Hyun-Ju Kim, Kyung-Ae Yoon, Hye-Jin Yoon, Jung Min Hong, Min-Jung Lee, In-Kyu Lee and Shin-Yoon Kim
LXRs are nuclear receptors that function as important regulators of lipid homeostasis and inflammatory responses. LXR activation has been shown to suppress RANKL-induced osteoclast differentiation, but its underlying mechanisms and its influence on inflammatory bone destruction remain unclear. In this study, we report that the LXR agonists T0901317 and GW3965 inhibit osteoclastogenesis from primary BMMs in a dose-dependent manner. LXR activation suppressed RANKL-induced transcriptional activity of NF-κB without affecting IκBα degradation and the phosphorylation of p38. LXR agonists significantly suppressed RANKL-induced expression of c-Fos and NFATc1, which are crucial transcription factors for osteoclastogenesis. The activation of LXRs also inhibited RANKL-mediated AP-1 transcriptional activity. Furthermore, LXR activation attenuated PPARγ ligand-induced c-Fos expression, and LXR suppressed AP-1 promoter activity by PPARγ. The inhibitory effect of LXR activation on osteoclastogenesis was reversed by overexpression of c-Fos, suggesting that c-Fos is a downstream target of the antiosteoclastogenic action of LXRs. In addition to osteoclast differentiation, LXR activation accelerated apoptosis in mature osteoclasts by the induction of caspase-3 and -9 activity and Bim expression. Consistent with the in vitro effects we observed, the administration of a LXR agonist protected from bone loss induced by LPS in vivo. Together, our data provide evidence that LXRs may have potential as therapeutic targets for bone resorption-associated diseases.