We investigated the modulation of critical transcriptional steps of C₂C₁₂ myoblast/osteoblast transdifferentiation triggered by the BMP2 signaling protein, in response to epigenetic inhibition of the endocytotic internalization of exogenous BMP2. BMP2 endocytosis was inhibited chemically with PEG-Chol and cyclodextrin, and mechanically by mild hypoosmotic treatment. BMP2-dependent nuclear translocation of the Smad1 transcription factor was ten times faster if BMP2 endocytosis was inhibited. Smad1-dependent expression of the JunB gene, the first transcriptional step in myoblast de-differentiation, was increased by a factor of 3 to 4. JunB-dependent levels of Myogenin repression, one of the critical marker of terminal myoblastic differentiation, was amplified by a factor of 3. Smad1-dependent levels of alkaline phosphatase expression, one of the C₂C₁₂ osteoblast differentiation markers, were 3.5 to 5 times higher. The same behaviour was observed for osteopontin, the other C₂C₁₂ osteoblast differentiation marker. These results suggest that the cell genome could "sense" tissue mechanical deformations by mechanical inhibition of signaling protein endocytosis, thereby translating mechanical strains into transcription events involved into cell differentiation.