skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Mitochondria related peptide MOTS-c suppresses ovariectomy-induced bone loss via AMPK activation

Abstract

Therapeutic targeting bone loss has been the focus of the study in osteoporosis. The present study is intended to evaluate whether MOTS-c, a novel mitochondria related 16 aa peptide, can protect mice from ovariectomy-induced osteoporosis. After ovary removal, the mice were injected with MOTS-c at a dose of 5 mg/kg once a day for 12 weeks. Our results showed that MOTS-c treatment significantly alleviated bone loss, as determined by micro-CT examination. Mechanistically, we found that the receptor activator of nuclear factor-κB ligand (RANKL) induced osteoclast differentiation was remarkably inhibited by MOTS-c. Moreover, MOTS-c increased phosphorylated AMPK levels, and compound C, an AMPK inhibitor, could partially abrogate the effects of the MOTS-c on osteoclastogenesis. Thus, our findings provide evidence that MOTS-c may exert as an inhibitor of osteoporosis via AMPK dependent inhibition of osteoclastogenesis. -- Highlights: •MOTS-c decreases OVX-induced bone loss in vivo. •MOTS-c inhibits RANKL-induced osteoclast formation. •MOTS-c inhibits RANKL-induced osteoclast-specific gene expression. •MOTS-c represses osteoclast differentiation via the activation of AMPK.

Authors:
 [1];  [2];  [3];  [4];  [5];  [1];  [1];  [1];  [1];  [1];
  1. State Key Laboratory of Cancer Biology, Department of Pharmacogenomics, Fourth Military Medical University, Xi’an 710032 (China)
  2. (China)
  3. Department of Gynecology of Shaanxi Provincial People’s Hospital, Xi’an, 710068 (China)
  4. Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an 710032 (China)
  5. Department of Occupational and Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi’an 710032 (China)
Publication Date:
OSTI Identifier:
22598794
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 476; Journal Issue: 4; Other Information: Copyright (c) 2016 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ABSORPTION SPECTROSCOPY; COMPUTERIZED TOMOGRAPHY; CONNECTIVE TISSUE CELLS; GENES; IN VIVO; INHIBITION; LIGANDS; MICE; MITOCHONDRIA; OSTEOPOROSIS; OVARIES; PEPTIDES; RECEPTORS; SKELETON

Citation Formats

Ming, Wei, E-mail: weiming@xiyi.edu.cn, Department of Pharmacology, Xi’an Medical University, Xi’an 710021, Lu, Gan, E-mail: leonming99@163.com, Xin, Sha, E-mail: 248967979@qq.com, Huanyu, Lu, E-mail: 2366927258@qq.com, Yinghao, Jiang, E-mail: jiangyh@fmmu.edu.cn, Xiaoying, Lei, E-mail: leixiaoy@fmmu.edu.cn, Chengming, Xu, E-mail: chengmingxu@yeah.net, Banjun, Ruan, E-mail: running@163.com, Li, Wang, E-mail: wanglifw@fmmu.edu.cn, and and others. Mitochondria related peptide MOTS-c suppresses ovariectomy-induced bone loss via AMPK activation. United States: N. p., 2016. Web. doi:10.1016/J.BBRC.2016.05.135.
Ming, Wei, E-mail: weiming@xiyi.edu.cn, Department of Pharmacology, Xi’an Medical University, Xi’an 710021, Lu, Gan, E-mail: leonming99@163.com, Xin, Sha, E-mail: 248967979@qq.com, Huanyu, Lu, E-mail: 2366927258@qq.com, Yinghao, Jiang, E-mail: jiangyh@fmmu.edu.cn, Xiaoying, Lei, E-mail: leixiaoy@fmmu.edu.cn, Chengming, Xu, E-mail: chengmingxu@yeah.net, Banjun, Ruan, E-mail: running@163.com, Li, Wang, E-mail: wanglifw@fmmu.edu.cn, & and others. Mitochondria related peptide MOTS-c suppresses ovariectomy-induced bone loss via AMPK activation. United States. doi:10.1016/J.BBRC.2016.05.135.
