of function mutations in fibroblast growth factor (FGF) receptors cause chondrodysplasia and craniosynostosis syndromes. The ligands interacting with FGF receptors (FGFRs) in developing bone have remained elusive, and the mechanisms by which FGF signaling regulates endochondral, periosteal, and intramembranous bone growth are not known. Here we show that Fgf18 is expressed in the perichondrium and that mice homozygous for a targeted disruption of Fgf18 exhibit a growth plate phenotype similar to that observed in mice lacking Fgfr3 and an ossification defect at sites that express Fgfr2. Mice lacking either Fgf18 or Fgfr3 exhibited expanded zones of proliferating and hypertrophic chondrocytes and increased chondrocyte proliferation, differentiation, and Indian hedgehog signaling. These data suggest that FGF18 acts as a physiological ligand for FGFR3. In addition, mice lacking Fgf18 display delayed ossification and decreased expression of osteogenic markers, phenotypes not seen in mice lacking Fgfr3. These data demonstrate that FGF18 signals through another FGFR to regulate osteoblast growth. Signaling to multiple FGFRs positions FGF18 to coordinate chondrogenesis in the growth plate with osteogenesis in cortical and trabecular bone.