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PLoS One. 2016 Jan 11;11(1):e0146544. doi: 10.1371/journal.pone.0146544. eCollection 2016.

Osteoprotegerin Regulates Pancreatic β-Cell Homeostasis upon Microbial Invasion.

Author information

1
Laboratory of Cell and Tissue Biology, Keio University School of Medicine, Tokyo, Japan.
2
Laboratory of Host Defense, WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan.
3
Department of Immunology Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
4
Mycobacterial Reference Center, The Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association, Tokyo, Japan.
5
Department of Systems Medicine, The Sakaguchi Laboratory, Keio University School of Medicine, Tokyo, Japan.
6
Nagahama Institute for Biochemical Science, Oriental Yeast Co., Shiga, Japan.
7
Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, Tokyo, Japan.

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.

PMID:
26751951
PMCID:
PMC4709133
DOI:
10.1371/journal.pone.0146544
[Indexed for MEDLINE]
Free PMC Article

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