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

Objective: The 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. Methods: Using 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. Results: Specifically, 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. Keywords: Bone resorption, Helioxanthin derivative, NO, Osteoclast, PDE inhibitor