title: Activation of p38 MAPK-regulated Bcl-xL signaling increases survival against zoledronic acid-induced apoptosis in osteoclast precursors.
abstract: The nitrogen-containing bisphosphonate zoledronic acid (ZA) induces apoptosis in osteoclasts and inhibits osteoclast-mediated bone resorption. It is widely used to treat osteoporosis. However, some patients are less responsive to ZA treatment, and the mechanisms of resistance are still unclear. Here, we identified that murine osteoclast precursors may develop resistance to ZA-induced apoptosis. These resistant cells survived the apoptotic effect of ZA following an increase in anti-apoptotic Bcl-xL. Pharmacologically inhibiting Bcl-xL facilitated ZA-induced apoptosis. Treatment with ZA activated p38 MAPK, increasing Bcl-xL expression and cell survival. Nuclear import of β-catenin regulated by p38 MAPK determined Bcl-xL mRNA expression and cell survival in response to ZA. ZA also inactivated glycogen synthase kinase (GSK)-3β, a negative upstream regulator of β-catenin, in a p38 MAPK-mediated manner. Synergistic pharmacological inhibition of p38 MAPK with ZA attenuated receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast differentiation and facilitated ZA-induced apoptosis. These results demonstrate that elevated Bcl-xL expression mediated by p38 MAPK-regulated GSK-3β/β-catenin signaling is required for cell survival of ZA-induced apoptosis in both osteoclast precursors and osteoclasts. Finally, we demonstrated that inhibiting p38 MAPK-mediated pathway enhanced ZA effect on increasing the bone mineral density of ovariectomized mice. This result suggests that targeting these pathways may represent a potential therapeutic strategy.
authors.affiliation: Institute of Biomedical Engineering, National Cheng Kung University, Tainan, Taiwan; Department of Orthopaedics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Orthopaedics, Hsinhua Branch, Tainan Hospital, Tainan, Taiwan.
authors.forename: Ta-Wei
authors.initials: TW
authors.lastname: Tai
authors.affiliation: Institute of Biomedical Engineering, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Fong-Chin
authors.initials: FC
authors.lastname: Su
authors.affiliation: Department of Orthopaedics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Ching-Yu
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Department of Orthopaedics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Electronic address: jming@mail.ncku.edu.tw.
authors.forename: I-Ming
authors.initials: IM
authors.lastname: Jou
authors.affiliation: Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Microbiology and Immunology, College of Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address: cflin@mail.ncku.edu.tw.
authors.forename: Chiou-Feng
authors.initials: CF
authors.lastname: Lin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D000077211:Zoledronic Acid; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: C494812:Bcl2l1 protein, mouse; D004164:Diphosphonates; D007093:Imidazoles; D051020:bcl-X Protein; D000077211:Zoledronic Acid; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Bcl-xL; Osteoclast precursor; Osteoporosis; Zoledronic acid; p38 MAPK; β-Catenin