AbstractIn the present study, we investigated whether the mitogen‐activated protein (MAP) kinase superfamily is involved in the bone morphogenetic protein (BMP)‐4‐stimulated synthesis of osteocalcin in osteoblast‐like MC3T3‐E1 cells. BMP‐4 dose‐dependently stimulated osteocalcin synthesis. BMP‐4 markedly induced the phosphorylation of p44/p42 MAP kinase and p38 MAP kinase, while having little effect on SAPK (stress‐activated protein kinase)/JNK (c‐Jun N terminal kinase) phosphorylation. SB203580 and PD169316, specific inhibitors of p38 MAP kinase, significantly reduced the osteocalcin synthesis stimulated by BMP‐4. In contrast, PD98059 and U0126, inhibitors of upstream kinase of p44/p42 MAP kinase, markedly enhanced the BMP‐4‐stimulated osteocalcin synthesis. The BMP‐4‐induced phosphorylation of p44/p42 MAP kinase was suppressed by PD98059, which did not, however, affect the BMP‐4‐induced phosphorylation of p38 MAP kinase. Taken together, our results strongly suggest that p38 MAP kinase takes part in BMP‐4‐stimulated osteocalcin synthesis as a positive regulator in osteoblasts, whereas p44/p42 MAP kinase acts as a negative regulator in the synthesis. J. Cell. Biochem. 84: 583–589, 2002. © 2001 Wiley‐Liss, Inc.