Karolak Matthew R, Yang Xiangli, Elefteriou Florent
Department of Pharmacology, Vanderbilt Center for Bone Biology.
Department of Pharmacology, Vanderbilt Center for Bone Biology, Department of Medicine and.
Hum Mol Genet. 2015 May 1;24(9):2552-64. doi: 10.1093/hmg/ddv019. Epub 2015 Jan 23.
Aberrant fibroblast growth factor receptor 3 (FGFR3) signaling disrupts chondrocyte proliferation and growth plate size and architecture, leading to various chondrodysplasias or bone overgrowth. These observations suggest that the duration, intensity and cellular context of FGFR signaling during growth plate chondrocyte maturation require tight, regulated control for proper bone elongation. However, the machinery fine-tuning FGFR signaling in chondrocytes is incompletely defined. We report here that neurofibromin, a Ras-GAP encoded by Nf1, has an overlapping expression pattern with FGFR1 and FGFR3 in prehypertrophic chondrocytes, and with FGFR1 in hypertrophic chondrocytes during endochondral ossification. Based on previous evidence that neurofibromin inhibits Ras-ERK signaling in chondrocytes and phenotypic analogies between mice with constitutive FGFR1 activation and Nf1 deficiency in Col2a1-positive chondrocytes, we asked whether neurofibromin is required to control FGFR1-Ras-ERK signaling in maturing chondrocytes in vivo. Genetic Nf1 ablation in Fgfr1-deficient chondrocytes reactivated Ras-ERK1/2 signaling in hypertrophic chondrocytes and reversed the expansion of the hypertrophic zone observed in mice lacking Fgfr1 in Col2a1-positive chondrocytes. Histomorphometric and gene expression analyses suggested that neurofibromin, by inhibiting Rankl expression, attenuates pro-osteoclastogenic FGFR1 signaling in hypertrophic chondrocytes. We also provide evidence suggesting that neurofibromin in prehypertrophic chondrocytes, downstream of FGFRs and via an indirect mechanism, is required for normal extension and organization of proliferative columns. Collectively, this study indicates that FGFR signaling provides an important input into the Ras-Raf-MEK-ERK1/2 signaling axis in chondrocytes, and that this input is differentially regulated during chondrocyte maturation by a complex intracellular machinery, of which neurofibromin is a critical component.
异常的成纤维细胞生长因子受体3（FGFR3）信号传导会破坏软骨细胞增殖以及生长板的大小和结构，导致各种软骨发育异常或骨过度生长。这些观察结果表明，生长板软骨细胞成熟过程中FGFR信号传导的持续时间、强度和细胞环境需要严格、受调控的控制，以实现正常的骨骼伸长。然而，在软骨细胞中微调FGFR信号传导的机制尚未完全明确。我们在此报告，神经纤维瘤蛋白是由Nf1编码的一种Ras-GAP，在软骨内骨化过程中，其在肥大前软骨细胞中与FGFR1和FGFR3具有重叠的表达模式，在肥大软骨细胞中与FGFR1具有重叠的表达模式。基于先前的证据表明神经纤维瘤蛋白抑制软骨细胞中的Ras-ERK信号传导，以及在Col2a1阳性软骨细胞中组成型FGFR1激活的小鼠与Nf1缺陷小鼠之间的表型相似性，我们询问神经纤维瘤蛋白是否是体内成熟软骨细胞中控制FGFR1-Ras-ERK信号传导所必需的。在Fgfr1缺陷的软骨细胞中进行基因Nf1缺失会重新激活肥大软骨细胞中的Ras-ERK1/2信号传导，并逆转在Col2a1阳性软骨细胞中缺乏Fgfr1的小鼠中观察到的肥大区扩张。组织形态计量学和基因表达分析表明，神经纤维瘤蛋白通过抑制Rankl表达，减弱肥大软骨细胞中促破骨细胞生成的FGFR1信号传导。我们还提供证据表明，肥大前软骨细胞中的神经纤维瘤蛋白在FGFRs下游并通过间接机制，是增殖柱正常延伸和组织所必需的。总体而言，这项研究表明FGFR信号传导为软骨细胞中的Ras-Raf-MEK-ERK1/2信号轴提供了重要输入，并且这种输入在软骨细胞成熟过程中由复杂的细胞内机制进行差异调节，其中神经纤维瘤蛋白是关键组成部分。
