Walker256/S担癌ラットの骨粗鬆症病態の発症機序の解析と病態モデルとしての評価に関する研究

取得学位：博士(薬学)，学位授与番号：博乙第198号，学位授与年月日：平成11年9月30日,学位授与年：199

Phosphodiesterase 4 inhibitor rolipram potentiates the inhibitory effect of calcitonin on osteoclastogenesis

金沢大学医学部附属病院薬剤部To assess the combination effect of calcitonin and the phosphodiesterase 4 inhibitor rolipram on osteoclastogenesis, adherent cell-depleted bone marrow cells from mouse tibia and femur (ACD-BMCs), which were cultured in the presence of 25 ng/ml colony-stimulating factor 1 (CSF-1) and 100 ng/ml soluble receptor activator of NF-κB ligand (sRANKL), were utilized. Calcitonin inhibited formation of tartrate-resistant acid phosphatase-positive multinucleated cells, as mature osteoclasts, by 70% even at 20 pM, whereas rolipram (10 μM) scarcely affected osteoclast formation; in contrast, the combination of both agents led to significant inhibition of multinucleation and pit formation ability of osteoclasts. The combined administration of calcitonin and rolipram attenuated calcitonin receptor mRNA expression in comparison to treatment with either agent alone, whereas expression of RANK and CSF-1 receptor mRNAs was unchanged. Alone, these agents scarcely elevated intracellular cyclic AMP (cAMP) concentration; however, combination treatment with both agents significantly increased cAMP concentration in osteoclast progenitors and osteoclasts. The combination effect was abolished by H-89, an inhibitor of protein kinase A. It appears that rolipram inhibited hydrolysis of cAMP formed by calcitonin in cells and potentiated the inhibitory effect of calcitonin on osteoclastogenesis. The escape phenomenon following calcitonin treatment may also be prevented by concomitant treatment with the phosphodiesterase 4 inhibitor. © Springer-Verlag Tokyo 2006

Selective drug delivery to bone using acidic oligopeptides

金沢大学附属病院薬剤