Overexpression of FGFR3, Stat1, Stat5 and p21Cip1 correlates with phenotypic severity and defective chondrocyte differentiation in FGFR3-related chondrodysplasias
Overexpression of FGFR3, Stat1, Stat5 and p21Cip1 correlates with phenotypic severity and defective chondrocyte differentiation in FGFR3-related chondrodysplasias
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DOI：
10.1016/j.bone.2003.09.002
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发表时间：
2004-01-01
期刊：
影响因子：
4.1
通讯作者：
Bonaventure, J
中科院分区：
文献类型：
--
作者：
Legeai-Mallet, L;Benoist-Lasselin, C;Bonaventure, J
软骨发育不全（ACH）和致死性发育不良（TD）是由成纤维细胞生长因子受体3（FGFR 3）突变引起的严重程度增加的人类骨骼疾病。通过小鼠模型工程试图阐明导致这些表型的分子信号传导途径，主要在出生后时期提供了相关信息。包括14例ACH和26例TD在内的大量人胎儿的可用性使得能够通过分析原代培养的软骨细胞和软骨生长板来评估产前期间FGFR 3突变对内源性受体表达的影响。在ACH和TD细胞中观察到FGFR 3完全糖基化亚型的过表达和配体非依赖性磷酸化。胎儿生长板的免疫组织化学分析显示X型胶原阳性肥大区的表型相关减少。异常高量的Stat 1，Stat 5和p21（Cip 1）蛋白被发现在prehypertrophic-hypertrophic软骨细胞，过度表达的程度直接相关的疾病的严重程度。双重免疫染色程序显示FGFR 3和Stat 1的表达在prehypertrophic-hypertrophic区的重叠，表明该受体的组成性激活占Stat过表达。相比之下，Stat和p21（Cip 1）蛋白在增殖区的表达与对照软骨仅略有不同，差异仅限于增殖细胞的最后阵列。我们的研究结果表明，FGFR 3突变在产前期间上调FGFR 3和Stat-p21（Cip 1）的表达，从而诱导过早退出增殖细胞的细胞周期和他们的分化成prehypertrophic软骨细胞。我们的结论是软骨细胞的分化缺陷是FGFR 3相关的人软骨发育不良中纵向骨生长迟缓的主要原因。(C)2003年爱思唯尔公司All rights reserved.
Achondroplasia (ACH) and thanatophoric dysplasia (TD) are human skeletal disorders of increasing severity accounted for by mutations in the fibroblast growth factor receptor 3 (FGFR3). Attempts to elucidate the molecular signaling pathways leading to these phenotypes through mouse model engineering have provided relevant information mostly in the postnatal period. The availability of a large series of human fetuses including 14 ACH and 26 TD enabled the consequences of FGFR3 mutations on endogenous receptor expression during the prenatal period to be assessed by analysis of primary cultured chondrocytes and cartilage growth plates. Overexpression and ligand-independent phosphorylation of the fully glycosylated isoform of FGFR3 were observed in ACH and TD cells. Immunohistochemical analysis of fetal growth plates showed a phenotype-related reduction of the collagen type X-positive hypertrophic zone. Abnormally high amounts of Stat1, Stat5 and p21(Cip1) proteins were found in prehypertrophic-hypertrophic chondrocytes, the extent of overexpression being directly related to the severity of the disease. Double immunostaining procedures revealed an overlap of FGFR3 and Stat1 expression in the prehypertrophic-hypertrophic zone, suggesting that constitutive activation of the receptor accounts for Stat overexpression. By contrast, expression of Stat and p21(Cip1) proteins in the proliferative zone differed only slightly from control cartilage and differences were restricted to the last arrays of proliferative cells. Our results indicate that FGFR3 mutations in the prenatal period upregulate FGFR3 and Stat-p21(Cip1) expression, thus inducing premature exit of proliferative cells from the cell cycle and their differentiation into prehypertrophic chondrocytes. We conclude that defective differentiation of chondrocytes is the main cause of longitudinal bone growth retardation in FGFR3-related human chondrodysplasias. (C) 2003 Elsevier Inc. All rights reserved.