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Signaling by fibroblast growth factors (FGF) and fibroblast growth factor receptor 2 (FGFR2)-activating mutations blocks mineralization and induces apoptosis in osteoblasts.
J Cell Biol. 2000 Jun 12; 149(6):1297-308.JC

Abstract

Fibroblast growth factors (FGF) play a critical role in bone growth and development affecting both chondrogenesis and osteogenesis. During the process of intramembranous ossification, which leads to the formation of the flat bones of the skull, unregulated FGF signaling can produce premature suture closure or craniosynostosis and other craniofacial deformities. Indeed, many human craniosynostosis disorders have been linked to activating mutations in FGF receptors (FGFR) 1 and 2, but the precise effects of FGF on the proliferation, maturation and differentiation of the target osteoblastic cells are still unclear. In this report, we studied the effects of FGF treatment on primary murine calvarial osteoblast, and on OB1, a newly established osteoblastic cell line. We show that FGF signaling has a dual effect on osteoblast proliferation and differentiation. FGFs activate the endogenous FGFRs leading to the formation of a Grb2/FRS2/Shp2 complex and activation of MAP kinase. However, immature osteoblasts respond to FGF treatment with increased proliferation, whereas in differentiating cells FGF does not induce DNA synthesis but causes apoptosis. When either primary or OB1 osteoblasts are induced to differentiate, FGF signaling inhibits expression of alkaline phosphatase, and blocks mineralization. To study the effect of craniosynostosis-linked mutations in osteoblasts, we introduced FGFR2 carrying either the C342Y (Crouzon syndrome) or the S252W (Apert syndrome) mutation in OB1 cells. Both mutations inhibited differentiation, while dramatically inducing apoptosis. Furthermore, we could also show that overexpression of FGF2 in transgenic mice leads to increased apoptosis in their calvaria. These data provide the first biochemical analysis of FGF signaling in osteoblasts, and show that FGF can act as a cell death inducer with distinct effects in proliferating and differentiating osteoblasts.

Authors+Show Affiliations

Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA. mansu01@med.nyu.eduNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

10851026

Citation

Mansukhani, A, et al. "Signaling By Fibroblast Growth Factors (FGF) and Fibroblast Growth Factor Receptor 2 (FGFR2)-activating Mutations Blocks Mineralization and Induces Apoptosis in Osteoblasts." The Journal of Cell Biology, vol. 149, no. 6, 2000, pp. 1297-308.
Mansukhani A, Bellosta P, Sahni M, et al. Signaling by fibroblast growth factors (FGF) and fibroblast growth factor receptor 2 (FGFR2)-activating mutations blocks mineralization and induces apoptosis in osteoblasts. J Cell Biol. 2000;149(6):1297-308.
Mansukhani, A., Bellosta, P., Sahni, M., & Basilico, C. (2000). Signaling by fibroblast growth factors (FGF) and fibroblast growth factor receptor 2 (FGFR2)-activating mutations blocks mineralization and induces apoptosis in osteoblasts. The Journal of Cell Biology, 149(6), 1297-308.
Mansukhani A, et al. Signaling By Fibroblast Growth Factors (FGF) and Fibroblast Growth Factor Receptor 2 (FGFR2)-activating Mutations Blocks Mineralization and Induces Apoptosis in Osteoblasts. J Cell Biol. 2000 Jun 12;149(6):1297-308. PubMed PMID: 10851026.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Signaling by fibroblast growth factors (FGF) and fibroblast growth factor receptor 2 (FGFR2)-activating mutations blocks mineralization and induces apoptosis in osteoblasts. AU - Mansukhani,A, AU - Bellosta,P, AU - Sahni,M, AU - Basilico,C, PY - 2000/6/13/pubmed PY - 2000/7/15/medline PY - 2000/6/13/entrez SP - 1297 EP - 308 JF - The Journal of cell biology JO - J. Cell Biol. VL - 149 IS - 6 N2 - Fibroblast growth factors (FGF) play a critical role in bone growth and development affecting both chondrogenesis and osteogenesis. During the process of intramembranous ossification, which leads to the formation of the flat bones of the skull, unregulated FGF signaling can produce premature suture closure or craniosynostosis and other craniofacial deformities. Indeed, many human craniosynostosis disorders have been linked to activating mutations in FGF receptors (FGFR) 1 and 2, but the precise effects of FGF on the proliferation, maturation and differentiation of the target osteoblastic cells are still unclear. In this report, we studied the effects of FGF treatment on primary murine calvarial osteoblast, and on OB1, a newly established osteoblastic cell line. We show that FGF signaling has a dual effect on osteoblast proliferation and differentiation. FGFs activate the endogenous FGFRs leading to the formation of a Grb2/FRS2/Shp2 complex and activation of MAP kinase. However, immature osteoblasts respond to FGF treatment with increased proliferation, whereas in differentiating cells FGF does not induce DNA synthesis but causes apoptosis. When either primary or OB1 osteoblasts are induced to differentiate, FGF signaling inhibits expression of alkaline phosphatase, and blocks mineralization. To study the effect of craniosynostosis-linked mutations in osteoblasts, we introduced FGFR2 carrying either the C342Y (Crouzon syndrome) or the S252W (Apert syndrome) mutation in OB1 cells. Both mutations inhibited differentiation, while dramatically inducing apoptosis. Furthermore, we could also show that overexpression of FGF2 in transgenic mice leads to increased apoptosis in their calvaria. These data provide the first biochemical analysis of FGF signaling in osteoblasts, and show that FGF can act as a cell death inducer with distinct effects in proliferating and differentiating osteoblasts. SN - 0021-9525 UR - https://www.unboundmedicine.com/medline/citation/10851026/Signaling_by_fibroblast_growth_factors__FGF__and_fibroblast_growth_factor_receptor_2__FGFR2__activating_mutations_blocks_mineralization_and_induces_apoptosis_in_osteoblasts_ L2 - https://rupress.org/jcb/article-lookup/doi/10.1083/jcb.149.6.1297 DB - PRIME DP - Unbound Medicine ER -