PDE4 inhibitor suppresses PGE₂-induced osteoclast formation via COX-2-mediated p27^KIP1 expression in RAW264.7 cells

We investigated the effects of phosphodiesterase 3 (PDE3) and PDE4 inhibitors, which are cAMP degrading enzymes, on prostaglandin E₂ (PGE₂)-induced osteoclast formation. A PDE4 inhibitor decreased PGE₂-induced osteoclast formation, whereas a PDE3 inhibitor did not, possibly due to the lack of PDE3 expression in RAW 264.7 cells. Cell cycle analysis revealed that the PDE4 inhibitor stimulated PGE₂-induced p27^KIP1 expression, which leads to increased growth arrest at G ₀/G₁ phase. The PDE4 inhibitor increased cyclooxygenase 2 (COX-2) expression in the presence of PGE₂. COX-2 overexpression was associated with growth suppression via p27^KIP1 expression in RAW 264.7 cells. Taken together, our data demonstrate that the PDE4 inhibitor enhances PGE₂-induced growth arrest of osteoclast precursors via COX-2-mediated p27^KIP1 expression, which in turn negatively regulates osteoclast formation.