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.
View: Text | PDF
Research Article Bone biology

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

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

×

Figure 1

IFN-γ directly suppresses and indirectly stimulates osteoclastogenesis in vitro.

Options: View larger image (or click on image) Download as PowerPoint
IFN-γ directly suppresses and indirectly stimulates osteoclastogenesis i...
(A) rIFN-γ suppresses osteoclastogenesis induced by RANKL (50 ng/ml) and M-CSF (10 ng/ml) in macrophages purified from BM and spleen. #P < 0.01 compared with vehicle-treated controls. (B) Cytokine levels in CM derived from cocultures of IFN-γ–pretreated WT macrophages and OT-II T cells were measured using ELISA. *P < 0.05 compared with vehicle-treated controls. (C) The expression of T cell cytokine mRNA was measured by real-time RT-PCR in T cells cocultured with rIFN-γ–pretreated macrophages. #P < 0.01 compared with vehicle-pretreated controls. (D) The ability of CM from cocultures of rIFN-γ–pretreated macrophages and OT-II T cells to enhance M-CSF– and RANKL-stimulated osteoclastogenesis was examined in macrophages from WT and IFN-γR–/– mice. *P < 0.05 compared with vehicle-treated controls. (E) The ability of CM from coculture of macrophages from sham-operated or ovx WT mice and OT-II T cells to induce osteoclastogenesis was examined in macrophages from WT mice in the presence of M-CSF and RANKL with or without neutralizing IFN-γ Ab (10 μg/ml ). *P < 0.05 compared with vehicle-treated controls. The proliferation (F) and rate of apoptosis (G) of maturing osteoclasts were determined by [3H]thymidine incorporation and intracellular caspase-3 activity in 3-day cultures of RANKL- and M-CSF–stimulated BMMs cultured in the presence of activated T cell CM and Abs directed against IFN-γ, TNF, and RANKL. *P < 0.05 compared with irrelevant IgG-treated controls. All data are expressed as mean ± SD.