The fungal metabolite (+)-terrein abrogates osteoclast differentiation via suppression of the RANKL signaling pathway through NFATc1
The fungal metabolite (+)-terrein abrogates osteoclast differentiation via suppression of the RANKL signaling pathway through NFATc1
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DOI：
10.1016/j.intimp.2020.106429
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发表时间：
2020-06-01
影响因子：
5.6
通讯作者：
Takashiba, Shogo
中科院分区：
文献类型：
--
作者：
Nakagawa, Saki;Omori, Kazuhiro;Takashiba, Shogo
病理生理性骨吸收通常与牙周病相关，并且涉及由活化的破骨细胞对骨基质的过度吸收。核因子受体激活因子（NF）-κ B配体（RANKL）信号通路已被提议作为抑制破骨细胞分化和骨吸收的靶点。真菌次级代谢产物（+）-terrein是一种天然化合物，来源于土曲霉，先前已显示出与炎性骨吸收相关的抗白细胞介素-6特性。然而，其对破骨细胞生成和骨吸收的作用及其分子机制尚不清楚。在本研究中，我们发现10 μ M合成的（+）-terrein以剂量依赖性方式抑制RANKL诱导的破骨细胞形成和骨吸收，且无细胞毒性。RANKL诱导的破骨细胞特异性标志物的信使RNA表达，包括活化T细胞胞质核因子1（NFATc 1）、破骨细胞生成的主要调节因子、组织蛋白酶K、抗酒石酸酸性磷酸酶（Trap），均被合成（+）-terrein处理完全抑制。此外，合成的（+）-terrein降低RANKL诱导的NFATc 1蛋白表达。这项研究表明，合成的（+）-terrein通过介导RANKL信号通路，特别是NFATc 1，减弱破骨细胞形成和骨吸收，并表明（+）-terrein对炎症性骨吸收的潜在作用，包括牙周病。
Pathophysiological bone resorption is commonly associated with periodontal disease and involves the excessive resorption of bone matrix by activated osteoclasts. Receptor activator of nuclear factor (NF)-kappa B ligand (RANKL) signaling pathways have been proposed as targets for inhibiting osteoclast differentiation and bone resorption. The fungal secondary metabolite (+)-terrein is a natural compound derived from Aspergillus terreus that has previously shown anti-interleukin-6 properties related to inflammatory bone resorption. However, its effects and molecular mechanism of action on osteoclastogenesis and bone resorption remain unclear. In the present study, we showed that 10 mu M synthetic (+)-terrein inhibited RANKL-induced osteoclast formation and bone resorption in a dose-dependent manner and without cytotoxicity. RANKL-induced messenger RNA expression of osteoclast-specific markers including nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), the master regulator of osteoclastogenesis, cathepsin K, tartrate-resistant acid phosphatase (Trap) was completely inhibited by synthetic (+)-terrein treatment. Furthermore, synthetic (+)-terrein decreased RANKL-induced NFATc1 protein expression. This study revealed that synthetic (+)-terrein attenuated osteoclast formation and bone resorption by mediating RANKL signaling pathways, especially NFATc1, and indicated the potential effect of (+)-terrein on inflammatory bone resorption including periodontal disease.