Rolipram, a phosphodiesterase 4 inhibitor, suppresses PGE(2)-induced osteoclast formation by lowering osteoclast progenitor cell viability

Abstract

We have previously shown that phosphodiesterase (PDE) inhibitors induce osteoclast formation by suppressing the degradation of intracellular cAMP. To determine the regulatory roles of PDE inhibitors on PGE(2)-induced osteoclastogenesis, we investigated the effect of PDE inhibitors on osteoclast formation in the presence of PGE(2). We found that IBMX, a nonselective PDE inhibitor, and rolipram, a specific PDE4 inhibitor, decreased PGE(2)-induced osteoclast formation in cocultures of mouse bone marrow cells and osteoblastic cells. These suppressive effects were observed only when cocultures were treated with PDE inhibitors in the presence of PGE(2) at an early stage of differentiation. Northern blot analysis revealed that the PDE4 inhibitor works synergistically with PGE(2) to increase the ratio of TRANCE/OPG mRNA in osteoblasts, suggesting that suppression of osteoclast formation by PGE(2) and the PDE4 inhibitor is not attributable to their indirect effect on calvarial osteoblasts. We further demonstrated that the PDE4 inhibitor augments the inhibitory effect of PGE(2) on osteoclast progenitor cell viability, showing that combined treatment with PGE(2) and rolipram suppresses osteoclast formation by directly reducing osteoclast progenitor cell viability.