A novel tyrosine kinase inhibitor restores chondrocyte differentiation and promotes bone growth in a gain-of-function Fgfr3 mouse model
A novel tyrosine kinase inhibitor restores chondrocyte differentiation and promotes bone growth in a gain-of-function Fgfr3 mouse model
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DOI：
10.1093/hmg/ddr514
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发表时间：
2012-02-15
影响因子：
3.5
通讯作者：
Legeai-Mallet, Laurence
中科院分区：
文献类型：
--
作者：
Jonquoy, Aurelie;Mugniery, Emilie;Legeai-Mallet, Laurence
激活种系成纤维细胞生长因子受体 3 (FGFR3) 突变会导致软骨发育不全 (ACH)，这是人类侏儒症和一系列骨骼发育不良的最常见形式。 FGFR3 是一种酪氨酸激酶受体，FGFR3 的组成型激活会损害软骨内骨化，并引发软骨严重瓦解，导致长骨缩短。为了破译 FGFR3 在软骨内骨化中的作用，我们分析了新型酪氨酸激酶抑制剂 (TKI) A31 对人类和小鼠突变型 FGFR3 表达细胞以及对 Fgfr3(Y367C/+) 侏儒小鼠骨骼的影响。我们发现 A31 抑制 FGFR3 的组成型磷酸化并使用离体培养系统恢复胚胎侏儒股骨的大小。经处理的突变型股骨长度增加是野生型的 2.6 倍。在 Fgfr3(Y367C/+) 生长板中观察到细胞周期过早退出和软骨细胞分化缺陷。 A31恢复细胞周期调节因子（增殖细胞核抗原、KI67、细胞周期蛋白D1和p57）的正常表达，并使肥大前软骨细胞正确分化为肥大软骨细胞。我们的数据揭示了 FGFR3 在细胞周期和软骨细胞分化中的特定作用，并支持开发用于治疗 FGFR3 相关软骨发育不良的 TKI。
Activating germline fibroblast growth factor receptor 3 (FGFR3) mutations cause achondroplasia (ACH), the most common form of human dwarfism and a spectrum of skeletal dysplasias. FGFR3 is a tyrosine kinase receptor and constitutive FGFR3 activation impairs endochondral ossification and triggers severe disorganization of the cartilage with shortening of long bones. To decipher the role of FGFR3 in endochondral ossification, we analyzed the impact of a novel tyrosine kinase inhibitor (TKI), A31, on both human and mouse mutant FGFR3-expressing cells and on the skeleton of Fgfr3(Y367C/+) dwarf mice. We found that A31 inhibited constitutive FGFR3 phosphorylation and restored the size of embryonic dwarf femurs using an ex vivo culture system. The increase in length of the treated mutant femurs was 2.6 times more than for the wild-type. Premature cell cycle exit and defective chondrocyte differentiation were observed in the Fgfr3(Y367C/+) growth plate. A31 restored normal expression of cell cycle regulators (proliferating cell nuclear antigen, KI67, cyclin D1 and p57) and allowed pre-hypertrophic chondrocytes to properly differentiate into hypertrophic chondocytes. Our data reveal a specific role for FGFR3 in the cell cycle and chondrocyte differentiation and support the development of TKIs for the treatment of FGFR3-related chondrodysplasias.