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J Biol Chem. 2012 Nov 2;287(45):37808-23. doi: 10.1074/jbc.M112.385369. Epub 2012 Sep 17.

Intracellular and extracellular ATP coordinately regulate the inverse correlation between osteoclast survival and bone resorption.

Author information

1
Department of Geriatric Medicine, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan. miyazak14@tmig.or.jp

Abstract

Osteoclasts, highly differentiated bone-resorbing cells of hematopoietic origin, have two conflicting tendencies: a lower capacity to survive and a higher capacity to execute energy-consuming activities such as bone resorption. Here, we report that when compared with their precursors, mature mitochondria-rich osteoclasts have lower levels of intracellular ATP, which is associated with receptor activator of nuclear factor κ-B ligand (RANKL)-induced Bcl-x(L) down-regulation. Severe ATP depletion, caused by disrupting mitochondrial transcription factor A (Tfam) gene, leads to increased bone-resorbing activity despite accelerated apoptosis. Although AMP-activated protein kinase (AMPK) activation by ATP depletion is not involved in the regulation of osteoclast function, the release of ATP from intracellular stores negatively regulates bone-resorbing activity through an autocrine/paracrine feedback loop by altering cytoskeletal structures. Furthermore, osteoclasts derived from aged mice exhibit reduced mitochondrial DNA (mtDNA) and intracellular ATP levels with increased bone-resorbing activity, implicating the possible involvement of age-related mitochondrial dysfunction in osteoporosis. Thus, our study provides evidence for a mechanism underlying the control of cellular functions by reciprocal changes in intracellular and extracellular ATP, which regulate the negative correlation between osteoclast survival and bone resorption.

PMID:
22988253
PMCID:
PMC3488055
DOI:
10.1074/jbc.M112.385369
[Indexed for MEDLINE]
Free PMC Article

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