Inhibitory Effects of 1′,2′-Dihydrorotenone on Osteoclast Differentiation and Bone Resorption In Vitro and In Vivo
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It is important to identify therapeutic compounds with no adverse effects for use in the chemotherapy of patients with bone-related diseases. The aim of this study was to identify a new compound that inhibits osteoclast differentiation and bone resorption. Herein, we examined the effects of 1′,2′-dihydrorotenone on osteoclast differentiation and bone resorption in vitro and in vivo. 1′,2′-dihydrorotenone inhibited receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation of cultured bone marrow macrophages (BMMs) in a dosedependent manner. However, 1′,2′-dihydrorotenone did not exert cytotoxic effect on BMMs. 1′,2′-dihydrorotenone suppressed the expression of c-fos and NFATc1 as well as osteoclast-specific genes in BMMs treated with RANKL. Treatment with RANKL inhibited the expression of inhibitors of differentiation/DNA binding (Id)1, 2, and 3; however,in the presence of 1′,2′-dihydrorotenone, RANKL did not suppress the expression of Id1, 2, and 3. Furthermore,1′,2′-dihydrorotenone inhibited bone resorption and considerably attenuated the erosion of trabecular bone induced by lipopolysaccharide treatment. Taken together, these results suggest that 1′,2′-dihydrorotenone has the potential to be applied in therapies for bone-related diseases.
Abstract
It is important to identify therapeutic compounds with no adverse effects for use in the chemotherapy of patients with bone-related diseases. The aim of this study was to identify a new compound that inhibits osteoclast differentiation and bone resorption. Herein, we examined the effects of 1′,2′-dihydrorotenone on osteoclast differentiation and bone resorption in vitro and in vivo. 1′,2′-dihydrorotenone inhibited receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation of cultured bone marrow macrophages (BMMs) in a dosedependent manner. However, 1′,2′-dihydrorotenone did not exert cytotoxic effect on BMMs. 1′,2′-dihydrorotenone suppressed the expression of c-fos and NFATc1 as well as osteoclast-specific genes in BMMs treated with RANKL. Treatment with RANKL inhibited the expression of inhibitors of differentiation/DNA binding (Id)1, 2, and 3; however,in the presence of 1′,2′-dihydrorotenone, RANKL did not suppress the expression of Id1, 2, and 3. Furthermore,1′,2′-dihydrorotenone inhibited bone resorption and considerably attenuated the erosion of trabecular bone induced by lipopolysaccharide treatment. Taken together, these results suggest that 1′,2′-dihydrorotenone has the potential to be applied in therapies for bone-related diseases.
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