Ming, Wei, E-mail: weiming@xiyi.edu.cn, Department of Pharmacology, Xi’an Medical University, Xi’an 710021, Lu, Gan, E-mail: leonming99@163.com, Xin, Sha, E-mail: 248967979@qq.com, Huanyu, Lu, E-mail: 2366927258@qq.com, Yinghao, Jiang, E-mail: jiangyh@fmmu.edu.cn, Xiaoying, Lei, E-mail: leixiaoy@fmmu.edu.cn, Chengming, Xu, E-mail: chengmingxu@yeah.net, Banjun, Ruan, E-mail: running@163.com, Li, Wang, E-mail: wanglifw@fmmu.edu.cn, and and others. Fri . "Mitochondria related peptide MOTS-c suppresses ovariectomy-induced bone loss via AMPK activation". United States. doi:10.1016/J.BBRC.2016.05.135.
@article{osti_22598794,
title = {Mitochondria related peptide MOTS-c suppresses ovariectomy-induced bone loss via AMPK activation},
author = {Ming, Wei, E-mail: weiming@xiyi.edu.cn and Department of Pharmacology, Xi’an Medical University, Xi’an 710021 and Lu, Gan, E-mail: leonming99@163.com and Xin, Sha, E-mail: 248967979@qq.com and Huanyu, Lu, E-mail: 2366927258@qq.com and Yinghao, Jiang, E-mail: jiangyh@fmmu.edu.cn and Xiaoying, Lei, E-mail: leixiaoy@fmmu.edu.cn and Chengming, Xu, E-mail: chengmingxu@yeah.net and Banjun, Ruan, E-mail: running@163.com and Li, Wang, E-mail: wanglifw@fmmu.edu.cn and and others},
abstractNote = {Therapeutic targeting bone loss has been the focus of the study in osteoporosis. The present study is intended to evaluate whether MOTS-c, a novel mitochondria related 16 aa peptide, can protect mice from ovariectomy-induced osteoporosis. After ovary removal, the mice were injected with MOTS-c at a dose of 5 mg/kg once a day for 12 weeks. Our results showed that MOTS-c treatment significantly alleviated bone loss, as determined by micro-CT examination. Mechanistically, we found that the receptor activator of nuclear factor-κB ligand (RANKL) induced osteoclast differentiation was remarkably inhibited by MOTS-c. Moreover, MOTS-c increased phosphorylated AMPK levels, and compound C, an AMPK inhibitor, could partially abrogate the effects of the MOTS-c on osteoclastogenesis. Thus, our findings provide evidence that MOTS-c may exert as an inhibitor of osteoporosis via AMPK dependent inhibition of osteoclastogenesis. -- Highlights: •MOTS-c decreases OVX-induced bone loss in vivo. •MOTS-c inhibits RANKL-induced osteoclast formation. •MOTS-c inhibits RANKL-induced osteoclast-specific gene expression. •MOTS-c represses osteoclast differentiation via the activation of AMPK.},
doi = {10.1016/J.BBRC.2016.05.135},
journal = {Biochemical and Biophysical Research Communications},
number = 4,
volume = 476,
place = {United States},
year = {Fri Aug 05 00:00:00 EDT 2016},
month = {Fri Aug 05 00:00:00 EDT 2016}
}
  • Lipoxin A4 (LXA4; 5S, 6R, 15Strihydroxy- 7,9,13-trans-11-eicosatetraenoic acid) is a metabolic product of arachidonic acid under the action of lipoxidase. This lipid molecule plays important roles in several biological functions, especially inflammatory processes. In vivo, LXA4 regulates the inflammatory response through several signaling pathways. Its mechanism suggests that it might have an effect on osteoclastogenesis and bone loss. Using both in vitro and in vivo studies, it was here observed that LXA4 could significantly inhibit the formation and function of osteoclasts and these effects could be blocked by Boc-2, the specific inhibitor of FPR2/ALX (the receptor of LXA4). Meanwhile, LXA4more » reduce the amount of ovariectomy-induced bone loss. These protective effects was found to be associated with inhibition of nuclear factor-κB (NF-κB), activator protein-1 (AP-1), PI3K-AKT, and p-38, ERK, and JNK in MAPKs. The expression of the receptor activator of the NF-κB ligand RANKL:osteoprotegerin ratio and serum levels of TNF-α, IL-1β, and IL-6 were decreased by LXA4. Moreover, LXA4 prevented the production of reactive oxygen species (ROS), the expression of osteoclast-specific genes, including tartrate-resistant acid