AMP kinase acts as a negative regulator of RANKL in the differentiation of osteoclasts |
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| Authors: | Young-Sun Lee Yang-Soon Kim Sun-Young Lee Geun-Hyang Kim Beom-Jun Kim Seung-Hun Lee Ki-Up Lee Ghi-Su Kim Seung-Whan Kim Jung-Min Koh |
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| Affiliation: | 1. MIMR-PHI Institute of Medical Research, Clayton, VIC, Australia;2. Department of Human Biosciences, La Trobe University, Bundoora, VIC, Australia;3. Barwon Biomedical Research, Department of Medicine, The Geelong Hospital, Geelong, VIC, Australia;4. School of Medicine, Deakin University, Geelong, VIC, Australia;5. Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia;6. Department of Orthopaedics, St Vincent''s Hospital, Fitzroy, VIC, Australia;7. Department of Surgery, St Vincent''s Hospital, Fitzroy, VIC, Australia;1. Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Department of Internal Medicine 3 – Rheumatology and Immunology, Universitätsklinikum Erlangen, Erlangen, Germany;2. Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany;3. AO Research Institute Davos, Davos, Switzerland;1. Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark, Odense, Denmark;2. Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, USA;3. Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark;4. OPEN, Odense Patient data Explorative Network, Odense University Hospital/Institute of Clinical Research, University of Southern Denmark, Odense, Denmark;5. Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark;6. Department of Endocrinology, Odense University Hospital, Odense, Denmark;7. Department of Endocrinology, Hospital of Southwest Denmark, Esbjerg, Denmark |
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| Abstract: | IntroductionAMP-activated protein kinase (AMPK) has been reported to stimulate differentiation and proliferation of osteoblasts, but the role of AMPK in the physiology of osteoclasts has not been investigated.MethodOsteoclasts were differentiated from mouse BMM?s. TRAP-positive multinucleated cells were considered to be osteoclasts using TRAP staining, and resorption area was determined by incubation of cells on dentine discs. Signaling pathways were investigated using Western blotting and RT-PCR.ResultsRANKL induced phosphorylation/activation of AMPK-α in BMM?s and stimulated formation of TRAP-positive multinucleated cells. Pharmacological inhibition of AMPK with compound C and siRNA-mediated knockdown of AMPK-α1, the predominant α-subunit isoform in BMM?s, increased RANKL-induced formation of TRAP-positive multinucleated cells and bone resorption via activation of the downstream signaling elements p38, JNK, NF-κB, Akt, CREB, c-Fos, and NFATc1. STO-609, an inhibitor of CaMKK, completely blocked the RANKL-induced activation of AMPK-α, but KN-93, an inhibitor of CaMK, did not. siRNA-mediated TAK1 knockdown also blocked RANKL-induced activation of AMPK-α. The AMPK activators metformin, (?)-epigallocatechin-3-gallate, berberine, resveratrol, and α-lipoic acid dose-dependently suppressed formation of TRAP-positive multinucleated cells and bone resorption.ConclusionAMPK negatively regulates RANKL, possibly by acting through CaMKK and TAK1. Thus, the development of AMPK activators may be a useful strategy for inhibiting the resorption of bone that is stimulated under RANKL-activated conditions. |
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