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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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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 4

Effects of LPS treatment for 3 weeks in WT and IFN-γ–/– mice.

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Effects of LPS treatment for 3 weeks in WT and IFN-γ–/– mice.
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LPS (25 mg/kg body weight) was injected once a week in 16-week-old mice. All mice were sacrificed at the end of the LPS treatment and bone, BM, and serum samples analyzed. (A) In vivo BMD measurements by DXA were obtained at baseline and weekly thereafter. (B) Analysis of BV/TV by μCT. (C) Serum CTX. (D) Serum osteocalcin. (E) Antigen presentation assay. (F) Measurement of CD4 and CD69 expression by flow cytometric analysis. 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. #P < 0.05 compared with LPS-treated WT mice.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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