Elsevier

Biochemical Pharmacology

Volume 54, Issue 5, 1 September 1997, Pages 613-617
Biochemical Pharmacology

Research paper
Reduction of bone loss by denbufylline, an inhibitor of phosphodiesterase 4

https://doi.org/10.1016/S0006-2952(97)00211-6Get rights and content

Abstract

The effects of denbufylline, a xanthine derivative with selective inhibitory activity on the phosphodiesterase (PDE) 4 isoenzyme, on bone loss in Walker 256/S-bearing rats and on mineralized nodule formation and osteoclastlike cell formation in bone marrow culture systems were examined. Serial oral administrations of denbufylline inhibited the decrease in the bone mineral density of femurs from Walker 256/S-bearing rats, without influence on the healthy rats. Denbufylline restored the bone mass and the number of osteoclasts and osteoblasts per trabecular surface in the femur metaphysis. Among PDE inhibitors, only PDE4-selective inhibitors increased the number of mineralized nodules and decreased the number of osteoclastlike cells in the in vitro bone marrow culture systems, and dibutyryl cyclic AMP mimicked these effects in the in vitro systems. These results suggest that the PDE4 isoenzyme may play an important role in bone turnover through cyclic AMP and that its inhibitors are candidates for therapeutic drugs for the bone loss diseases.

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    Several recent studies suggest a role of PDE4 in the regulation of bone metabolism. In rats, inoculated with Walker 256/S carcinoma to induce an artificial osteoporotic state, bone loss was reduced by over 50% after a two-week treatment with the PDE4 selective inhibitor denbufylline [35]. Rolipram, and two novel PDE4 inhibitors XT-44 and XT-611, have been shown to increase mineralized nodule formation [36] and PGE2-mediated anabolic effects [37] in rat bone marrow culture.

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This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan.

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