Effects of diadenosine tetraphosphate on FGF9-induced chloride flux changes in achondroplastic chondrocytes |
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Authors: | Fernando Huete Ana Guzman-Aranguez Javier Ort??n Charles H V Hoyle Jes??s Pintor |
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Institution: | Departamento de Bioquímica, E.U. Óptica, Universidad Complutense de Madrid, c/Arcos de Jalón 118, 28037 Madrid, Spain |
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Abstract: | Achondroplasia, the most common type of dwarfism, is characterized by a mutation in the fibroblast growth factor receptor
3 (FGFR3). Achondroplasia is an orphan pathology with no pharmacological treatment so far. However, the possibility of using
the dinucleotide diadenosine tetraphosphate (Ap4A) with therapeutic purposes in achondroplasia has been previously suggested. The pathogenesis involves the constitutive activation
of FGFR3, resulting in altered biochemical and physiological processes in chondrocytes. Some of these altered processes can
be influenced by changes in cell volume and ionic currents. In this study, the action of mutant FGFR3 on chondrocyte size
and chloride flux in achondroplastic chondrocytes was investigated as well as the effect of the Ap4A on these processes triggered by mutant FGFR3. Stimulation with the fibroblast growth factor 9 (FGF9), the preferred ligand
for FGFR3, induced an enlarged achondroplastic chondrocyte size and an increase in the intracellular chloride concentration,
suggesting the blockade of chloride efflux. Treatment with the Ap4A reversed the morphological changes triggered by FGF9 and restored the chloride efflux. These data provide further evidence
for the therapeutic potential of this dinucleotide in achondroplasia treatment. |
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Keywords: | Diadenosine tetraphosphate Dinucleotides Achondroplasia Chondrocytes Chloride flux Fibroblast growth factor receptor 3 |
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