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

Abstract

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+Ly6Chi 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+Ly6Chi OCPs. Activation of LXRs by treatment with GW3965, a selective LXR agonist, significantly decreased Pg‐induced accumulation of CD11b+c‐fms+Ly6Chi 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.

Regulation of metabolism and inflammation: The host response

“…Synthetic small molecule antagonists of LXRs proved protective against periodontal bone loss in a mouse ligature model of periodontitis through suppression of the abundance and osteoclastogenic potential of osteoclast precursor cells. Intriguingly, there was no change in the expression of IL-6 or TNF, commensurate with previous observations of context-dependent functions of LXRs (Zhao et al, 2023).…”