Cited by 43Bone Metabolism and DiseasesSirtuins and Resveratrol in MedicineOsteomyelitis and Bone Disorders Research

AMPK negatively regulates RANKL-induced osteoclast differentiation by controlling oxidative stress

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Tanaka, Miori, Inoue, Hirofumi, Takahashi, Nobuyuki, Uehara, Mariko·2023·Free Radical Biology and Medicine

Abstract

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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Crossref · 10.1016/j.freeradbiomed.2023.05.033

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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
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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