Osteoprotegerin Regulates Pancreatic β-Cell Homeostasis upon Microbial Invasion

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Female
  • Homeostasis / drug effects
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / metabolism*
  • Lipopolysaccharides / pharmacology
  • Mice
  • Mice, Mutant Strains
  • Mycobacterium / physiology
  • Oncogene Proteins v-fos / metabolism
  • Osteoprotegerin / metabolism*
  • Osteoprotegerin / pharmacology
  • RANK Ligand / metabolism
  • Salmonella / physiology
  • Staphylococcus / physiology
  • Transcription Factor AP-1 / metabolism

Substances

  • Lipopolysaccharides
  • Oncogene Proteins v-fos
  • Osteoprotegerin
  • RANK Ligand
  • Transcription Factor AP-1

Grant support

This work was supported by Keio Gijuku Academic Development Funds (YK), the Ministry of Health, Labor and Welfare of Japan 201322003A (KM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The Oriental Yeast Co. provided support in the form of a salary for author HY, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of this author is articulated in the Author Contributions section.