RANKL-induced osteoclastogenesis in bone marrow-derived macrophages is suppressed by cisapride

Cisapride is a selective 5-hydroxytryptamine (5-HT)₄ receptor (5-HT₄R)agonist. However, the effects of cisapride on osteoclasts and osteoblasts have not been fully explored. We therefore examined the effects of cisapride on osteoclastogenesis in cultured primary bone marrow-derived macrophages (BMMs), and on osteoblast differentiation in cultured primary calvarial pre-osteoblasts. Cisapride significantly inhibited tartrate-resistant acid phosphatase (TRAP)-positive multinuclear osteoclasts and F-actin ring formation during receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis. No cytotoxicity was observed. Cisapride also suppressed RANKL-induced expression of NF-ATc1, TRAP, and cathepsin K genes in BMMs. In addition, cisapride significantly stimulated apoptotic cell death of osteoclasts. However, cisapride had no effect on osteoblast differentiation, as assessed by alkaline phosphatase (ALP)activity and mineralized nodule formation in the cultured primary pre-osteoblasts. Overall, our findings suggest that cisapride may improve the clinical management of metabolic bone diseases such as osteoporosis.