phosphatase (TRAP), cathepsin K (CK), matrix metalloproteinase (MMP)-9, RANK, and osteoclastic related transcription factors of c-Fos, NFATc1 could also be significantly inhibited by LXA4 in a dose-dependent manner. Studies have demonstrated that LXA4 can inhibit the formation and function of osteoclasts through modulation of several pathways both upstream and downstream of RANKL signaling and FPR2/ALX was involved in the procedures. This shows that LXA4 may be used as a new strategy for the treatment of osteoclast-related diseases. - Highlights: • Lipoxin A4 can significantly inhibit the formation and function of osteoclasts. • Several pathways both upstream and downstream of RANKL signaling can be inhibit by Lipoxin A4. • Lipoxin A4 can alleviate ovariectomy-induced bone loss effectively.« less
  • Tenuigenin, a major active component of polygala tenuifolia root, has been used to treat patients with insomnia, dementia, and neurosis. In this study, we aimed to investigate the effects of tenuigenin on osteoclastogenesis and clarify the possible mechanism. We showed that tenuigenin inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation and bone resorption without cytotoxicity, which was further demonstrated by reduced osteoclast specific gene expression such as TRAP, c-Src, ATP6v0d2, etc. Moreover, the inhibitory effect of tenuigenin was associated with impaired NF-κB activity owing to delayed degradation/regeneration of IkBa and inhibition of p65 nuclear translocation. Consistent with themore » in vitro results, micro-ct scanning and analysis data showed that tenuigenin suppressed RANKL-induced bone loss in an animal model. Taken together, our data demonstrate that tenuigenin inhibit osteoclast formation and bone resorption both in vitro and in vivo, and comprise a potential therapeutic alternative for osteoclast-related disorders such as osteoporosis and cancer-induced bone destruction. - Highlights: • Tenuigenin suppresses osteoclasts formation, survival and function in vitro. • Tenuigenin impairs NF-κB activation. • Tenuigenin suppresses RANKL-induced bone lose in vivo. • Tenuigenin may be used for treating osteoclast related diseases.« less
  • Molybdenum (Mo), a well-known toxic environmental and industrial pollutant, causes adverse health effects and diseases in humans and has received attention as a potential risk factor for DM. However, the roles of Mo in the mechanisms of the toxicological effects in pancreatic β-cells are mostly unclear. In this study, the results revealed dysfunction of insulin secretion and apoptosis in the pancreatic β-cell-derived RIN-m5F cells and the isolated mouse islets in response to Mo. These effects were accompanied by a mitochondria-dependent apoptotic signals including a decreased in the MMP, an increase in cytochrome c release, and the activation of caspase cascadesmore » and PARP. In addition, ER stress was triggered as indicated by several key molecules of the UPR. Furthermore, exposure to Mo induced the activation of ERK1/2, JNK, AMPKα, and GSK3-α/β. Pretreatment with specific pharmacological inhibitors (in RIN-m5F cells and isolated mouse islets) of JNK (SP600125) and AMPK (Compound C) or transfection with si-RNAs (in RIN-m5F cells) specific to JNK and AMPKα effectively prevented the Mo-induced apoptosis and related signals, but inhibitors of ERK1/2 and GSK3-α/β (PD98059 and LiCl, respectively) did not reverse the Mo-induced effects. Additionally, both the inhibitors and specific si-RNAs could suppress the Mo-induced phosphorylation of JNK and AMPKα each other. Taken together, these results suggest that Mo exerts its cytotoxicity on pancreatic β-cells by inducing dysfunction and apoptosis via interdependent JNK and AMPK activation downstream-regulated mitochondrial-dependent and ER stress-triggered apoptosis pathways. - Highlights: • Molybdenum (Mo) induces pancreatic β-cell dysfunction and apoptosis. • Mo causes β-cell death via mitochondria-dependent caspase cascades signals. • ER stress-triggered apoptotic pathway also regulates Mo-induced β-cell death. • Interdependent of JNK and AMPK activation involves in Mo-induced β-cell apoptosis.« less
