Reduced expression and function of bone morphogenetic protein-2 in bones of Fgf2 null mice.
Disruption of the fibroblast growth factor 2 (FGF-2) gene results in reduced bone mass in mice and impairs expression of bone morphogenic protein-2 (BMP-2) an important mediator of osteoblast and osteoclast differentiation. Since the relationship between FGF-2 and BMP-2 in bone remodeling has not been fully determined, in this study we examined whether endogenous FGF-2 was necessary for maximal effect of BMP-2 on periosteal bone formation in vivo and bone nodule formation and osteoclast formation in vitro in Fgf2-/- mice. We showed that BMP-2 significantly increased periosteal bone formation by 57% in Fgf2+/+ mice but the changes were not significant in Fgf2-/- littermates. In line with these results we found no significant increase in alkaline phosphatase positive (ALP) activity in calvarial osteoblasts or ALP mineralized colonies in stromal cultures from Fgf2-/- mice after BMP-2 treatment. Moreover, BMP-2 induced osteoclast formation was also impaired in marrow stromal cultures from Fgf2-/- mice. Interestingly, BMP-2 induced nuclear accumulation of the runt related transcription factor (Runx2) was markedly impaired in osteoblasts from Fgf2-/- mice. Examination of the effect of loss of FGF-2 on BMP-2 signaling pathway showed that BMP-2 caused a similar induction of phospho-Smad1/5/8 within 30 min in calvarial osteoblasts from both genotypes. In contrast BMP-2-induced p42/44 MAPK was reduced in Fgf2-/- mice. These findings strongly demonstrated that endogenous FGF-2 is important in the maximal responses of BMP-2 in bone and that this may be dependent on the p42/44 MAPK signaling pathway and downstream modulation of Runx2.
Naganawa
Takahiro
T
Department of Medicine, University of Connecticut Health Center, Farmington, Connecticut 06030, USA.
Xiao
Liping
L
Coffin
J D
JD
Doetschman
Thomas
T
Sabbieti
Maria Giovanna
MG
Agas
Dimitrios
D
Hurley
Marja M
MM
D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology / Q000502:physiology*; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology / Q000502:physiology*; D010012:Osteogenesis / Q000502:physiology*; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D012886:Skull / Q000166:cytology; D016212:Transforming Growth Factor beta / Q000494:pharmacology / Q000502:physiology*
C525718:BMP2 protein, human; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D050659:Core Binding Factor Alpha 1 Subunit; D011994:Recombinant Proteins; C493716:Runx2 protein, mouse; D016212:Transforming Growth Factor beta; D016222:Fibroblast Growth Factor 2; D000469:Alkaline Phosphatase