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Signaling pathways implicated in PGF2alpha effects on Fgf2+/+ and Fgf2-/- osteoblasts.
Maria Giovanna Sabbieti1, Dimitrios Agas, Luigi Marchetti
1School of Biosciences and Biotechnology, University of Camerino, Camerino, MC, Italy. giovanna.sabbieti@unicam.it
Journal of Cellular Physiology
|May 1, 2010
Summary
Prostaglandin F2alpha (PGF2alpha) stimulates osteoblast proliferation through fibroblast growth factor-2 (FGF-2) and its receptor (FGFR1). This autocrine signaling pathway involves Ras/MAPK activation and cell cycle progression, independent of p53.
Area of Science:
- Cell Biology
- Molecular Biology
- Endocrinology
Background:
- Prostaglandin F2alpha (PGF2alpha) is known to regulate osteoblast function.
- Fibroblast growth factor-2 (FGF-2) and its receptors (FGFRs) play crucial roles in bone cell biology.
- The interplay between PGF2alpha and FGF-2 signaling in osteoblasts requires further elucidation.
Purpose of the Study:
- To investigate the role of endogenous FGF-2 in PGF2alpha-induced osteoblast proliferation.
- To identify the specific signaling pathways activated by PGF2alpha in osteoblasts.
- To determine the involvement of the exported FGF-2 isoform in PGF2alpha's effects.
Main Methods:
- Calvarial osteoblasts (COBs) from wild-type (Fgf2+/+) and FGF-2 knockout (Fgf2-/-) mice were used.
- FGF-2 neutralizing antibody was employed to block FGF-2/FGFR1 binding.
- Western blotting and immunofluorescence were utilized to assess protein levels, activation states, and cellular localization.
Main Results:
- PGF2alpha increased Ras/MAPK cascade activity, Bcl-2, and c-Myc levels in Fgf2+/+ COBs, but not in Fgf2-/- COBs.
- PGF2alpha promoted nuclear accumulation and co-localization of Bcl-2/c-Myc in Fgf2+/+ COBs.
- While p53 levels increased, p53 phosphorylation remained unchanged in Fgf2+/+ COBs, contrasting with Fgf2-/- COBs.
- PGF2alpha-induced osteoblast proliferation involved increased cyclins D and E, and G2/M phase expansion in Fgf2+/+ COBs.
- Blocking FGFR1 abolished PGF2alpha-induced increases in phospho-MDM2 and cyclins.
Conclusions:
- PGF2alpha stimulates osteoblast proliferation through an autocrine mechanism involving endogenous FGF-2 and its exported isoform acting via FGFR1.
- The PGF2alpha-FGF-2 signaling axis activates Ras/MAPK pathways and promotes cell cycle progression.
- MDM2 overexpression, induced by PGF2alpha via FGF-2, may contribute to the lack of p53 activation in wild-type osteoblasts.
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