Environmental arginine controls multinuclear giant cell metabolism and formation

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

doi:10.1038/s41467-020-14285-1

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.

Highlights

Multinucleated giant cells (MGCs) are implicated in many diseases including schistosomiasis, sarcoidosis and arthritis
Local cathepsin K (Ctsk), Acp[5] and Tnf transcripts increased in paws of ill versus healthy animals, confirming that the disease was linked to elevated osteoclastogenesis and inflammation
While previous studies highlighted an importance for cellular arginase 1 (ARG1) in negatively regulating osteoclastogenesis[36], here we demonstrate that extracellular arginine is essential for RANKLinduced metabolism

Summary

Introduction

Multinucleated giant cells (MGCs) are implicated in many diseases including schistosomiasis, sarcoidosis and arthritis. 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. We reasoned that manipulating environmental arginine could alter local cellular metabolism within bone, possibly through impacts on tissue resident osteoclasts and change the trajectory of arthritis-induced bone loss. To test this hypothesis, we used recArg[1] to study the effects of arginine depletion in arthritis and osteoclastogenesis. Our results highlight the importance of environmental arginine in MGC development and show therapeutic effects of systemic extracellular arginine depletion in murine arthritis

Methods

Results

Conclusion