  • Highlights: •A GST-FSH fusion protein was successfully expressed in E. coli. •Immunization with GST-FSH antigen can raise high-titer anti-FSH polyclonal sera. •Anti-FSH polyclonal sera can neutralize osteoclastogenic effect of FSH in vitro. •FSH immunization can prevent bone loss in a rat osteoporosis model. -- Abstract: Osteoporosis, a metabolic bone disease, threatens postmenopausal women globally. Hormone replacement therapy (HTR), especially estrogen replacement therapy (ERT), is used widely in the clinic because it has been generally accepted that postmenopausal osteoporosis is caused by estrogen deficiency. However, hypogonadal α and β estrogen receptor null mice were only mildly osteopenic, and mice with eithermore » receptor deleted had normal bone mass, indicating that estrogen may not be the only mediator that induces osteoporosis. Recently, follicle-stimulating hormone (FSH), the serum concentration of which increases from the very beginning of menopause, has been found to play a key role in postmenopausal osteoporosis by promoting osteoclastogenesis. In this article, we confirmed that exogenous FSH can enhance osteoclast differentiation in vitro and that this effect can be neutralized by either an anti-FSH monoclonal antibody or anti-FSH polyclonal sera raised by immunizing animals with a recombinant GST-FSHβ fusion protein antigen. Moreover, immunizing ovariectomized rats with the GST-FSHβ antigen does significantly prevent trabecular bone loss and thereby enhance the bone strength, indicating that a FSH-based vaccine may be a promising therapeutic strategy to slow down bone loss in postmenopausal women.« less
  • Niclosamide (5-chloro-salicyl-(2-chloro-4-nitro) anilide) is an oral anthelmintic drug used for treating intestinal infection of most tapeworms. Recently, niclosamide was shown to have considerable efficacy against some tumor cell lines, including colorectal, prostate, and breast cancers, and acute myelogenous leukemia. Specifically, the drug was identified as a potent inhibitor of signal transducer and activator of transcription 3 (STAT3), which is associated with osteoclast differentiation and function. In this study, we assessed the effect of niclosamide on osteoclastogenesis in vitro and in vivo. Our in vitro study showed that receptor activator of nuclear factor-kappaB ligand (RANKL)-induced osteoclast differentiation was inhibited by niclosamide, due to inhibitionmore » of serine–threonine protein kinase (Akt) phosphorylation, inhibitor of nuclear factor-kappaB (IκB), and STAT3 serine{sup 727}. Niclosamide decreased the expression of the major transcription factors c-Fos and NFATc1, and thereafter abrogated the mRNA expression of osteoclast-specific genes, including TRAP, OSCAR, αv/β3 integrin (integrin αv, integrin β3), and cathepsin K (CtsK). In an in vivo model, niclosamide prevented lipopolysaccharide-induced bone loss by diminishing osteoclast activity. Taken together, our results show that niclosamide is effective in suppressing osteoclastogenesis and may be considered as a new and safe therapeutic candidate for the clinical treatment of osteoclast-related diseases such as osteoporosis. - Highlights: • We first investigated the anti-osteoclastogenic effects of niclosamide in vitro and in vivo. • Niclosamide impairs the activation of the Akt-IκB-STAT3 ser{sup 727} signaling axis. • Niclosamide acts a negative regulator of actin ring formation during osteoclast differentiation. • Niclosamide suppresses LPS-induced bone loss in vivo. • Niclosamide deserves new evaluation as a potential treatment target in various bone diseases.« less