1. Environmental arginine controls multinuclear giant cell metabolism and formation.
- Author
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Brunner JS, Vulliard L, Hofmann M, Kieler M, Lercher A, Vogel A, Russier M, Brüggenthies JB, Kerndl M, Saferding V, Niederreiter B, Junza A, Frauenstein A, Scholtysek C, Mikami Y, Klavins K, Krönke G, Bergthaler A, O'Shea JJ, Weichhart T, Meissner F, Smolen JS, Cheng P, Yanes O, Menche J, Murray PJ, Sharif O, Blüml S, and Schabbauer G
- Subjects
- Animals, Arthritis genetics, Arthritis metabolism, Arthritis physiopathology, Bone Remodeling, Citric Acid Cycle, Female, Giant Cells cytology, Humans, Interleukin-4 metabolism, Mechanistic Target of Rapamycin Complex 1 genetics, Mechanistic Target of Rapamycin Complex 1 metabolism, Mice, Mice, Inbred C57BL, Osteoclasts cytology, Osteoclasts metabolism, Osteogenesis, RANK Ligand genetics, RANK Ligand metabolism, Arginine metabolism, Giant Cells immunology
- 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.
- Published
- 2020
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