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.

Abstract.A chemoattractant lectin from the dorsal spines of the redfin velvetfish, Hypodytes rubripinnis , was isolated using a combination of affinity chromatography techniques. The glycoprotein, with a molecular mass of 110 kDa, is named Karatoxin. Karatoxin caused agglutination of rabbit erythrocytes. This agglutination was effectively inhibited by D -mannose. In addition, Karatoxin exhibited not only mitogenic activity in the presence of murine splenocytes, but also chemotactic activity in the presence of guinea-pig neutrophils and macrophages. Thus, Karatoxin appears to be a novel chemoattractant lectin. These results suggest that the redfin velvetfish Hypodytes rubripinnis may be a novel source of biologically active substances.

ObjectiveThe helioxanthin derivative 4-(4-methoxyphenyl)thieno[2,3-b:5,4-c′]dipyridine-2-carboxamide (TH) is a low-molecular-weight compound that was identified through screening for osteogenic compounds that enhance the activity of mouse preosteoblastic MC3T3-E1 cells. In the present study, we found that TH suppressed osteoclast differentiation.MethodsUsing the hematopoietic stem cells of ddY mice, TH was added to the culture in the experimental group, and the number of osteoclasts was measured with rhodamine phalloidin staining and TRAP staining. In osteo assay, bone resorption area was compared by the von Kossa staining.ResultsSpecifically, TH inhibited the cyclic guanosine monophosphate (cGMP)-degrading activity of phosphodiesterase (PDE), promoted nitric oxide (NO) production, and dose-dependently suppressed osteoclast differentiation in an osteoclast formation culture of mouse bone marrow cells. The NO-competitive guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) attenuated the suppressive activity of TH on osteoclast differentiation. Conclusion: Given the previously reported suppressive action of cGMP on osteoclastogenesis, our data suggest that TH negatively impacts osteoclast differentiation at least to some extent by stimulating NO production and inhibiting PDE activity, both of which lead to the upregulation of intracellular cGMP. This study supports the potential use of TH as a novel antiosteoporotic reagent that not only stimulates bone formation but also inhibits bone resorption.

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