title: Reactive oxygen species are required for zoledronic acid-induced apoptosis in osteoclast precursors and mature osteoclast-like cells.
abstract: Inhibiting osteoclasts and osteoclast precursors to reduce bone resorption is an important strategy to treat osteoclast-related diseases, such as osteoporosis, inflammatory bone loss, and malignant bone metastasis. However, the mechanism by which apoptosis is induced in the osteoclasts and their precursors are not completely understood. Here, we used nitrogen-containing bisphosphonate zoledronic acid (ZA) to induce cell apoptosis in human and murine osteoclast precursors and mature osteoclast-like cells. Caspase-3-mediated cell apoptosis occurred following the ZA (100 μM) treatment. Reactive oxygen species (ROS) were also generated in a time-dependent manner. Following knock-down of the p47phoxexpression, which is required for ROS activation, or co-treatment with the ROS inhibitor, N-acetyl-L-cysteine, ZA-induced apoptosis was significantly suppressed in both osteoclast precursors and mature osteoclast-like cells. The ROS-activated mitogen-activated protein kinases pathways did not trigger cell apoptosis. However, a ROS-regulated Mcl-1 decrease simultaneously with glycogen synthase kinase (GSK)-3β promoted cell apoptosis. These findings show that ZA induces apoptosis in osteoclast precursors and mature osteoclast-like cells by triggering ROS- and GSK-3β-mediated Mcl-1 down-regulation.
authors.affiliation: Department of Orthopedics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.|Department of Biomedical Engineering, College of Engineering, National Cheng Kung University, Tainan 701, Taiwan.
authors.forename: Ta-Wei
authors.initials: TW
authors.lastname: Tai
authors.affiliation: Department of Orthopedics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
authors.forename: Ching-Yu
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Department of Biomedical Engineering, College of Engineering, National Cheng Kung University, Tainan 701, Taiwan.
authors.forename: Fong-Chin
authors.initials: FC
authors.lastname: Su
authors.affiliation: Department of Orthopedics, E-Da Hospital, Kaohsiung 824, Taiwan.
authors.forename: Yuan-Kun
authors.initials: YK
authors.lastname: Tu
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
authors.forename: Tsung-Ting
authors.initials: TT
authors.lastname: Tsai
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.|Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
authors.forename: Chiou-Feng
authors.initials: CF
authors.lastname: Lin
authors.affiliation: Department of Biomedical Engineering, College of Engineering, National Cheng Kung University, Tainan 701, Taiwan.|Department of Orthopedics, E-Da Hospital, Kaohsiung 824, Taiwan.
authors.forename: I-Ming
authors.initials: IM
authors.lastname: Jou
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004164:Diphosphonates / Q000494:pharmacology*; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism; D000067996:RAW 264.7 Cells; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism; D000074084:THP-1 Cells; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D017382:Reactive Oxygen Species; D000077211:Zoledronic Acid; D000071679:Glycogen Synthase Kinase 3 beta; D053148:Caspase 3; D000111:Acetylcysteine