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-κB 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 Ca 2+ oscillation, but had little effect on nuclear factor-κB (NF-κB) 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.

中文翻译：

---

巯基酸通过抑制RANKL诱导的NFATc1激活来减弱破骨细胞的形成和功能。

破骨细胞的过度形成和功能被认为是溶骨性疾病如骨质疏松和溶骨的主要原因。因此，破骨细胞是用于治疗骨质疏松症或其他与破骨细胞相关的疾病的潜在治疗靶标。最初从烟曲霉分离出的一种霉菌毒素-羟乙酸（HA）已被发现是一种有效的广谱抗菌剂，并具有广泛的药理特性。在此，HA首次被证明能够通过抑制活化T细胞1（NFATc1）的核因子而在体外显着抑制核因子-κB配体（RANKL）诱导的破骨细胞生成和骨吸收的受体激活剂。这种抑制作用之后，NFATc1靶向基因的表达急剧下降，包括Ctr（编码降钙素受体），Acp5（编码抗酒石酸酸性磷酸酶[TRAcP]），Ctsk（编码组织蛋白酶K），Apt6v0d2（编码液泡H + ATPase V0） d2亚单位[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被证明可大大减弱多个上游途径，包括细胞外信号调节激酶（ERK）磷酸化，c-Fos信号传导和细胞内Ca 2+振荡，但对核因子-κB（NF-κB）激活的影响很小。此外，HA还减少了RANKL诱导的细胞内活性氧的产生。在一起 我们的研究表明，HA可有效抑制RANKL诱导的破骨细胞形成和功能。因此，我们提出HA可以潜在地用于开发与破骨细胞相关的骨疾病的新药。