title: Involvement of hydrogen peroxide in the differentiation and apoptosis of preosteoclastic cells exposed to arsenite.
abstract: Long-term exposure to sodium arsenite (AsO(2)) promotes the development of various cancers. Paradoxically, arsenic also induces pro-myelomonocytic leukemia cell differentiation, and at higher concentrations, apoptosis. The present study investigated the effects of AsO(2) on preosteoclasts. When treated with 2.5-5microM AsO(2), RAW264.7 cells underwent osteoclast differentiation as evidenced by an increase in the number of multinucleate cells expressing tartrate resistant acid phosphatase (TRAP). The appearance of these phenotypic markers was preceded by a low level increase in extracellular production of H(2)O(2) and was prevented by the addition of catalase (4.5microg/ml), an enzyme that removes H(2)O(2). Only at high concentrations (10-25microM) of AsO(2) was a significant loss of cell viability and a high level increase in H(2)O(2) production (1.5microM) observed. Apoptosis was blocked by pretreatment with diphenylene iodonium chloride (2microM), a NAD(P)H-flavoprotein inhibitor, suggesting the involvement of NADPH-oxidase. The data show that AsO(2), dose-dependently, stimulates increasing amounts of H(2)O(2) production. Moreover, at concentrations found in tissues of individuals exposed to geochemical AsO(2), osteoclasts underwent an H(2)O(2)-dependent differentiation. Therefore, chronic exposure to low-level amounts of AsO(2) could result in increased bone resorption and contribute to bone related pathologies.
authors.affiliation: Department of Orthopaedic Surgery, Thomas Jefferson University, 1015 Walnut Street, Suite 501 Curtis, Philadelphia, PA, USA. Krysia.Szymczyk@jefferson.edu
authors.forename: K H
authors.initials: KH
authors.lastname: Szymczyk
authors.forename: B A E
authors.initials: BA
authors.lastname: Kerr
authors.forename: T A
authors.initials: TA
authors.lastname: Freeman
authors.forename: C S
authors.initials: CS
authors.lastname: Adams
authors.forename: M J
authors.initials: MJ
authors.lastname: Steinbeck
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D018053:Arsenites / Q000633:toxicity*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D006861:Hydrogen Peroxide / Q000378:metabolism*; D020287:In Situ Nick-End Labeling; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects*; D017670:Sodium Compounds / Q000633:toxicity*; D000071681:Tartrate-Resistant Acid Phosphatase
chemical_list: D018053:Arsenites; D007527:Isoenzymes; D017670:Sodium Compounds; C017947:sodium arsenite; D006861:Hydrogen Peroxide; D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; C015001:arsenite