Amlexanox Suppresses Osteoclastogenesis and Prevents Ovariectomy-Induced Bone Loss.
Amlexanox Suppresses Osteoclastogenesis and Prevents Ovariectomy-Induced Bone Loss.
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Amlexanox 抑制破骨细胞生成并防止卵巢切除术引起的骨质流失。
DOI：
10.1038/srep13575
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发表时间：
2015-09-04
影响因子：
4.6
通讯作者：
Li F
中科院分区：
文献类型：
--
作者：
Zhang Y;Guan H;Li J;Fang Z;Chen W;Li F
蛋白激酶IKK-ε和tank结合激酶1 （TBK1）的活性已被证明与炎症性疾病有关。氨lexanox作为IKK-ε和TBK1的抑制剂，是一种抗炎、抗过敏、免疫调节剂，临床用于治疗溃疡、变应性鼻炎和哮喘。我们假设氨lexanox可能用于治疗破骨细胞相关疾病，这些疾病通常与低度全身性炎症有关。在这项研究中，我们研究了氨lexanox对rankl诱导的体外破骨细胞发生和卵巢切除术介导的体内骨质流失的影响。在原代骨髓源性巨噬细胞（BMMs）中，氨lexanox抑制破骨细胞的形成和骨吸收。在分子水平上，氨lexanox抑制rankl诱导的核因子-κB （NF-κB）、丝裂原活化蛋白激酶（MAPKs）、c-Fos和NFATc1的活化。Amlexanox降低了破骨细胞特异性基因的表达，包括TRAP、MMP9、Cathepsin K和NFATc1。此外，氨来沙诺能促进骨髓间充质干细胞成骨细胞的分化。在卵巢切除（OVX）小鼠模型中，氨lexanox通过抑制破骨细胞活性来预防OVX诱导的骨质流失。综上所述，我们的研究结果表明，氨lexanox抑制破骨细胞生成，防止ovx诱导的骨质流失。因此，氨lexanox可能被认为是一种新的治疗候选的破骨细胞相关疾病，如骨质疏松症和类风湿性关节炎。
The activity of protein kinases IKK-ε and TANK-binding kinase 1 (TBK1) has been shown to be associated with inflammatory diseases. As an inhibitor of IKK-ε and TBK1, amlexanox is an anti-inflammatory, anti-allergic, immunomodulator and used for treatment of ulcer, allergic rhinitis and asthma in clinic. We hypothesized that amlexanox may be used for treatment of osteoclast-related diseases which frequently associated with a low grade of systemic inflammation. In this study, we investigated the effects of amlexanox on RANKL-induced osteoclastogenesis in vitro and ovariectomy-mediated bone loss in vivo. In primary bone marrow derived macrophages (BMMs), amlexanox inhibited osteoclast formation and bone resorption. At the molecular level, amlexanox suppressed RANKL-induced activation of nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPKs), c-Fos and NFATc1. Amlexanox decreased the expression of osteoclast-specific genes, including TRAP, MMP9, Cathepsin K and NFATc1. Moreover, amlexanox enhanced osteoblast differentiation of BMSCs. In ovariectomized (OVX) mouse model, amlexanox prevented OVX-induced bone loss by suppressing osteoclast activity. Taken together, our results demonstrate that amlexanox suppresses osteoclastogenesis and prevents OVX-induced bone loss. Therefore, amlexanox may be considered as a new therapeutic candidate for osteoclast-related diseases, such as osteoporosis and rheumatoid arthritis.