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.

Chemotactic and Immunoregulatory Properties of Bone Cells are Modulated by Endotoxin-Stimulated Lymphocytes

“…Moreover, LPS-pulsed splenocytes enhanced OCL differentiation, confirming that inflammatory environment lead to bone destruction as a serious complication of bacterial infections of bones or adjacent tissues [6,9,[12][13][14][15][16]37]. In conclusion, our results demonstrate that there is a bidirectional communication during endotoxin-induced inflammation between bone and immune cells.…”

“…In conclusion, our results demonstrate that there is a bidirectional communication during endotoxin-induced inflammation between bone and immune cells. We are aware of the limitation of our co-culture system being in vitro model to mimic the inflammatory environment, but it provides a specific setting in which we excluded the direct effects that LPS has on bone cells [9,12,26,47]. LPS-pulsed lymphocytes stimulate bone resorption by enhancing OCL and suppressing OBL differentiation with increased RANKL/OPG ratio, while bone cells create a chemotactic gradient and enhance the production of RANKL by T lymphocyte.…”

“…LPS promotes bone resorption in mice, by stimulating pro-inflammatory cytokines, antigen presentation and OBL expression of osteoclastogenic cytokines RANKL and tumor necrosis factor (TNF)-α [9][10][11][12]. B lymphocytes, highly susceptible to LPS, additionally contribute to osteoclastogenic effect of LPS in vitro and in vivo [13][14].…”

Ovariectomy disregulates osteoblast and osteoclast formation through the T-cell receptor CD40 ligand

“…This phenomenon results from enhanced thymic-dependent differentiation of BM-derived progenitors and peripheral expansion of mature T cells (41,42). Ovx causes the peripheral expansion of T cells by enhancing antigen presentation through increased expression of MHCII (41,43), which, in turn, is driven by a complex mechanism that involves increased production of IFN-γ and IL-7, blunted generation of TGF-β in the BM (22,25,41,44), and up-regulation of the costimulatory molecule CD80 on dendritic cells secondary to increased oxidative stress (43,45).…”

The roles of immune cells in bone healing; what we know, do not know and future perspectives

“…Furthermore, TNF-a stimulates the production of M-CSF by MSCs that in turn, induce the differentiation of osteoclast progenitors [119]. Similarly, IFN-g has a positive influence on the osteoclastogenesis [120]. Furthermore, IL-1 and IL-17 has been linked to the bone loss within highly inflammatory milieu [121,122].…”