title: Osteoprotegerin Regulates Pancreatic β-Cell Homeostasis upon Microbial Invasion.
abstract: Osteoprotegerin (OPG), a decoy receptor for receptor activator of NF-κB ligand (RANKL), antagonizes RANKL's osteoclastogenic function in bone. We previously demonstrated that systemic administration of lipopolysaccharide (LPS) to mice elevates OPG levels and reduces RANKL levels in peripheral blood. Here, we show that mice infected with Salmonella, Staphylococcus, Mycobacteria or influenza virus also show elevated serum OPG levels. We then asked whether OPG upregulation following microbial invasion had an effect outside of bone. To do so, we treated mice with LPS and observed OPG production in pancreas, especially in β-cells of pancreatic islets. Insulin release following LPS administration was enhanced in mice lacking OPG, suggesting that OPG inhibits insulin secretion under acute inflammatory conditions. Consistently, treatment of MIN6 pancreatic β-cells with OPG decreased their insulin secretion following glucose stimulation in the presence of LPS. Finally, our findings suggest that LPS-induced OPG upregulation is mediated in part by activator protein (AP)-1 family transcription factors, particularly Fos proteins. Overall, we report that acute microbial infection elevates serum OPG, which maintains β-cell homeostasis by restricting glucose-stimulated insulin secretion, possibly preventing microbe-induced exhaustion of β-cell secretory capacity.
authors.affiliation: Laboratory of Cell and Tissue Biology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Kuroda
authors.affiliation: Laboratory of Host Defense, WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Maruyama
authors.affiliation: Department of Immunology Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Fujii
authors.affiliation: Mycobacterial Reference Center, The Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association, Tokyo, Japan.
authors.forename: Isamu
authors.initials: I
authors.lastname: Sugawara
authors.affiliation: Department of Systems Medicine, The Sakaguchi Laboratory, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Shigeru B H
authors.initials: SB
authors.lastname: Ko
authors.affiliation: Nagahama Institute for Biochemical Science, Oriental Yeast Co., Shiga, Japan.
authors.forename: Hisataka
authors.initials: H
authors.lastname: Yasuda
authors.affiliation: Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Matsui
authors.affiliation: Laboratory of Cell and Tissue Biology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Matsuo
mesh_terms: D000818:Animals; D002460:Cell Line; D005260:Female; D006706:Homeostasis / Q000187:drug effects; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008817:Mice, Mutant Strains; D009161:Mycobacterium / Q000502:physiology; D016761:Oncogene Proteins v-fos / Q000378:metabolism; D053244:Osteoprotegerin / Q000378:metabolism* / Q000494:pharmacology; D053245:RANK Ligand / Q000378:metabolism; D012475:Salmonella / Q000502:physiology; D013210:Staphylococcus / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D016761:Oncogene Proteins v-fos; D053244:Osteoprotegerin; D053245:RANK Ligand; D018808:Transcription Factor AP-1