Bone Abstracts

Although EGF has been known to inhibit osteoblast differentiation, its molecular mechanism has not been clearly elucidated. Smurf1 acts as a negative regulator of BMP signaling by inducing ubiquitination and proteasomal degradation of BMP type I receptor and R-Smads. In this study, we investigated the effect of EGF on the expression of Smurf1 and the role of Smurf1 in EGF-induced inhibition of BMP2-induced osteogenesis. EGF increased Smurf1 expression which was blocked by treatment with a specific inhibitor of EGFR tyrosine kinase, JNK or ERK. Reporter assay using the constructs containing the sequence of Smurf1 promoter, demonstrated that AP-1 and Runx2 are the transcription factors activated by JNK and ERK, respectively. EGF treatment or Smurf1 overexpression suppressed BMP2-induced expression of osteogenic marker genes, whereas knockdown of Smurf1 partially rescued the expression of these genes in EGF-treated cells. Taken together, these results suggest that the JNK-c-Jun and the ERK-Runx2 signaling pathways play an important role in the regulation of Smurf1 expression by EGF and that Smurf1 partially mediates the inhibitory effect of EGF on osteogenic differentiation.