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IFN-γ stimulates osteoclast formation and bone loss in vivo via antigen-driven T cell activation
Yuhao Gao, … , M. Neale Weitzmann, Roberto Pacifici
Yuhao Gao, … , M. Neale Weitzmann, Roberto Pacifici
Published January 2, 2007
Citation Information: J Clin Invest. 2007;117(1):122-132. https://doi.org/10.1172/JCI30074.
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Categories: Research Article Bone biology

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

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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.

Authors

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

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Figure 2

Systemic administration of rIFN-γ stimulates bone resorption in WT mice and nude mice reconstituted with WT T cells (Nude + T), but not in T cell–deficient nude mice.

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Systemic administration of rIFN-γ stimulates bone resorption in WT mice ...
rIFN-γ (1 × 106 IU/kg body weight) was injected subcutaneously twice a week into 16-week-old WT mice, T cell–deficient nude mice, and nude mice reconstituted with WT T cells, and spine BMD (A); serum CTX (B) and serum osteocalcin levels (C); and T cell production of TNF (D), RANKL (E), and IFN-γ (F) were measured 3 weeks after initial IFN-γ injection. The percentages in A represent the change compared with baseline. All data are expressed as mean ± SD. *P < 0.05 compared with vehicle-treated controls. ND, not detectable.
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