AMPK negatively regulates RANKL-induced osteoclast differentiation by controlling oxidative stress
Open accessAbstract
AMP-activated protein kinase (AMPK) is a crucial energy sensor of cellular metabolism under various metabolic stresses, such as oxidative stress and inflammation. AMPK deficiency increases osteoclast numbers and reduces bone mass; however, the precise mechanisms remain unclear. This study aimed to clarify the mechanistic connection between AMPK and osteoclast differentiation, and the potential role of AMPK in the anti-resorptive effects of several phytochemicals. We found that receptor activator of nuclear factor-kappa B (NF-κB) ligand (RANKL)-induced osteoclast differentiation, osteoclastic gene expression, and activation of mitogen-activated protein kinase (MAPK) and NF-κB were promoted in cells transfected with AMPK siRNA. AMPK knockdown led to defective synthesis of heme oxygenase-1, an antioxidant enzyme, and the upstream mediator, nuclear factor erythroid-2-related factor 2. Furthermore, treatment with N-acetyl-l-cysteine, an antioxidant, abolished osteoclast differentiation and MAPK/NF-κB activation induced by AMPK knockdown. AMPK activators, hesperetin, gallic acid, resveratrol, and curcumin, suppressed osteoclast differentiation via the activation of AMPK. These results suggest that AMPK inhibits RANKL-induced osteoclast differentiation by enhancing antioxidant defense system and regulating oxidative stress. AMPK activation by dietary-derived phytochemicals may be effective for the treatment of bone diseases.
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Reduction of ROS levels attenuates RANKL-induced activation of NF-κB and MAPK signaling pathways.
“Firstly, the reduction of ROS levels attenuates the RANKL-induced activation of NF-κB and MAPK signaling pathways55.”
From Intelligence-responsive wettability switch coating on magnesium implants for treating osteoporotic fracture (2026) · cites this paper as [55]
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- Authors
- Tanaka, M., Inoue, H., Takahashi, N., & Uehara, M.
- Affiliations
- Tokyo University of Agriculture (JP)
- Corresponding author
- Uehara, Mariko
- Venue
- Free Radical Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 2023-08
- Volume
- 205
- Pages
- 107-115
- ISSN
- 0891-5849 (ISSN-L)
- OpenAlex
- W4378978209
- Cited by
- 41
- References
- 59
- Citations by year
- 2026: 16 · 2025: 18 · 2024: 6 · 2023: 1
- FWCI
- 3.65
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (am, 313 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Free Radical Biology and Medicine (acceptedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society of Nutrition and Food Science
- Japan Society for the Promotion of Science (JP19K24321, JP20H02938, JP21K17646)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Health Sciences › Medicine › Rheumatology › Osteomyelitis and Bone Disorders Research
- Keywords
- AMPK, osteoclastogenesis, RANKL, oxidative stress, heme oxygenase-1, NF-κB, MAPK signaling, N-acetylcysteine, phytochemicals, resveratrol, hesperetin, gallic acid, curcumin, bone resorption, bone disease, antioxidant defense
- MeSH terms
- Antioxidants, Cell Differentiation, Osteoclasts, NF-kappa B, Oxidative Stress, Mitogen-Activated Protein Kinases, RANK Ligand, AMP-Activated Protein Kinases
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