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1-(5-Oxohexyl)-3,7-Dimethylxanthine, a Phosphodiesterase Inhibitor, Activates MAPK Cascades and Promotes Osteoblast Differentiation by a Mechanism Independent of PKA Activation (Pentoxyfilline Promotes Osteoblast Differentiation)

Bone Diseases Group, Aventis (G.R., C.F., S.S.-J., S.R.-R., Y.B., R.B.), 93230 Romainville, France; and Departments of Cell Biology and Orthopedics, Yale University School of Medicine (R.B.), New Haven, Connecticut 06510

Address all correspondence and requests for reprints to: Dr. Georges Rawadi, Bone Disease Group, Aventis, 102 route de Noisy, 93230 Romainville Cedex, France. E-mail: georges.rawadi{at}aventis.com

We have investigated the effect of 1-(5-oxohexyl)-3,7-dimethylxanthine or pentoxifylline (PeTx), a nonselective phosphodiesterase inhibitor, on osteoblastic differentiation in vitro by using two mesenchymal cell lines, C3H10T1/2 and C2C12, which are able to acquire the osteoblastic phenotype in the presence of bone morphogenetic protein-2 (BMP-2). PeTx induced the osteoblastic markers, osteocalcin and Osf2/Cbfa1, in C3H10T1/2 and C2C12 cells and enhanced BMP-2-induced expression of osteocalcin, Osf2/Cbfa1, and alkaline phosphatase. This activity was partially attributed to the fact that PeTx is able to enhance BMP-2-induced Smad1 transcriptional activity. Although PeTx clearly stimulates PKA in these cells, neither pretreatment of cells with the PKA inhibitor H89 nor transfection with the specific PKA inhibitor PKI prevented the induction or enhancement of osteoblast markers by PeTx, demonstrating that these effects were independent of PKA activation. On the other hand, PeTx induced the activation of ERK1/2 and p38 kinase pathways independently of the activation of PKA. Selective inhibitors of these MAPK cascades prevented the induction of osteoblastic markers in cells treated with PeTx, suggesting that the activation of these two pathways plays a role in the effect of PeTx on osteoblastic differentiation.