AbstractDisruption 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. J. Cell. Biochem. 103: 1975–1988, 2008. © 2007 Wiley‐Liss, Inc.