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.

中文翻译：

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肝脏 X 受体的激活抑制破骨细胞前体的丰度和破骨细胞生成潜力以及牙周骨质流失

肝脏 X 受体 (LXR) 是参与胆固醇和脂质代谢的重要核激素受体。人们还认为它们可以调节炎症以及生理和病理性骨转换。我们之前已经证明，小鼠感染牙周病原体牙龈卟啉单胞菌（Pg）会增加骨髓（BM）、脾脏（SPL）和外周血中CD11b ⁺ c-fms ⁺ Ly6C ^{hi细胞的丰度。}Pg 感染后，这些细胞还表现出增强的破骨细胞活性和独特的基因谱。在这里，我们研究了 LXR 在调节这些破骨细胞前体 (OCP) 和牙周骨丢失中的作用。^{我们发现，Pg 感染下调 CD11b +} c-fms ⁺ Ly6C ^hi OCP中 LXR 以及 LXR 转录靶标 ApoE 的基因表达。通过选择性 LXR 激动剂 GW3965 处理来激活 LXR，可显着降低 BM 和 SPL 中 Pg 诱导的 CD11b ⁺ c-fms ⁺ Ly6C ^hi群体的积累。GW3965 治疗还显着抑制了 Pg 感染诱导的这些 OCP 的破骨潜力。此外，LXR 的激活降低了 BM 中全身和牙周组织中局部 OCP 的丰度，并减轻了结扎诱导的牙周炎模型中牙龈 c-fms 的表达和牙周骨丢失。这些数据表明 LXR 在调节炎性骨质流失中 OCP 丰度和破骨细胞潜能方面具有新作用。