title: New insight on FGFR3-related chondrodysplasias molecular physiopathology revealed by human chondrocyte gene expression profiling.
abstract: 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.
authors.affiliation: Unité U781, Institut National de la Santé et de la Recherche Médicale, Université Paris Descartes-Hôpital Necker, Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Schibler
authors.forename: Linda
authors.initials: L
authors.lastname: Gibbs
authors.forename: Catherine
authors.initials: C
authors.lastname: Benoist-Lasselin
authors.forename: Charles
authors.initials: C
authors.lastname: Decraene
authors.forename: Jelena
authors.initials: J
authors.lastname: Martinovic
authors.forename: Philippe
authors.initials: P
authors.lastname: Loget
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Delezoide
authors.forename: Marie
authors.initials: M
authors.lastname: Gonzales
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Jais
authors.forename: Laurence
authors.initials: L
authors.lastname: Legeai-Mallet
mesh_terms: D002356:Cartilage / Q000196:embryology* / Q000378:metabolism; D049109:Cell Proliferation; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism*; D005097:Exostoses, Multiple Hereditary / Q000235:genetics* / Q000378:metabolism; D005109:Extracellular Matrix; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006579:Heterozygote; D006801:Humans; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D011509:Proteoglycans / Q000378:metabolism; D011786:Quality Control; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D011509:Proteoglycans; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3