Helvolic acid attenuates osteoclast formation and function via suppressing RANKL-induced NFATc1 activation
Helvolic acid attenuates osteoclast formation and function via suppressing RANKL-induced NFATc1 activation
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DOI：
10.1002/jcp.27385
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发表时间：
2019-05-01
影响因子：
5.6
通讯作者：
Xu, Jiake
中科院分区：
文献类型：
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作者：
Chen, Kai;Yuan, Yu;Xu, Jiake
破骨细胞的过度形成和功能被认为是骨质疏松和骨溶解等溶骨性疾病的主要原因。因此，破骨细胞是治疗骨质疏松症或其他破骨细胞相关疾病的潜在靶点。Helvolic acid(HA)是一种从烟曲霉中分离出来的真菌毒素，已被发现是一种有效的广谱抗菌剂，具有广泛的药理作用。本实验首次证实HA通过抑制活化T细胞核因子1(NFATc1)的活化，在体外能够显著抑制核因子-kappaB受体激活剂(RANKL)诱导的破骨细胞形成和骨吸收。在这种抑制之后，NFATc1靶向基因的表达显著减少，包括CTR(编码降钙素受体)、Acp5(编码抗酒石酸酸性磷酸酶[TRACP])、CTSK(编码组织蛋白K)、Atp6v0d2(编码空泡H+ATPase V0亚单位D2[V-ATPase-D2])和Mmp9(编码基质金属肽酶9)，它们是破骨细胞形成和功能所需的破骨细胞特异性基因。从机制上讲，HA可显著减弱多种上游途径，包括细胞外信号调节激酶(ERK)的磷酸化、c-Fos信号转导和细胞内钙振荡，但对核因子-kappaB(NF-kappa B)的激活影响不大。此外，HA还可减少RANKL诱导的细胞内活性氧的产生。综上所述，我们的研究表明HA有效地抑制了RANKL诱导的破骨细胞的形成和功能。因此，我们认为HA有可能被用于开发一种治疗破骨细胞相关骨病的新药。
Excessive osteoclast formation and function are considered as the main causes of bone lytic disorders such as osteoporosis and osteolysis. Therefore, the osteoclast is a potential therapeutic target for the treatment of osteoporosis or other osteoclast-related diseases. Helvolic acid (HA), a mycotoxin originally isolated from Aspergillus fumigatus , has been discovered as an effective broad-spectrum antibacterial agent and has a wide range of pharmacological properties. Herein, for the first time, HA was demonstrated to be capable of significantly inhibiting receptor activator of nuclear factor-kappa B ligand (RANKL)-induced osteoclastogenesis and bone resorption in vitro by suppressing nuclear factor of activated T cells 1 (NFATc1) activation. This inhibition was followed by the dramatically decreased expression of NFATc1-targeted genes including Ctr (encoding calcitonin receptor), Acp5 (encoding tartrate-resistant acid phosphatase [TRAcP]), Ctsk (encoding cathepsin K), Atp6v0d2 (encoding the vacuolar H+ ATPase V0 subunit d2 [V-ATPase-d2]) and Mmp9 (encoding matrix metallopeptidase 9) which are osteoclastic-specific genes required for osteoclast formation and function. Mechanistically, HA was shown to greatly attenuate multiple upstream pathways including extracellular signal-regulated kinase (ERK) phosphorylation, c-Fos signaling, and intracellular Ca2+ oscillation, but had little effect on nuclear factor-kappa B (NF-kappa B) activation. In addition, HA also diminished the RANKL-induced generation of intracellular reactive oxygen species. Taken together, our study indicated HA effectively suppressed RANKL-induced osteoclast formation and function. Thus, we propose that HA can be potentially used in the development of a novel drug for osteoclast-related bone diseases.