Kim Ju-Young, Lee Myeung Su, Baek Jong Min, Park Jongtae, Youn Byung-Soo, Oh Jaemin
Imaging Science-based Lung and Bone Diseases Research Center, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea.
Imaging Science-based Lung and Bone Diseases Research Center, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea; Division of Rheumatology, Department of Internal Medicine, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea; Institute for Skeletal Disease, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea.
Bone Rep. 2015 Oct 8;3:83-94. doi: 10.1016/j.bonr.2015.10.003. eCollection 2015 Dec.
Osteoporosis is an aging-associated disease requiring better therapeutic modality. Eupatilin is a major flavonoid from plants such as and which has been reported to possess various beneficial biological effects including anti-inflammation, anti-tumor, anti-cancer, anti-allergy, and anti-oxidation activity. Complete blockade of RANK-dependent osteoclastogenesis was accomplished upon stimulation prior to the receptor activator of nuclear factor κB (RANK)-ligand (RANKL) treatment or post-stimulation of bone marrow macrophages (BMCs) in the presence of RANKL with eupatilin. This blockade was accompanied by inhibition of rapid phosphorylation of Akt, GSK3β, ERK and IκB as well as downregulation of c-Fos and NFATc1 at protein, suggesting that transcriptional suppression is a key mechanism for anti-osteoclastogenesis. Transient reporter assays or gain of function assays confirmed that eupatilin was a potent transcriptional inhibitor in osteoclasts (OC). Surprisingly, when mature osteoclasts were cultured on bone scaffolds in the presence of eupatilin, bone resorption activity was also completely blocked by dismantling the actin rings, suggesting that another major acting site of eupatilin is cytoskeletal rearrangement. The eupatilin-treated mature osteoclasts revealed a shrunken cytoplasm and accumulation of multi-nuclei, eventually becoming fibroblast-like cells. No apoptosis occurred. Inhibition of phosphorylation of cofilin by eupatilin suggests that actin may play an important role in the morphological change of multinucleated cells (MNCs). Human OC similarly responded to eupatilin. However, eupatilin has no effects on osteoblast differentiation and shows cytotoxicity on osteoblast in the concentration of 50 μM. When eupatilin was administered to LPS-induced osteoporotic mice after manifestation of osteoporosis, it prevented bone loss. Ovariectomized (OVX) mice remarkably exhibited bone protection effects. Taken together, eupatilin is an effective versatile therapeutic intervention for osteoporosis via; 1) transcriptional suppression of c-Fos and NFATc1 of differentiating OC and 2) inhibition of actin rearrangement of pathogenic MNCs.
骨质疏松症是一种与衰老相关的疾病，需要更好的治疗方式。灯盏乙素是一种从植物中提取的主要黄酮类化合物，据报道它具有多种有益的生物学效应，包括抗炎、抗肿瘤、抗癌、抗过敏和抗氧化活性。在核因子κB受体激活剂（RANK）配体（RANKL）处理之前刺激或在RANKL存在下用灯盏乙素对骨髓巨噬细胞（BMCs）进行刺激后，可完全阻断RANK依赖性破骨细胞生成。这种阻断伴随着Akt、GSK3β、ERK和IκB快速磷酸化的抑制以及c-Fos和NFATc1蛋白水平的下调，表明转录抑制是抗破骨细胞生成的关键机制。瞬时报告基因检测或功能获得检测证实灯盏乙素是破骨细胞（OC）中一种有效的转录抑制剂。令人惊讶的是，当在灯盏乙素存在下将成熟破骨细胞培养在骨支架上时，通过破坏肌动蛋白环，骨吸收活性也被完全阻断，这表明灯盏乙素的另一个主要作用位点是细胞骨架重排。用灯盏乙素处理的成熟破骨细胞显示细胞质收缩和多核聚集，最终变成成纤维细胞样细胞。未发生凋亡。灯盏乙素对丝切蛋白磷酸化的抑制表明肌动蛋白可能在多核细胞（MNCs）的形态变化中起重要作用。人破骨细胞对灯盏乙素也有类似反应。然而，灯盏乙素对成骨细胞分化没有影响，并且在50μM浓度下对成骨细胞具有细胞毒性。当骨质疏松症表现出来后给LPS诱导的骨质疏松小鼠施用灯盏乙素时，它可预防骨质流失。去卵巢（OVX）小鼠显著表现出骨保护作用。综上所述，灯盏乙素是一种有效的通用骨质疏松症治疗干预药物，通过：1）转录抑制分化中的破骨细胞的c-Fos和NFATc1；2）抑制致病性多核细胞的肌动蛋白重排。
