Bajijiasu Abrogates Osteoclast Differentiation via the Suppression of RANKL Signaling Pathways through NF-κB and NFAT.
Bajijiasu Abrogates Osteoclast Differentiation via the Suppression of RANKL Signaling Pathways through NF-κB and NFAT.
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DOI：
10.3390/ijms18010203
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发表时间：
2017-01-19
影响因子：
5.6
通讯作者：
Xu J
中科院分区：
文献类型：
--
作者：
Hong G;Zhou L;Shi X;He W;Wang H;Wei Q;Chen P;Qi L;Tickner J;Lin L;Xu J
病理性骨溶解通常与骨质疏松、骨肿瘤、骨坏死和慢性炎症有关。它涉及激活的破骨细胞对骨基质的过度吸收。抑制核因子受体激活剂B配体(RANKL)信号通路被认为是抑制破骨细胞分化和骨吸收的良好靶点。巴戟天素是一种从巴戟天中提取的天然化合物，先前已被证明具有抗氧化应激特性，但其在破骨细胞形成和骨吸收中的作用及其分子机制尚不清楚。在本研究中，我们发现巴结甲素从0.1 mM起剂量依赖性地抑制RANKL诱导的破骨细胞形成和骨吸收，并在0.4 mM时达到半数最大抑制效应(IC50)，且无毒性。八甲舒可抑制RANKL诱导的破骨细胞特异性标志基因组织蛋白酶K(CTSK)、活化T细胞胞浆核因子1(NFATc1)、抗酒石酸酸性磷酸酶(TRACP)、空泡型H+-ATPase V0亚单位D2(V-ATPase D2)和基质金属蛋白酶-2(MMP2)的表达。荧光素酶报告基因研究表明，八倍甲素能显著降低NFAT的表达和转录活性以及RANKL诱导的NF-κB的激活，并呈剂量依赖关系。此外，还发现巴结加素可降低RANKL诱导的细胞外信号调节激酶、κB-α(IκB-α)、NFAT和V-ATPase D2的磷酸化。综上所述，本研究揭示了八记甲素可通过介导RANKL信号通路来抑制破骨细胞的形成和骨吸收，提示了巴吉甲素对溶骨性骨病的潜在作用。
Pathological osteolysis is commonly associated with osteoporosis, bone tumors, osteonecrosis, and chronic inflammation. It involves excessive resorption of bone matrix by activated osteoclasts. Suppressing receptor activator of NF-κB ligand (RANKL) signaling pathways has been proposed to be a good target for inhibiting osteoclast differentiation and bone resorption. Bajijiasu—a natural compound derived from Morinda officinalis F. C. How—has previously been shown to have anti-oxidative stress property; however, its effect and molecular mechanism of action on osteoclastogenesis and bone resorption remains unclear. In the present study, we found that Bajijiasu dose-dependently inhibited RANKL-induced osteoclast formation and bone resorption from 0.1 mM, and reached half maximal inhibitory effects (IC50) at 0.4 mM without toxicity. Expression of RANKL-induced osteoclast specific marker genes including cathepsin K (Ctsk), nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), tartrate resistant acid phosphatase (TRAcP), vacuolar-type H+-ATPase V0 subunit D2 (V-ATPase d2), and (matrix metalloproteinase-2 (MMP2) was inhibited by Bajijiasu treatment. Luciferase reporter gene studies showed that Bajijiasu could significantly reduce the expression and transcriptional activity of NFAT as well as RANKL-induced NF-κB activation in a dose-dependent manner. Further, Bajijiasu was found to decrease the RANKL-induced phosphorylation of extracellular signal-regulated kinases (ERK), inhibitor of κB-α (IκB-α), NFAT, and V-ATPase d2. Taken together, this study revealed Bajijiasu could attenuate osteoclast formation and bone resorption by mediating RANKL signaling pathways, indicative of a potential effect of Bajijiasu on osteolytic bone diseases.