New insight on FGFR3-related chondrodysplasias molecular physiopathology revealed by human chondrocyte gene expression profiling.
New insight on FGFR3-related chondrodysplasias molecular physiopathology revealed by human chondrocyte gene expression profiling.
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DOI：
10.1371/journal.pone.0007633
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发表时间：
2009-10-29
期刊：
影响因子：
3.7
通讯作者：
Legeai-Mallet L
中科院分区：
文献类型：
--
作者：
Schibler L;Gibbs L;Benoist-Lasselin C;Decraene C;Martinovic J;Loget P;Delezoide AL;Gonzales M;Munnich A;Jais JP;Legeai-Mallet L
软骨内成骨是指阑尾骨骼、面骨、椎骨和内侧锁骨形成的过程，依赖于软骨细胞成熟的严格控制。成纤维细胞生长因子受体（FGFR）3在骨发育和维持中起作用，属于一个配体亲和力和组织分布不同的蛋白质家族。FGFR3基因的激活突变导致颅缝闭锁和多种严重程度不同的骨骼发育不良：嗜盐性发育不良（TD）、软骨发育不全和软骨发育不全。尽管在表征fgfr3介导的软骨发育调节方面取得了进展，但许多方面仍不清楚。本研究的目的和新颖之处在于使用Affymetrix技术检测从td感染胎儿的正常软骨或病理软骨分离的原代人软骨细胞中发生的全基因表达差异。软骨细胞标志物的高表达证实了原代细胞的表型。观察到与许多细胞过程相关的基因表达改变，包括细胞生长和增殖、细胞周期、细胞粘附、细胞运动、代谢途径、信号转导、细胞周期过程和细胞信号传导。大多数细胞周期过程基因被下调，包括参与细胞周期进程、DNA生物合成、纺锤体动力学和细胞分裂的基因。大约8%的调节基因被发现影响细胞外基质（ECM）的结构和周转，特别是糖胺聚糖（GAG）和蛋白聚糖的生物合成和磺化。总之，基因表达分析为FGFR3突变在细胞周期调节、前肥大分化和伴随的代谢变化中的后果提供了新的见解。此外，受损的运动性和ECM特性也可能提供生长板紊乱的线索。这些结果还表明，许多信号通路可能直接或间接地被FGFR3改变，并证实了FGFR3在控制生长板发育中的关键作用。
Endochondral ossification is the process by which the appendicular skeleton, facial bones, vertebrae and medial clavicles are formed and relies on the tight control of chondrocyte maturation. Fibroblast growth factor receptor (FGFR)3 plays a role in bone development and maintenance and belongs to a family of proteins which differ in their ligand affinities and tissue distribution. Activating mutations of the FGFR3 gene lead to craniosynostosis and multiple types of skeletal dysplasia with varying degrees of severity: thanatophoric dysplasia (TD), achondroplasia and hypochondroplasia. Despite progress in the characterization of FGFR3-mediated regulation of cartilage development, many aspects remain unclear. The aim and the novelty of our study was to examine whole gene expression differences occurring in primary human chondrocytes isolated from normal cartilage or pathological cartilage from TD-affected fetuses, using Affymetrix technology. The phenotype of the primary cells was confirmed by the high expression of chondrocytic markers. Altered expression of genes associated with many cellular processes was observed, including cell growth and proliferation, cell cycle, cell adhesion, cell motility, metabolic pathways, signal transduction, cell cycle process and cell signaling. Most of the cell cycle process genes were down-regulated and consisted of genes involved in cell cycle progression, DNA biosynthesis, spindle dynamics and cytokinesis. About eight percent of all modulated genes were found to impact extracellular matrix (ECM) structure and turnover, especially glycosaminoglycan (GAG) and proteoglycan biosynthesis and sulfation. Altogether, the gene expression analyses provide new insight into the consequences of FGFR3 mutations in cell cycle regulation, onset of pre-hypertrophic differentiation and concomitant metabolism changes. Moreover, impaired motility and ECM properties may also provide clues about growth plate disorganization. These results also suggest that many signaling pathways may be directly or indirectly altered by FGFR3 and confirm the crucial role of FGFR3 in the control of growth plate development.
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影响因子：
9.2
作者：
Bumeister, R;Rosse, C;White, MA
通讯作者：
White, MA
影响因子：
12.3
作者：
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影响因子：
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作者：
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Wagner, EF
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4.8
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Lee, K
影响因子：
7.7
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Grashoff, C;Aszódi, A;Fässler, R
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Fässler, R