title: Intracellular and extracellular ATP coordinately regulate the inverse correlation between osteoclast survival and bone resorption.
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.
authors.affiliation: Department of Geriatric Medicine, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan. miyazak14@tmig.or.jp
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Miyazaki
authors.forename: Mitsuyasu
authors.initials: M
authors.lastname: Iwasawa
authors.forename: Tomoki
authors.initials: T
authors.lastname: Nakashima
authors.forename: Shuuichi
authors.initials: S
authors.lastname: Mori
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Shigemoto
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nakamura
authors.forename: Hideki
authors.initials: H
authors.lastname: Katagiri
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takayanagi
authors.forename: Sakae
authors.initials: S
authors.lastname: Tanaka
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000375:Aging; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D049628:Body Size / Q000235:genetics; D001862:Bone Resorption / Q000378:metabolism*; D002470:Cell Survival; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D006609:High Mobility Group Proteins / Q000235:genetics / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism*; D053245:RANK Ligand / Q000494:pharmacology; D034622:RNA Interference; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C494812:Bcl2l1 protein, mouse; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; C546469:P2rx7 protein, mouse; D053245:RANK Ligand; D058486:Receptors, Purinergic P2X7; C081930:Tfam protein, mouse; D051020:bcl-X Protein; D000255:Adenosine Triphosphate