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Helvolic acid attenuates osteoclast formation and function via suppressing RANKL-induced NFATc1 activation |
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| Authors: | Kai Chen Yu Yuan Ziyi Wang Dezhi Song Jinmin Zhao Zhen Cao Junhao Chen Qiang Guo Li Chen Jennifer Tickner Jiake Xu |
| Affiliation: | 1. School of Biomedical Sciences, University of Western Australia, Perth, Western Australia, Australia Kai Chen and Yu Yuan contributed equally to this work.;2. School of Biomedical Sciences, University of Western Australia, Perth, Western Australia, Australia;3. School of Biomedical Sciences, University of Western Australia, Perth, Western Australia, Australia Research Centre for Regenerative Medicine, Guangxi Medical University, Nanning, Guangxi, China;4. Research Centre for Regenerative Medicine, Guangxi Medical University, Nanning, Guangxi, China Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Guangxi, China International Joint Laboratory on Regeneration of Bone and Soft Tissues, Guangxi Medical University, Guangxi, China;5. School of Biomedical Sciences, University of Western Australia, Perth, Western Australia, Australia Department of Biomedical Materials Science, Third Military Medical University, Chongqing, China;6. School of Biomedical Sciences, University of Western Australia, Perth, Western Australia, Australia Department of Spine Surgery, Xiangya Hospital, Central South University, Changsha, China;7. School of Biomedical Sciences, University of Western Australia, Perth, Western Australia, Australia Melbourne Medical School, University of Melbourne, Parkville, Victoria, Australia |
| Abstract: | 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. |
| Keywords: | helvolic acid (HA) nuclear factor of activated T cells 1 (NFATc1) osteoclast reactive oxygen species (ROS) |