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.
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.
A collaborative study was performed to determine the different types and mechanisms of intestinal abnormalities during gestation. Cases had to fulfill one or more of the following three criteria: (1) ...meconium ileus, (2) intestinal stenosis or atresia, and (3) meconium peritonitis. Esophageal atresia, anorectal atresia, and abdominal wall defects were excluded. One hundred two cases were reviewed from the autopsies of 42 induced abortions, 22 stillborns, and the surgical findings in 38 neonates. Meconium ileus was detected mainly during the second trimester (28/38), and was associated with cystic fibrosis (15), fetal blood deglutition (4), infection (6), or multiple-abnormalities (10), in which three chromosomal aberrations were found. Intestinal stenosis or atresia was more commonly detected during the third trimester of gestation (46/56). Sixteen of the 30 duodenal malformations were associated with trisomy 21, whereas in the 26 small intestinal atresias, signs of distress or ischemia were most frequently detected. Only 8 of 25 meconium peritonitis cases were isolated. A total of 20 cystic fibrosis cases could be proved. In this series, functional abnormalities were observed predominantly in the second trimester and associated mainly with cystic fibrosis or amniotic fluid abnormalities. Anatomic lesions were commonly detected later on and associated with ischemic conditions, chromosomal aberrations, and even cystic fibrosis.
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