The role of MAPK pathway in bone and soft tissue tumors. Expression of mitogen-activated protein kinase (MAPK) signaling and its role in cell proliferation of the bone malignancies, osteosarcoma (OS) and malignant fibrous histiocytoma (MFH) were investigated.Gene expression and protein levels of RAF1 and MEK1/2 in 6 human sarcoma cell lines and 7 surgically obtained OS specimens were assessed by RT-PCR and immunohistochemistry, respectively. MEK inhibitor, U0126 [1,4-diamino-2,3-dicyano-1,4-bis (2-aminophynyltio) butadiene], was used for cell proliferation assays.RAF1 and MEK 1/2 mRNA was detected in all cell lines and OS specimens. RAF1, MEK 1/2 and p-MEK protein was also expressed in the cells, as was MEK1/2 in OS specimens. Treatment with U0126 resulted in dose- and time-dependent inhibition of cell proliferation and suppression of p-ERK expression, opposite to promotion of p-MEK.U0126 blocks MAPK signaling and decreases cell proliferation in OS and MFH. Thus, selective MAPK inhibitors might be therapeutically advantageous in the treatment of bone and soft tissue sarcomas.