Effect of PPADS on achondroplasic chondrocytes: inhibition of FGF receptor type 3 over-activity.
Achondroplasia, results from a mutation in the FGF receptor type 3, leading to receptor hyperactivation and subsequent amplification of FGF receptor type 3 signals. We have tested the ability of pyridoxal-5'-phosphate-6-azophenyl-2', 4'-disulfonate (PPADS) to decrease the overactivation and signalling of FGF receptor type 3 in achondroplasic chondrocytes. PPADS reduced the tyrosine phosphorylation of FGF receptor type 3 triggered by fibroblast growth factor 9 (FGF9) (50% reduction), as well as the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) pathway. As a consequence of this inhibitory effect on ERK1/2 activity the loss of extracellular matrix was also reversed by PPADS. The action of PPADS seems to be due to a mechanism independent of P2 receptor antagonism.
Guzmán-Aránguez
Ana
A
Departamento de Bioquímica y Biología Molecular IV, Universidad Complutense de Madrid, 28037 Madrid, Spain.
Crooke
Almudena
A
Yayon
Avner
A
Pintor
Jesús
J
D000130:Achondroplasia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D019902:Chondrocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000378:metabolism; D051525:Fibroblast Growth Factor 9 / Q000378:metabolism; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D058919:Purinergic P2 Receptor Antagonists; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism
D051525:Fibroblast Growth Factor 9; D047428:Protein Kinase Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; C077792:pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid; D014443:Tyrosine; D011732:Pyridoxal Phosphate; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3