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

Abstract

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 phosphatasepositive 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.

Prostaglandin F2α negatively regulates bone resorption in murine osteoclast development

“…Calcitonin receptor is expressed only in differentiated-osteoclasts and therefore it is used for an marker gene of osteoclastic cell differentiation, however, calcitonin does not influence osteoclast cell differentiation in itself 44 . In addition, depression effect of bone resorption by calcitonin does not persist so that cAMP induced by calcitonin suppresses an expression of calcitonin receptor mRNA 45,46 On the other hand, in contrast to calcitonin, because an expression of FP is not influenced at all by PGF 2α (Fig. 5A), inhibitory effect for bone resorption by PGF 2α may act continuously.…”

An osteogenic helioxanthin derivative suppresses the formation of bone-resorbing osteoclasts

“…Theophylline, a xanthine derivative, has been shown to possess PDE inhibitory activity that suppresses osteoclast bone resorption [10]. Therefore, the PDE inhibitory activity of the xanthine derivative TH was investigated.…”

“…Indeed, as observed with the typical bisphosphonate alendronate, bone mass increases after being treated with compounds capable of inhibiting osteoclastic bone resorption [8]. Theophylline, a xanthine derivative, has been shown to inhibit phosphodiesterase (PDE) activity [9], and PDE inhibitors have been reported to inhibit osteoclast formation and bone resorption [10], [11].…”

Effects of Biological/Targeted Therapies on Bone Mineral Density in Inflammatory Arthritis

“…Phosphodiesterase 4 (PDE4) is an enzyme in the process of cyclic adenosine monophosphate (cAMP) degradation, which involves numerous biologic responses in human cells [145]. Previous literature has suggested the pathogenic role of cAMP inhibition on diseases such as chronic obstructive pulmonary disorder, inflammatory bowel disease, and PsA [146]. As PDE4 is involved in these inflammatory processes, inhibition of PDE4 may provide profound anti-inflammatory properties.…”