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Potential role of PC‐1 expression and pyrophosphate elaboration in the molecular etiology of the FGFR‐associated craniosynostosis syndromes
Author(s) -
Hatch NE
Publication year - 2007
Publication title -
orthodontics and craniofacial research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.664
H-Index - 55
eISSN - 1601-6343
pISSN - 1601-6335
DOI - 10.1111/j.1601-6343.2007.00387.x
Subject(s) - pyrophosphate , fibroblast growth factor receptor , fibroblast growth factor , signal transduction , fibroblast growth factor 23 , microbiology and biotechnology , alkaline phosphatase , biology , chemistry , biochemistry , medicine , receptor , enzyme , calcium , parathyroid hormone
Structured Abstract Author – Hatch NE Background – Fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) signaling is associated with the aberrant mineralization phenotype of the craniosynostosis syndromes. One critical aspect of mineralization involves the elaboration and transport of pyrophosphate into the extracellular matrix with subsequent enzymatic hydrolysis into phosphate. We have previously shown that FGF2 up‐regulates expression of the pyrophosphate generating enzyme, PC‐1, and the pyrophosphate channel, ANK, while down‐regulating expression of the pyrophosphate hydrolyzing enzyme, tissue non‐specific alkaline phosphatase in pre‐osteoblastic, MC3T3E1(C4) cells. These results suggest that FGF/FGFR signaling may affect mineralization via changes in the elaboration and metabolism of pyrophosphate. Objectives – We are currently conducting experiments towards a more systematic analysis of PC‐1 expression in osteoblastic cells, in order to more clearly elucidate the significance of pyrophosphate elaboration in the process of normal bone mineralization and in the molecular etiology of the FGFR‐associated craniosynostosis syndromes. Design – Towards this goal we have constructed a PC‐1 gene promoter/firefly luciferase reporter construct, in order to more directly investigate the regulation of PC‐1 by FGF/FGFR signaling in osteoblastic and non‐osteoblastic cells. Results and Conclusions – Preliminary results confirm that FGF/FGFR signaling, either via treatment with FGF2 or via expression of a Crouzon syndrome‐associated mutant FGFR2, induces PC‐1 promoter activity in osteoblastic cells in culture. This appears to be a cell type specific phenomenon. These results suggest that the expression of PC‐1 downstream of FGF signaling is an integral aspect of osteoblastic function, and that pyrophosphate elaboration may play a significant role in the pathology of craniosynostosis.