Activation of liver X receptors suppresses the abundance and osteoclastogenic potential of osteoclast precursors and periodontal bone loss.

Liver-X receptors (LXRs) are essential nuclear hormone receptors involved in cholesterol and lipid metabolism. They are also believed to regulate inflammation and physiological and pathological bone turnover. We have previously shown that infection with the periodontal pathogen Porphyromonas gingivalis (Pg) in mice increases the abundance of CD11b + c-fms + Ly6C hi cells in bone marrow (BM), spleen (SPL), and peripheral blood. These cells also demonstrated enhanced osteoclastogenic activity and a distinctive gene profile following Pg infection. Here, we investigated the role of LXRs in regulating these osteoclast precursors (OCPs) and periodontal bone loss. We found that Pg infection downregulates the gene expression of LXRs, as well as ApoE, a transcription target of LXRs, in CD11b + c-fms + Ly6C hi OCPs. Activation of LXRs by treatment with GW3965, a selective LXR agonist, significantly decreased Pg-induced accumulation of CD11b + c-fms + Ly6C hi population in BM and SPL. GW3965 treatment also significantly suppressed the osteoclastogenic potential of these OCPs induced by Pg infection. Furthermore, the activation of LXRs reduces the abundance of OCPs systemically in BM and locally in the periodontium, as well as mitigates gingival c-fms expression and periodontal bone loss in a ligature-induced periodontitis model. These data implicate a novel role of LXRs in regulating OCP abundance and osteoclastogenic potential in inflammatory bone loss.