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

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.

• Authors: Miori Tanaka, Hirofumi Inoue, Nobuyuki Takahashi, Mariko Uehara
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 205 Pg. 107-115 (Aug 20 2023) ISSN: 1873-4596 [Electronic] United States
• PMID: 37270032 (Publication Type: Journal Article)
• Copyright: Copyright © 2023 Elsevier Inc. All rights reserved.

Chemical References

• NF-kappa B
• Antioxidants
• AMP-Activated Protein Kinases
• Mitogen-Activated Protein Kinases
• RANK Ligand

Topics

• Osteoclasts (metabolism)
• NF-kappa B (genetics, metabolism)
• Antioxidants (pharmacology, metabolism)
• AMP-Activated Protein Kinases (genetics, metabolism)
• Cell Differentiation
• Oxidative Stress
• Mitogen-Activated Protein Kinases (metabolism)
• RANK Ligand (pharmacology)