Differential effects of PD98059 and U0126 on osteogenesis and adipogenesis.

PD98059 and U0126 are considered as specific inhibitors of the p42/44 mitogen-activated protein kinases (MAPK) pathway, which affects osteogenesis and adipogenesis. Here, we show unexpected differential effects of PD98059 and U0126 on osteogenesis and adipogenesis as well as on estrogen (E2)-induced actions in osteoprogenitor KS483 cells. PD98059 dose-dependently inhibited osteogenesis indicated by cellular alkaline phosphatase (ALP) activity and nodule formation, but stimulated adipogenesis shown by the number of adipocytes. In contrast, U0126 slightly decreased osteogenesis but had no effects on adipogenesis, although it inhibited p42/44 MAPK more potently than PD98059. Furthermore, PD98059, but not U0126, counteracted E2-induced osteogenesis and adipogenesis. Transfection experiments showed that PD98059, but not U0126, had estrogenic transcriptional activity. Interestingly, both PD98059 and U0126 potentiated E2-induced estrogenic transcriptional activity in KS483 cells, which is opposite to the response in MCF7 breast cancer cells. Our data indicate that the cross-talk between growth factors and estrogen receptor (ER)-mediated pathways in KS483 cells is different from that in MCF7 cells. In summary, the differential effects of PD98059 and U0126 indicate their actions are not exclusively due to an inhibition of MAPK pathway. Caution should be taken in the interpretation of the results obtained using these inhibitors.