TY - JOUR
T1 - Pharmacology-based molecular docking of 4-methylcatechol and its role in RANKL-mediated ROS/Keap1/Nrf2 signalling axis and osteoclastogenesis
AU - Xu, Yang
AU - Song, Dezhi
AU - Su, Yuangang
AU - Chen, Junchun
AU - Wu, Liwei
AU - Lian, Haoyu
AU - Hai, Na
AU - li, Jing
AU - Jiang, Jie
AU - Zhao, Jinmin
AU - Xu, Jiake
AU - Liu, Qian
N1 - Funding Information:
This research was supported by the National Natural Science Foundation of China ( 81960405 ), Guangxi Science and Technology Base and Talent Special Project (Grant No. GuikeAD19254003 ) and Guangxi Natural Science Foundation ( 2018GXNSFAA050092 and 2021GXNSFAA196039 ), and the Training Program for One Thousand Young and Middle-aged Backbone Teachers in Guangxi Colleges and Universities. We thank all the support from the department of Guangxi Key Laboratory of Regenerative Medicine, Research Centre for Regenerative Medicine, Guangxi Medical University. We are grateful to all the staff who contributed to this study.
Publisher Copyright:
© 2022 The Authors
PY - 2023/3
Y1 - 2023/3
N2 - 4-Methylcatechol (4-MC) is an agonist of various neurotrophic factors, which can upregulate the expression of Heme oxygenase 1 (HO-1) protein by activating nuclear factor erythroid 2-related factor 2 (Nrf2), thereby inhibiting oxidative stress-induced neural stem cell death. During RANKL-stimulated osteoclast differentiation, intracellular reactive oxygen species (ROS) levels were increased. Nonetheless, the effect of 4-MC on osteoclast formation and bone resorption function has not been researched. In this study, we investigated the effect of HO-1 upregulation by 4-MC on RANKL-induced osteoclastogenesis and explored the molecular mechanism of HO-1 upregulation by 4-MC. We found that the small molecule compound 4-MC could bind to Keap1 amino acid residue of glycine GLY 367, isoleucine ILE 559 and valine VAL 606, with a predicted binding energy of −4.99 kcal/mol. 4-MC was found to inhibit osteoclast differentiation in vitro by activating Nrf2 to scavenge ROS, inhibiting NF-κB phosphorylation, and alleviating osteoporosis in ovariectomized (OVX) mice. Taken together, 4-MC reduces ROS by inhibiting Keap1, thereby preventing OVX-induced bone loss.
AB - 4-Methylcatechol (4-MC) is an agonist of various neurotrophic factors, which can upregulate the expression of Heme oxygenase 1 (HO-1) protein by activating nuclear factor erythroid 2-related factor 2 (Nrf2), thereby inhibiting oxidative stress-induced neural stem cell death. During RANKL-stimulated osteoclast differentiation, intracellular reactive oxygen species (ROS) levels were increased. Nonetheless, the effect of 4-MC on osteoclast formation and bone resorption function has not been researched. In this study, we investigated the effect of HO-1 upregulation by 4-MC on RANKL-induced osteoclastogenesis and explored the molecular mechanism of HO-1 upregulation by 4-MC. We found that the small molecule compound 4-MC could bind to Keap1 amino acid residue of glycine GLY 367, isoleucine ILE 559 and valine VAL 606, with a predicted binding energy of −4.99 kcal/mol. 4-MC was found to inhibit osteoclast differentiation in vitro by activating Nrf2 to scavenge ROS, inhibiting NF-κB phosphorylation, and alleviating osteoporosis in ovariectomized (OVX) mice. Taken together, 4-MC reduces ROS by inhibiting Keap1, thereby preventing OVX-induced bone loss.
KW - 4-Methylcatechol
KW - Keap1
KW - Nrf2
KW - Osteoclast
UR - https://www.scopus.com/pages/publications/85146182747
U2 - 10.1016/j.biopha.2022.114101
DO - 10.1016/j.biopha.2022.114101
M3 - Article
C2 - 36640671
AN - SCOPUS:85146182747
SN - 0753-3322
VL - 159
JO - Biomedicine and Pharmacotherapy
JF - Biomedicine and Pharmacotherapy
M1 - 114101
ER -