Aberrant bone resorption by osteoclasts causes bone destruction in joint diseases such as rheumatoid arthritis (RA). The generation of osteoclasts is influenced by cytokines in the surrounding environment, such as receptor activator of NF-κB ligand (RANKL), and might also be affected by extracellular nutrients. A new study published in Nature Communications shows that depletion of the amino acid arginine attenuates osteoclastogenesis and ameliorates arthritis in mice.
“We previously showed that arginase 1 was actively secreted by alternatively activated macrophages in the context of autoimmunity,” explains Gernot Schabbauer, co-corresponding author on the new study. “This finding led us to believe that arginase 1-mediated extracellular arginine degradation could be important in regulating autoimmunity, by dampening immune cell metabolism.”
To test whether depletion of systemic arginine could alter cellular metabolism in bone and impede the progression of inflammatory arthritis, the authors investigated the effects of a recombinant modified form of arginase 1 (recArg1) in vitro and in mouse models of disease.
“By combining mouse models of arthritis with omics approaches (transcriptomics, proteomics and metabolomics) in the presence and absence of recArg1, we showed that RANKL-mediated osteoclastogenesis depends on extracellular arginine,” says co-corresponding author Stephan Blüml. “Systemic arginine restriction improved outcomes in diverse mouse arthritis models, especially regarding osteoclast-mediated bone destruction.”
Arginine depletion prevented the transcriptional and metabolic effects of RANKL and led to metabolic quiescence of osteoclast precursor cells. The effects of arginine restriction on osteoclast formation were reversible, and arginine precursors could compensate for their absence.
depletion of the amino acid arginine attenuates osteoclastogenesis
“We plan to test the importance of extracellular arginine depletion in other multinucleated giant cell-mediated diseases,” explains Schabbauer. “Looking into the future, our work might pave the way to test dietary interventions such as avoidance of arginine-rich food for arthritis management,” concludes Blüml.
Brunner, J. S. et al. Environmental arginine controls multinuclear giant cell metabolism and formation. Nat. Commun. 11, 431 (2020)
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McHugh, J. Arginine restriction attenuates bone loss in arthritis. Nat Rev Rheumatol 16, 128 (2020). https://doi.org/10.1038/s41584-020-0387-3