Poncirin Inhibits Osteoclast Differentiation and Bone Loss through Down-Regulation of NFATc1 In Vitro and In Vivo
Poncirin Inhibits Osteoclast Differentiation and Bone Loss through Down-Regulation of NFATc1 In Vitro and In Vivo
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DOI：
10.4062/biomolther.2018.216
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发表时间：
2020-07-01
影响因子：
3.7
通讯作者：
Hwang, Gwi Seo
中科院分区：
文献类型：
--
作者：
Chun, Kwang-Hoon;Jin, Hyun Chul;Hwang, Gwi Seo
破骨细胞的激活和成骨细胞的失活导致骨量丢失和骨吸收，导致骨质疏松症的病理进展。 NF-κ B 配体受体激活剂 (RANKL) 是 TNF 超家族的成员，是破骨细胞分化的关键介质。枳苷是从枳实果实中分离出来的黄烷酮苷，具有抗过敏、降胆固醇、抗炎和抗血小板活性。本研究探讨了枸杞苷对 RANKL 刺激的 RAW264.7 细胞破骨细胞分化的影响。我们观察到接触枳苷后 RANKL 刺激的 TRAP 阳性多核细胞（破骨细胞的形态特征）形成减少。实时 qPCR 分析显示，枳苷处理后，RANKL 介导的关键破骨细胞生成分子（如 NFATc1、TRAP、c-Fos、MMP9 和组织蛋白酶 K）的诱导受到抑制。枳实苷还抑制 RANKL 介导的 NF-kappa B 激活，尤其是 JNK 激活，而 RAW264.7 细胞中 ERK 和 p38 表达没有变化。此外，我们评估了枳实苷在脂多糖（LPS）诱导的骨侵蚀模型中的体内功效。评估股骨的显微 CT 表明，经过枳苷处理的小鼠的骨侵蚀明显减弱。我们的结果表明，枳实苷通过抑制破骨细胞分化在体外和体内发挥抗破骨细胞作用。我们相信，枳实苷是炎症性骨质流失治疗的有前途的候选药物。
Activation of osteoclast and inactivation of osteoblast result in loss of bone mass with bone resorption, leading to the pathological progression of osteoporosis. The receptor activator of NF-kappa B ligand (RANKL) is a member of the TNF superfamily, and is a key mediator of osteoclast differentiation. A flavanone glycoside isolated from the fruit of Poncirus trifoliata, poncirin has anti-allergic, hypocholesterolemic, anti-inflammatory and anti-platelet activities. The present study investigates the effect of poncirin on osteoclast differentiation of RANKL-stimulated RAW264.7 cells. We observed reduced formation of RANKL-stimulated TRAP-positive multinucleated cells (a morphological feature of osteoclasts) after poncirin exposure. Real-time qPCR analysis showed suppression of the RANKL-mediated induction of key osteoclastogenic molecules such as NFATc1, TRAP, c-Fos, MMP9 and cathepsin K after poncirin treatment. Poncirin also inhibited the RANKL-mediated activation of NF-kappa B and, notably, JNK, without changes in ERK and p38 expression in RAW264.7 cells. Furthermore, we assessed the in vivo efficacy of poncirin in the lipopolysaccharide (LPS)-induced bone erosion model. Evaluating the micro-CT of femurs revealed that bone erosion in poncirin treated mice was markedly attenuated. Our results indicate that poncirin exerts anti-osteoclastic effects in vitro and in vivo by suppressing osteoclast differentiation. We believe that poncirin is a promising candidate for inflammatory bone loss therapeutics.