IFN-γ stimulates osteoclast formation and bone loss in vivo via antigen-driven T cell activation

Yuhao Gao, Francesco Grassi, Michaela Robbie Ryan, Masakazu Terauchi, Karen Page, Xiaoying Yang, M. Neale Weitzmann, Roberto Pacifici

Research output: Contribution to journalArticle

Abstract

T cell-produced cytokines play a pivotal role in the bone loss caused by inflammation, infection, and estrogen deficiency. IFN-γ is a major product of activated T helper cells that can function as a pro- or antiresorptive cytokine, but the reason why IFN-γ has variable effects in bone is unknown. Here we show that IFN-γ blunts osteoclast formation through direct targeting of osteoclast precursors but indirectly stimulates osteoclast formation and promotes bone resorption by stimulating antigen-dependent T cell activation and T cell secretion of the osteoclastogenic factors RANKL and TNF-α. Analysis of the in vivo effects of IFN-γ in 3 mouse models of bone loss - ovariectomy, LPS injection, and inflammation via silencing of TGF-β signaling in T cells - reveals that the net effect of IFN-γ in these conditions is that of stimulating bone resorption and bone loss. In summary, IFN-γ has both direct anti-osteoclastogenic and indirect pro-osteoclastogenic properties in vivo. Under conditions of estrogen deficiency, infection, and inflammation, the net balance of these 2 opposing forces is biased toward bone resorption. Inhibition of IFN-γ signaling may thus represent a novel strategy to simultaneously reduce inflammation and bone loss in common forms of osteoporosis.

Original languageEnglish
Pages (from-to)122-132
Number of pages11
JournalJournal of Clinical Investigation
Volume117
Issue number1
DOIs
Publication statusPublished - Jan 4 2007

ASJC Scopus subject areas

  • Medicine(all)

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    Gao, Y., Grassi, F., Ryan, M. R., Terauchi, M., Page, K., Yang, X., Weitzmann, M. N., & Pacifici, R. (2007). IFN-γ stimulates osteoclast formation and bone loss in vivo via antigen-driven T cell activation. Journal of Clinical Investigation, 117(1), 122-132. https://doi.org/10.1172/JCI30074