Projects per year
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.
Original language | English |
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Pages (from-to) | 6477-6488 |
Number of pages | 12 |
Journal | Journal of Cellular Physiology |
Volume | 234 |
Issue number | 5 |
DOIs | |
Publication status | Published - May 2019 |
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Dive into the research topics of 'Helvolic acid attenuates osteoclast formation and function via suppressing RANKL-induced NFATc1 activation'. Together they form a unique fingerprint.Projects
- 2 Finished
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Furin: Carving-up vital substrates for bone remodelling and homeostasis
Xu, J. (Investigator 01), Pavlos, N. (Investigator 02) & Tickner, J. (Investigator 03)
NHMRC National Health and Medical Research Council
1/01/16 → 31/12/19
Project: Research
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The influence of mutant p62 proteins expressed in Pagets Disease of bone on cell survival & death
Xu, J. (Investigator 01), Walsh, J. (Investigator 02), Rea, S. (Investigator 03), Pavlos, N. (Investigator 04) & Ratajczak, T. (Investigator 05)
NHMRC National Health and Medical Research Council
1/01/12 → 31/12/14
Project: Research