Helvolic acid attenuates osteoclast formation and function via suppressing RANKL‐induced NFATc1 activation
Journal of Cellular Physiology
Published online on October 20, 2018
Abstract
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- "\nAbstract\nExcessive 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 \nCtr (encoding calcitonin receptor),
\nAcp5 (encoding tartrate‐resistant acid phosphatase [TRAcP]), \nCtsk (encoding
cathepsin K), \nAtp6v0d2 (encoding the vacuolar H+ ATPase V0 subunit d2 [V‐ATPase‐d2])
and \nMmp9 (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\n2+ 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."
- Journal of Cellular Physiology, EarlyView.