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Apert syndrome mutant FGFR2 and its soluble form reciprocally alter osteogenesis of primary calvarial osteoblasts.
J Cell Physiol. 2012 Sep; 227(9):3267-77.JC

Abstract

Apert syndrome is characterized by craniosynostosis and syndactyly, and is predominantly caused by mutation of either S252W or P253W in the fibroblast growth factor receptor (FGFR) 2 gene. In this study, we characterized the effects of one of the mutations (S252W) using primary calvarial osteoblasts derived from transgenic mice, Ap-Tg and sAp-Tg, that expressed an Apert-type mutant FGFR2 (FGFR2IIIc-S252W; FGFR2IIIc-Ap), and the soluble form (extracellular domain only) of the mutant FGFR2 (sFGFR2IIIc-Ap), respectively. Compared to WT-derived osteoblasts, osteoblasts from Ap-Tg mouse showed a higher proliferative activity and enhanced differentiation, while those from sAp-Tg mouse exhibited reduced potential for proliferation and osteogenic differentiation. When transplanted with β-tricalcium phosphate (β-TCP) granules into immunodeficient mice, Ap-Tg-derived osteoblasts showed a higher bone forming capacity, whereas sAp-Tg-derived osteoblasts were completely deficient for this phenotype. Phosphorylation of extracellular signal-regulated kinase (ERK), MEK, PLCγ, and p38 was increased in Ap-Tg-derived osteoblasts, whereas phosphorylation of these signaling molecules was reduced in sAp-Tg-derived osteoblasts. Interestingly, when these experiments were carried out using osteoblasts from the mice generated by crossing Ap-Tg and sAp-Tg (Ap/sAp-Tg), which co-expressed FGFR2IIIc-Ap and sFGFR2IIIc-Ap, the results were comparable to those obtained from WT-derived osteoblasts. Taken together, these results indicate that osteoblasts expressing FGFR2IIIc-Ap proliferate and differentiate via highly activated MEK, ERK, and p38 pathways, while these pathways are suppressed in osteoblasts expressing sFGFR2IIIc-Ap. Our findings also suggest that altered FGFR2IIIc signaling in osteoblasts is mostly responsible for the phenotypes seen in Apert syndrome, therefore these osteoblast cell lines are useful tools for investigating the pathogenesis of Apert syndrome.

Authors+Show Affiliations

Department of Maxillofacial Reconstruction and Function, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22105374

Citation

Suzuki, Hiroyuki, et al. "Apert Syndrome Mutant FGFR2 and Its Soluble Form Reciprocally Alter Osteogenesis of Primary Calvarial Osteoblasts." Journal of Cellular Physiology, vol. 227, no. 9, 2012, pp. 3267-77.
Suzuki H, Suda N, Shiga M, et al. Apert syndrome mutant FGFR2 and its soluble form reciprocally alter osteogenesis of primary calvarial osteoblasts. J Cell Physiol. 2012;227(9):3267-77.
Suzuki, H., Suda, N., Shiga, M., Kobayashi, Y., Nakamura, M., Iseki, S., & Moriyama, K. (2012). Apert syndrome mutant FGFR2 and its soluble form reciprocally alter osteogenesis of primary calvarial osteoblasts. Journal of Cellular Physiology, 227(9), 3267-77. https://doi.org/10.1002/jcp.24021
Suzuki H, et al. Apert Syndrome Mutant FGFR2 and Its Soluble Form Reciprocally Alter Osteogenesis of Primary Calvarial Osteoblasts. J Cell Physiol. 2012;227(9):3267-77. PubMed PMID: 22105374.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Apert syndrome mutant FGFR2 and its soluble form reciprocally alter osteogenesis of primary calvarial osteoblasts. AU - Suzuki,Hiroyuki, AU - Suda,Naoto, AU - Shiga,Momotoshi, AU - Kobayashi,Yukiho, AU - Nakamura,Masataka, AU - Iseki,Sachiko, AU - Moriyama,Keiji, PY - 2011/11/23/entrez PY - 2011/11/23/pubmed PY - 2012/7/26/medline SP - 3267 EP - 77 JF - Journal of cellular physiology JO - J. Cell. Physiol. VL - 227 IS - 9 N2 - Apert syndrome is characterized by craniosynostosis and syndactyly, and is predominantly caused by mutation of either S252W or P253W in the fibroblast growth factor receptor (FGFR) 2 gene. In this study, we characterized the effects of one of the mutations (S252W) using primary calvarial osteoblasts derived from transgenic mice, Ap-Tg and sAp-Tg, that expressed an Apert-type mutant FGFR2 (FGFR2IIIc-S252W; FGFR2IIIc-Ap), and the soluble form (extracellular domain only) of the mutant FGFR2 (sFGFR2IIIc-Ap), respectively. Compared to WT-derived osteoblasts, osteoblasts from Ap-Tg mouse showed a higher proliferative activity and enhanced differentiation, while those from sAp-Tg mouse exhibited reduced potential for proliferation and osteogenic differentiation. When transplanted with β-tricalcium phosphate (β-TCP) granules into immunodeficient mice, Ap-Tg-derived osteoblasts showed a higher bone forming capacity, whereas sAp-Tg-derived osteoblasts were completely deficient for this phenotype. Phosphorylation of extracellular signal-regulated kinase (ERK), MEK, PLCγ, and p38 was increased in Ap-Tg-derived osteoblasts, whereas phosphorylation of these signaling molecules was reduced in sAp-Tg-derived osteoblasts. Interestingly, when these experiments were carried out using osteoblasts from the mice generated by crossing Ap-Tg and sAp-Tg (Ap/sAp-Tg), which co-expressed FGFR2IIIc-Ap and sFGFR2IIIc-Ap, the results were comparable to those obtained from WT-derived osteoblasts. Taken together, these results indicate that osteoblasts expressing FGFR2IIIc-Ap proliferate and differentiate via highly activated MEK, ERK, and p38 pathways, while these pathways are suppressed in osteoblasts expressing sFGFR2IIIc-Ap. Our findings also suggest that altered FGFR2IIIc signaling in osteoblasts is mostly responsible for the phenotypes seen in Apert syndrome, therefore these osteoblast cell lines are useful tools for investigating the pathogenesis of Apert syndrome. SN - 1097-4652 UR - https://www.unboundmedicine.com/medline/citation/22105374/Apert_syndrome_mutant_FGFR2_and_its_soluble_form_reciprocally_alter_osteogenesis_of_primary_calvarial_osteoblasts_ L2 - https://doi.org/10.1002/jcp.24021 DB - PRIME DP - Unbound Medicine ER -