Environmental arginine controls multinuclear giant cell metabolism and formation

Julia S. Brunner, Loan Vulliard, Melanie Hofmann, Markus Kieler, Alexander Lercher, Andrea Vogel, Marion Russier, Johanna B. Brüggenthies, Martina Kerndl, Victoria Saferding, Birgit Niederreiter, Alexandra Junza, Annika Frauenstein, Carina Scholtysek, Yohei Mikami, Kristaps Klavins, Gerhard Krönke, Andreas Bergthaler, John J. O’Shea, Thomas WeichhartFelix Meissner, Josef S. Smolen, Paul Cheng, Oscar Yanes, Jörg Menche, Peter J. Murray, Omar Sharif, Stephan Blüml, Gernot Schabbauer

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Multinucleated giant cells (MGCs) are implicated in many diseases including schistosomiasis, sarcoidosis and arthritis. MGC generation is energy intensive to enforce membrane fusion and cytoplasmic expansion. Using receptor activator of nuclear factor kappa-Β ligand (RANKL) induced osteoclastogenesis to model MGC formation, here we report RANKL cellular programming requires extracellular arginine. Systemic arginine restriction improves outcome in multiple murine arthritis models and its removal induces preosteoclast metabolic quiescence, associated with impaired tricarboxylic acid (TCA) cycle function and metabolite induction. Effects of arginine deprivation on osteoclastogenesis are independent of mTORC1 activity or global transcriptional and translational inhibition. Arginine scarcity also dampens generation of IL-4 induced MGCs. Strikingly, in extracellular arginine absence, both cell types display flexibility as their formation can be restored with select arginine precursors. These data establish how environmental amino acids control the metabolic fate of polykaryons and suggest metabolic ways to manipulate MGC-associated pathologies and bone remodelling.

Original languageEnglish
Article number431
JournalNature communications
Volume11
Issue number1
DOIs
Publication statusPublished - 2020 Dec 1

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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  • Cite this

    Brunner, J. S., Vulliard, L., Hofmann, M., Kieler, M., Lercher, A., Vogel, A., Russier, M., Brüggenthies, J. B., Kerndl, M., Saferding, V., Niederreiter, B., Junza, A., Frauenstein, A., Scholtysek, C., Mikami, Y., Klavins, K., Krönke, G., Bergthaler, A., O’Shea, J. J., ... Schabbauer, G. (2020). Environmental arginine controls multinuclear giant cell metabolism and formation. Nature communications, 11(1), [431]. https://doi.org/10.1038/s41467-020-14285-1