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.
Highlights
Endochondral ossification, the process by which the appendicular skeleton, facial bones, vertebrae and medial clavicles are formed, relies on a tightly controlled chondrocyte maturation process, characterized by successive changes in cell morphology and gene expression
In order for endochondral ossification to occur, precise temporal and spatial coordination between the different factors providing both positive and negative signals at each step of the process is essential. These factors can act in a synergistic manner, or form negative feedback loops and may participate in signaling pathways such as parathyroid hormone related peptide (PTHrP), Indian hedgehog (IHH), C-type natriuretic peptide (CNP), bone morphogenetic protein (BMP), Wnt and fibroblast growth factor receptor (FGFR) pathways [1,2,3]
Sample collection The study was performed using two batches of human chondrocyte primary cultures derived from seven TDI and four control fetuses without skeletal pathology, aged 18 to 25 weeks
Summary
Endochondral ossification, the process by which the appendicular skeleton, facial bones, vertebrae and medial clavicles are formed, relies on a tightly controlled chondrocyte maturation process, characterized by successive changes in cell morphology and gene expression. In order for endochondral ossification to occur, precise temporal and spatial coordination between the different factors providing both positive and negative signals at each step of the process is essential. These factors can act in a synergistic manner, or form negative feedback loops and may participate in signaling pathways such as parathyroid hormone related peptide (PTHrP), Indian hedgehog (IHH), C-type natriuretic peptide (CNP), bone morphogenetic protein (BMP), Wnt and fibroblast growth factor receptor (FGFR) pathways [1,2,3]. Intracellular pathways triggered by these signals, as well as their targets are still poorly defined and only a few downstream transcription factors have been studied including the SOX, RUNX, AP1 and the CREB/ATF families [16,17] as well as Nkx3.2 [18], Snail1 [19] and BAG-1 [20]
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