Journal Article

Environmental arginine controls multinuclear giant cell metabolism and formation

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

2020

Overview

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. Multinucleated giant cells (MGCs) are important in the pathogenesis of various diseases. Here, the authors demonstrate that extracellular presence of the amino acid arginine is required for MGC formation and metabolism, suggesting a translational impact for strategies utilizing systemic arginine depletion in MGC-mediated diseases.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/106 / 45/91 / 64/60 / 692/4023/808 / 692/698/690/797 / 692/699/1670/407 / 82/58 / 82/80 / 96/95 / Amino acids / Animal models / Animals / Arginine / Arginine - metabolism / Arthritis / Arthritis - genetics / Arthritis - metabolism / Arthritis - physiopathology / Biomedical materials / Bone Remodeling / Citric Acid Cycle / Depletion / Deprivation / Female / Giant cells / Giant Cells - cytology / Giant Cells - immunology / Humanities and Social Sciences / Humans / Interleukin 4 / Interleukin-4 - metabolism / Mechanistic Target of Rapamycin Complex 1 - genetics / Mechanistic Target of Rapamycin Complex 1 - metabolism / Membrane fusion / Metabolism / Metabolites / Mice / Mice, Inbred C57BL / multidisciplinary / Osteoclastogenesis / Osteoclasts - cytology / Osteoclasts - metabolism / Osteogenesis / Pathogenesis / RANK Ligand - genetics / RANK Ligand - metabolism / Sarcoidosis / Schistosomiasis / Science / Science (multidisciplinary) / TRANCE protein / Transcription / Translation / Tricarboxylic acid cycle