Bone morphogenetic protein-2 (BMP-2) is strongly involved in the induction of osteoblast differentiation from mesenchymal cell precursors, as well as in enhancing bone matrix production by osteoblastic cells. Likewise, the osteoporotic phenotype of PTHrP deficient mice makes clear the importance of this paracrine regulator in bone physiology. Here, we report that BMP-2 rapidly down-regulated PTHrP gene expression through a transcriptional mechanism in pluripotent mesenchymal C2C12 cells, whereas BMP-2 increased expression of PTHrP receptor. PTHrP did not significantly alter the BMP-dependent Smad transcriptional pathway. Similarly, PTHrP did not significantly modify the BMP-regulated expression of RANKL or OPG, cytokines involved in osteoclastogenesis. More importantly, addition of PTHrP, through the PKA signaling pathway, partially prevented the BMP-dependent induction of some osteogenic markers such as Runx2 and Osterix in C2C12 cells. Our data suggest that BMP-2 down-regulation of PTHrP could facilitate terminal differentiation of osteoblasts.