IFN-gamma stimulates osteoclast formation and bone loss in vivo via antigen-driven T cell activation.
T cell-produced cytokines play a pivotal role in the bone loss caused by inflammation, infection, and estrogen deficiency. IFN-gamma is a major product of activated T helper cells that can function as a pro- or antiresorptive cytokine, but the reason why IFN-gamma has variable effects in bone is unknown. Here we show that IFN-gamma 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-alpha. Analysis of the in vivo effects of IFN-gamma in 3 mouse models of bone loss - ovariectomy, LPS injection, and inflammation via silencing of TGF-beta signaling in T cells - reveals that the net effect of IFN-gamma in these conditions is that of stimulating bone resorption and bone loss. In summary, IFN-gamma 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-gamma signaling may thus represent a novel strategy to simultaneously reduce inflammation and bone loss in common forms of osteoporosis.
Gao
Yuhao
Y
Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University, Atlanta, Georgia 30322, USA.
Grassi
Francesco
F
Ryan
Michaela Robbie
MR
Terauchi
Masakazu
M
Page
Karen
K
Yang
Xiaoying
X
Weitzmann
M Neale
MN
Pacifici
Roberto
R
D016301:Alveolar Bone Loss / Q000503:physiopathology*; D000818:Animals; D000941:Antigens / Q000276:immunology; D007371:Interferon-gamma / Q000494:pharmacology*; D008213:Lymphocyte Activation; D051379:Mice; D023421:Models, Animal; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D053245:RANK Ligand / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology*
D000941:Antigens; D053245:RANK Ligand; D011994:Recombinant Proteins; D007371:Interferon-gamma