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 Weichhart, Felix Meissner, Josef S. Smolen, Paul Cheng, Oscar Yanes, Jörg Menche, Peter J. Murray, Omar Sharif, Stephan Blüml () and Gernot Schabbauer ()
Additional contact information
Julia S. Brunner: Medical University Vienna
Loan Vulliard: CeMM Research Centre for Molecular Medicine of the Austrian Academy of Sciences
Melanie Hofmann: Medical University Vienna
Markus Kieler: Medical University Vienna
Alexander Lercher: CeMM Research Centre for Molecular Medicine of the Austrian Academy of Sciences
Andrea Vogel: Medical University Vienna
Marion Russier: Max Planck Institute of Biochemistry
Johanna B. Brüggenthies: Max Planck Institute of Biochemistry
Martina Kerndl: Medical University Vienna
Victoria Saferding: Medical University of Vienna
Birgit Niederreiter: Medical University of Vienna
Alexandra Junza: CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM)
Annika Frauenstein: Max Planck Institute of Biochemistry
Carina Scholtysek: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen
Yohei Mikami: National Institutes of Health
Kristaps Klavins: CeMM Research Centre for Molecular Medicine of the Austrian Academy of Sciences
Gerhard Krönke: Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen
Andreas Bergthaler: CeMM Research Centre for Molecular Medicine of the Austrian Academy of Sciences
John J. O’Shea: National Institutes of Health
Thomas Weichhart: Medical University of Vienna
Felix Meissner: Max Planck Institute of Biochemistry
Josef S. Smolen: Medical University of Vienna
Paul Cheng: Bio Cancer Treatment International Ltd.
Oscar Yanes: CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM)
Jörg Menche: CeMM Research Centre for Molecular Medicine of the Austrian Academy of Sciences
Peter J. Murray: Max Planck Institute of Biochemistry
Omar Sharif: Medical University Vienna
Stephan Blüml: Christian Doppler Laboratory for Arginine Metabolism in Rheumatoid Arthritis and Multiple Sclerosis
Gernot Schabbauer: Medical University Vienna

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14285-1

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