Constitutive activation of MEK1 in chondrocytes causes Stat1-independent achondroplasia-like dwarfism and rescues the Fgfr3-deficient mouse phenotype
Constitutive activation of MEK1 in chondrocytes causes Stat1-independent achondroplasia-like dwarfism and rescues the Fgfr3-deficient mouse phenotype
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DOI：
10.1101/gad.1179104
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发表时间：
2004-02-01
影响因子：
10.5
通讯作者：
de Crombrugghe, B
中科院分区：
文献类型：
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作者：
Murakami, S;Balmes, G;de Crombrugghe, B
我们培育出了在软骨细胞中表达MEK1基因活性突变体的转基因小鼠。这些小鼠表现出类似于软骨发育不全的矮小表型，软骨发育不全是人类最常见的侏儒症，由FGFR3的激活突变引起。这些小鼠显示生长板软骨细胞不完全肥大，软骨内骨化普遍延迟，而软骨细胞增殖未受影响。转基因胚胎颅底免疫组织化学分析显示，软骨细胞中X型胶原染色减少，Sox9持续表达。这些观察表明，MAPK途径抑制软骨细胞的肥大分化，负向调控骨生长，但不抑制软骨细胞的增殖。在FGFR3基因缺陷小鼠的软骨细胞中表达具有结构性活性的MEK1突变体抑制了骨骼的过度生长，强烈地表明FGFR3对骨生长的调控至少部分是通过MAPK途径介导的。虽然STAT1的缺失恢复了表达FGFR3软骨发育突变的小鼠软骨细胞增殖的减少，但它并没有挽救减少的肥厚区、次级骨化中心的形成延迟以及软骨发育不良样表型。这些观察结果表明，FGFR3信号通过MAPK途径抑制软骨细胞分化，通过STAT1抑制软骨细胞增殖，从而抑制骨生长。
We generated transgenic mice that express a constitutively active mutant of MEK1 in chondrocytes. These mice showed a dwarf phenotype similar to achondroplasia, the most common human dwarfism, caused by activating mutations in FGFR3. These mice displayed incomplete hypertrophy of chondrocytes in the growth plates and a general delay in endochondral ossification, whereas chondrocyte proliferation was unaffected. Immunohistochemical analysis of the cranial base in transgenic embryos showed reduced staining for collagen type X and persistent expression of Sox9 in chondrocytes. These observations indicate that the MAPK pathway inhibits hypertrophic differentiation of chondrocytes and negatively regulates bone growth without inhibiting chondrocyte proliferation. Expression of a constitutively active mutant of MEK1 in chondrocytes of Fgfr3-deficient mice inhibited skeletal overgrowth, strongly suggesting that regulation of bone growth by FGFR3 is mediated at least in part by the MAPK pathway. Although loss of Stat1 restored the reduced chondrocyte proliferation in mice expressing an achondroplasia mutant of Fgfr3, it did not rescue the reduced hypertrophic zone, the delay in formation of secondary ossification centers, and the achondroplasia-like phenotype. These observations suggest a model in which Fgfr3 signaling inhibits bone growth by inhibiting chondrocyte differentiation through the MAPK pathway and by inhibiting chondrocyte proliferation through Stat1.