Effect of phosphodiesterase inhibitor-4, rolipram, on new bone formations by recombinant human bone morphogenetic protein-2

Collagen sponge disks (6 mm diameter, 1 mm thickness) were impregnated with recombinant human bone morphogenetic protein-2 (rhBMP-2) (5 μg/disk) and implanted onto the back muscles of mice. Ten or 20 mg/kg per day of Rolipram, a selective inhibitory agent to phosphodiesterase type 4 (PDE-4), or vehicle, was injected subcutaneously into the host mice for 3 weeks. After treatment, rhBMP-2-induced ectopic ossicles were harvested and examined by radiographic and histologic methods to determine the size, bone quality, and mineral content of the ossicles. The ossicles from a group treated with 20 mg/kg per day Rolipram were significantly larger in size and higher in bone mineral density (BMD) and bone mineral content (BMC) than the control samples. No significant differences were noted in mice treated with 10 mg/kg per day of Rolipram. Histologically, ossicles from the high-dose (20 mg/kg per day) Rolipram-treated group showed densely packed, thicker trabeculae when compared with those from the control group. These experimental results indicate that the PDE-4 inhibitor, Rolipram, may enhance the bone-inducing capacity of BMP-2 in mesenchymal cells. This in turn may result in increased responsiveness to BMP-2 and point to a potential use of PDE-4 inhibitors for the promotion of rhBMP-dependent bone repair.