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Role of N-cadherin and protein kinase C in osteoblast gene activation induced by the S252W fibroblast growth factor receptor 2 mutation in Apert craniosynostosis.
J Bone Miner Res. 2001 May; 16(5):832-45.JB

Abstract

Apert (Ap) syndrome is characterized by premature cranial suture ossification caused by fibroblast growth factor receptor 2 (FGFR-2) mutations. We studied the role of cadherins and signaling events in the phenotypic alterations induced by the Ap FGFR-2 S252W mutation in mutant immortalized fetal human calvaria osteoblasts. The FGFR-2 mutation caused increased expression of the osteoblast markers alkaline phosphatase (ALP), type 1 collagen (COLIA1), and osteocalcin (OC) in long-term culture. The mutation also increased cell-cell aggregation, which was suppressed by specific neutralizing anti-N- and anti-E-cadherin antibodies. Mutant osteoblasts showed increased N- and E-cadherin, but not N-cell adhesion molecule (N-CAM) messenger RNA (mRNA) and protein levels. This was confirmed in vivo by the abundant immunoreactive N- and E-cadherins in preosteoblasts in the Ap suture whereas N-CAM and alpha- and beta-catenins were unaffected. Neutralizing anti-N-cadherin antibody or N-cadherin antisense (AS) oligonucleotides but not anti-E-cadherin antibody or AS reduced ALP activity as well as ALP, COLIA1, and OC mRNA overexpression in mutant osteoblasts. Analysis of signal transduction revealed increased phospholipase Cgamma (PLCgamma) and protein kinase Calpha (PKCalpha) phosphorylation and increased PKC activity in mutant cells in basal conditions. Inhibition of PKC by calphostin C or the PKCalpha-specific inhibitor Gö6976 suppressed the increased N-cadherin mRNA and protein levels as well as the overexpression of ALP, COLIA1, and OC mRNA in mutant cells. Thus, N-cadherin plays a role in the activation of osteoblast differentiation marker genes in mutant osteoblasts and PKCalpha signaling appears to be involved in the increased N-cadherin and osteoblast gene expression induced by the S252W FGFR-2 mutation in human osteoblasts.

Authors+Show Affiliations

Institut National de la Santé et de la Recherche Médicale U 349, Centre National de la Recherche Scientifique, Lariboisière Hospital, Paris, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

11341328

Citation

Lemonnier, J, et al. "Role of N-cadherin and Protein Kinase C in Osteoblast Gene Activation Induced By the S252W Fibroblast Growth Factor Receptor 2 Mutation in Apert Craniosynostosis." Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, vol. 16, no. 5, 2001, pp. 832-45.
Lemonnier J, Haÿ E, Delannoy P, et al. Role of N-cadherin and protein kinase C in osteoblast gene activation induced by the S252W fibroblast growth factor receptor 2 mutation in Apert craniosynostosis. J Bone Miner Res. 2001;16(5):832-45.
Lemonnier, J., Haÿ, E., Delannoy, P., Lomri, A., Modrowski, D., Caverzasio, J., & Marie, P. J. (2001). Role of N-cadherin and protein kinase C in osteoblast gene activation induced by the S252W fibroblast growth factor receptor 2 mutation in Apert craniosynostosis. Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, 16(5), 832-45.
Lemonnier J, et al. Role of N-cadherin and Protein Kinase C in Osteoblast Gene Activation Induced By the S252W Fibroblast Growth Factor Receptor 2 Mutation in Apert Craniosynostosis. J Bone Miner Res. 2001;16(5):832-45. PubMed PMID: 11341328.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Role of N-cadherin and protein kinase C in osteoblast gene activation induced by the S252W fibroblast growth factor receptor 2 mutation in Apert craniosynostosis. AU - Lemonnier,J, AU - Haÿ,E, AU - Delannoy,P, AU - Lomri,A, AU - Modrowski,D, AU - Caverzasio,J, AU - Marie,P J, PY - 2001/5/9/pubmed PY - 2002/1/5/medline PY - 2001/5/9/entrez SP - 832 EP - 45 JF - Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research JO - J. Bone Miner. Res. VL - 16 IS - 5 N2 - Apert (Ap) syndrome is characterized by premature cranial suture ossification caused by fibroblast growth factor receptor 2 (FGFR-2) mutations. We studied the role of cadherins and signaling events in the phenotypic alterations induced by the Ap FGFR-2 S252W mutation in mutant immortalized fetal human calvaria osteoblasts. The FGFR-2 mutation caused increased expression of the osteoblast markers alkaline phosphatase (ALP), type 1 collagen (COLIA1), and osteocalcin (OC) in long-term culture. The mutation also increased cell-cell aggregation, which was suppressed by specific neutralizing anti-N- and anti-E-cadherin antibodies. Mutant osteoblasts showed increased N- and E-cadherin, but not N-cell adhesion molecule (N-CAM) messenger RNA (mRNA) and protein levels. This was confirmed in vivo by the abundant immunoreactive N- and E-cadherins in preosteoblasts in the Ap suture whereas N-CAM and alpha- and beta-catenins were unaffected. Neutralizing anti-N-cadherin antibody or N-cadherin antisense (AS) oligonucleotides but not anti-E-cadherin antibody or AS reduced ALP activity as well as ALP, COLIA1, and OC mRNA overexpression in mutant osteoblasts. Analysis of signal transduction revealed increased phospholipase Cgamma (PLCgamma) and protein kinase Calpha (PKCalpha) phosphorylation and increased PKC activity in mutant cells in basal conditions. Inhibition of PKC by calphostin C or the PKCalpha-specific inhibitor Gö6976 suppressed the increased N-cadherin mRNA and protein levels as well as the overexpression of ALP, COLIA1, and OC mRNA in mutant cells. Thus, N-cadherin plays a role in the activation of osteoblast differentiation marker genes in mutant osteoblasts and PKCalpha signaling appears to be involved in the increased N-cadherin and osteoblast gene expression induced by the S252W FGFR-2 mutation in human osteoblasts. SN - 0884-0431 UR - https://www.unboundmedicine.com/medline/citation/11341328/Role_of_N_cadherin_and_protein_kinase_C_in_osteoblast_gene_activation_induced_by_the_S252W_fibroblast_growth_factor_receptor_2_mutation_in_Apert_craniosynostosis_ L2 - https://doi.org/10.1359/jbmr.2001.16.5.832 DB - PRIME DP - Unbound Medicine ER -