期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 117, 期 1, 页码 122-132出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI30074
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资金
- NATIONAL CANCER INSTITUTE [U54CA119338] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [R01AR049659] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK055746, R21DK067389] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG028278] Funding Source: NIH RePORTER
- NCI NIH HHS [U54CA119338, U54 CA119338] Funding Source: Medline
- NIAMS NIH HHS [R01 AR049659, AR 49659] Funding Source: Medline
- NIA NIH HHS [AG 28278, R01 AG028278] Funding Source: Medline
- NIDDK NIH HHS [R01 DK055746, R21 DK067389, DK67389, DK55746] Funding Source: Medline
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.
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