Bone morphogenetic protein 2 (BMP‐2) is one of the most potent regulators of osteoblast differentiation and bone formation. R‐Smads (Smads 1/5/8) are the major transducers for BMPs receptors and, once activated, they are translocated in the nucleus regulating transcription target genes by interacting with various transcription factors. Runx‐2 proteins have been shown to interact through their C‐terminal segment with Smads and this interaction is required for in vivo osteogenesis. In particular, recruitment of Smads to intranuclear sites is Runx‐2 dependent, and Runx‐2 factor may accommodate the dynamic targeting of signal transducer to active transcription sites. Previously, we have shown, by in vitro and in vivo experiments, that BMP‐2 up‐regulated FGF‐2 which is important for the maximal responses of BMP‐2 in bone. In this study, we found that endogenous FGF2 is necessary for BMP‐2 induced nuclear accumulation and co‐localization of Runx‐2 and phospho‐Smads1/5/8, while Runx/Smads nuclear accumulation and co‐localization was reduced in Fgf2−/− osteoblasts. Based on these novel data, we conclude that the impaired nuclear accumulation of Runx‐2 in Fgf2−/− osteoblasts reduces R‐Smads sub‐nuclear targeting with a consequent decreased expression of differentiating markers and impaired bone formation in Fgf2 null mice. J. Cell. Physiol. 228: 2149–2158, 2013. © 2013 Wiley Periodicals, Inc.