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Published on: February 28, 2017
Signaling by fibroblast growth factors (FGF) and fibroblast growth factor receptor 2 (FGFR2)-activating mutations
A Mansukhani1, P Bellosta, M Sahni
1Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA. mansu01@med.nyu.edu
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.
Insights
Fibroblast growth factors (FGF) dual role in bone development: promoting proliferation in immature osteoblasts but causing apoptosis and inhibiting differentiation in mature cells. Craniosynostosis mutations exacerbate these effects.
Area of Science:
- Cell Biology
- Developmental Biology
- Molecular Biology
Background:
- Fibroblast growth factors (FGF) are crucial for bone development, influencing chondrogenesis and osteogenesis.
- Unregulated FGF signaling in intramembranous ossification can lead to craniosynostosis and craniofacial deformities.
- Activating mutations in FGF receptors (FGFR) 1 and 2 are linked to human craniosynostosis, but FGF's precise role in osteoblast function remains unclear.
Purpose of the Study:
- To investigate the effects of FGF signaling on osteoblast proliferation, maturation, and differentiation.
- To analyze the impact of craniosynostosis-associated FGFR mutations on osteoblast behavior.
- To elucidate the biochemical mechanisms underlying FGF's role in osteogenesis and craniofacial development.
Main Methods:
- Treatment of primary murine calvarial osteoblasts and a novel osteoblastic cell line (OB1) with FGF.
- Analysis of downstream signaling pathways, including the Grb2/FRS2/Shp2 complex and MAP kinase activation.
- Introduction of FGFR2 mutations (C342Y and S252W) into OB1 cells to model Crouzon and Apert syndromes.
- Assessment of osteoblast proliferation, apoptosis, alkaline phosphatase expression, and mineralization.
- Study of FGF2 overexpression in transgenic mice calvaria.
Main Results:
- FGF signaling exhibits a dual effect: promoting proliferation in immature osteoblasts but inducing apoptosis and inhibiting differentiation in mature osteoblasts.
- FGF treatment suppressed alkaline phosphatase expression and blocked mineralization in differentiating osteoblasts.
- Craniosynostosis-linked FGFR2 mutations (C342Y, S252W) significantly inhibited differentiation and markedly increased apoptosis in OB1 cells.
- Overexpression of FGF2 in transgenic mice resulted in increased calvarial apoptosis.
Conclusions:
- FGF signaling acts as a potent inducer of cell death in differentiating osteoblasts.
- Distinct effects of FGF on proliferating versus differentiating osteoblasts highlight its complex role in bone development.
- Understanding FGF's role and the impact of FGFR mutations is critical for addressing craniosynostosis and craniofacial deformities.
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