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

研究成果: Article査読

15 被引用数 (Scopus)

抄録

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.

本文言語English
論文番号431
ジャーナルNature communications
11
1
DOI
出版ステータスPublished - 2020 12月 1

ASJC Scopus subject areas

  • 化学 (全般)
  • 生化学、遺伝学、分子生物学(全般)
  • 一般
  • 物理学および天文学(全般)

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