title: Complementary antagonistic actions between C-type natriuretic peptide and the MAPK pathway through FGFR-3 in ATDC5 cells.
abstract: We previously reported that C-type natriuretic peptide (CNP) stimulates endochondral ossification and corrects the reduction in body length of achondroplasia model mouse with constitutive active fibroblast growth factor receptor 3 (FGFR-3). In order to examine the interaction between CNP and FGFR-3, we studied intracellular signaling by using ATDC5 cells, a mouse chondrogenic cell line, and found that FGF2 and FGF18 markedly reduced CNP-dependent intracellular cGMP production, and that these effects were attenuated by MAPK inhibitors. Western blot analysis demonstrated that the level of GC-B, a particulate guanylyl cyclase specific for CNP, was not changed by treatment with FGFs. Conversely, CNP and 8-bromo-cGMP strongly and dose-dependently inhibited the induction of ERK phosphorylation by FGF2 and FGF18 without changing the level of FGFR-3, although they did not affect the phosphorylation of STAT-1. In the organ-cultured fetal mouse tibias, CNP and FGF18 counteracted on the longitudinal bone growth, and both the size and number of hypertrophic chondrocytes. The FGF/FGFR-3 pathway is known as the negative regulator of endochondral ossification. We found that FGFs inhibited CNP-stimulated cGMP production by disrupting the signaling pathway through GC-B while CNP antagonized the activation of the MAPK cascade by FGFs. These results suggest that the CNP/GC-B pathway plays an important role in growth plate chondrocytes and constitutes the negative cross talk between FGFs and the activity of MAPK. Our results may explain one of the molecular mechanisms of the growth stimulating action of CNP and suggest that activation of the CNP/GC-B pathway may be effective as a novel therapeutic strategy for achondroplasia.
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Ami
authors.initials: A
authors.lastname: Ozasa
authors.forename: Yasato
authors.initials: Y
authors.lastname: Komatsu
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yasoda
authors.forename: Masako
authors.initials: M
authors.lastname: Miura
authors.forename: Yoko
authors.initials: Y
authors.lastname: Sakuma
authors.forename: Yuko
authors.initials: Y
authors.lastname: Nakatsuru
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Arai
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Itoh
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
mesh_terms: D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002452:Cell Count; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D048429:Cell Size / Q000187:drug effects; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006152:Cyclic GMP / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D006132:Growth Plate / Q000166:cytology / Q000187:drug effects; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008813:Mice, Inbred ICR; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020098:Natriuretic Peptide, C-Type / Q000494:pharmacology*; D009570:Nitriles / Q000494:pharmacology; D009924:Organ Culture Techniques; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics / Q000502:physiology*; D013977:Tibia / Q000187:drug effects / Q000196:embryology / Q000502:physiology
chemical_list: D002070:Butadienes; D005419:Flavonoids; D009570:Nitriles; D047428:Protein Kinase Inhibitors; C113580:U 0126; C113569:fibroblast growth factor 18; D016222:Fibroblast Growth Factor 2; D020098:Natriuretic Peptide, C-Type; D005346:Fibroblast Growth Factors; C496366:Fgfr3 protein, mouse; D051498:Receptor, Fibroblast Growth Factor, Type 3; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D006162:Guanylate Cyclase; D006152:Cyclic GMP; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one