Nicorandil inhibits osteoclast differentiation in vitro

Abstract

Nicorandil is a hybrid angina therapeutic agent that has nitric oxide (NO) action and the ability to open ATP-sensitive K channels (K channels). A transient increase in NO and intracellular Ca has been demonstrated to be highly involved in the differentiation and activation of osteoclasts. The objective of this study was to verify that the pharmacological effect of nicorandil suppresses the differentiation process of osteoclasts in vitro. Although little authentic NO production was detected in the culture medium in osteoclast formation assays, NO production increased only in the presence of nicorandil. The number of osteoclasts decreased markedly at late time-points after nicorandil addition compared with the number at early time-points. Both the number of TRAP-positive multinucleated cells and the number of cells that obtained F-actin rings decreased in the presence of nicorandil in a concentration-dependent manner. The osteo assay showed that the bone resorption area was also reduced with nicorandil in a concentration-dependent manner. An inhibition recovery experiment was conducted by adding a soluble guanylyl cyclase (sGC) inhibitor (ODQ) and a K channel-opening inhibitor (glibenclamide) during the osteoclast formation process. In the inhibition recovery experiment, the inhibitory effect of nicorandil on osteoclastogenesis was blocked by the addition of ODQ and glibenclamide. These results suggest that both the NO and K channel-opening activity of nicorandil inhibit osteoclast differentiation. Further study of nicorandil may lead to the development of drugs for osteoporosis treatment.

Effects of deficiency of Kelch‐like ECH‐associated protein 1 on skeletal organization: a mechanism for diminished nuclear factor of activated T cells cytoplasmic 1 during osteoclastogenesis

“…RANKL‐induced expression of iNOS and production of NO act as negative feedback signals during osteoclastogenesis (39). A recent study reported that nicorandil, an angina therapeutic agent that has NO action, suppresses osteoclast formation and bone resorption (40). Given that previous studies have demonstrated that Nrf2 activators regulate the induction of iNOS and NO production (41, 42), Keap 1 deficiency might affect iNOS induction and NO production during osteoclastogenesis.…”

ATP‐Sensitive Potassium Channels and Their Physiological and Pathophysiological Roles

“…There are reports of K ATP channels in joint tissues such as articular chondrocytes and also in bone cells such as osteoclasts (249; 364). Interestingly, nicorandil inhibits osteoclast differentiation: an effect that is dependent both on its ability to act as an NO donor and also to activate K ATP channels (249). K ATP channel subunits are also expressed in the hair follicle and may be involved in regulating the follicle growth cycle (482).…”

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

“…[17] showed that NO is directly involved in osteoclast activity; thereafter, Iwaki et al. [18] demonstrated that NO suppresses the differentiation of osteoclasts and thereby suppresses bone resorption.…”