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 (Ap(4)A) 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 Ap(4)A 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 Ap(4)A 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.