Interleukin-7 stimulates osteoclast formation by up-regulating the T-cell production of soluble osteoclastogenic cytokines

In unstimulated conditions osteoclast renewal occurs as a result of the str omal cell production of the key osteoclastogenic factors, receptor activato r of NFkB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF), Inflammation is known to cause increased osteoclastogenesis; however, the m echanisms responsible for this phenomenon are poorly understood. We now sho w that interleukin-1 (II-1) and tumor necrosis factor alpha (TNF alpha), cy tokines typically produced in inflammatory conditions, increase the stromal cell production of IL-7, This factor, in turn, up-regulates production of osteoclastogenic cytokines by T cells leading to stimulation of osteoclast (OC) formation. Although T cells were found to produce soluble forms of bot h RANKL and M-CSF, saturating concentrations of osteoprotegerin failed to i nhibit approximately 40% of the OC formation, suggesting that IL-7 acts via both RANKL-dependent and RANKL-independent pathways, Despite the identific ation of T-cell-secreted M-CSF, this cytokine was not essential for either RANKL-dependent or -independent OC formation, suggesting that T cells secre te other cytokines capable of substituting for M-CSF action, On the basis o f our data, we propose a novel mechanism for inflammatory bone loss in whic h induction of IL-7 from stromal cells by IL-l and TNF alpha leads to the p roduction of soluble osteoclastogenic cytokines by T cells. Thus, the mecha nism by which IL-7 causes bone resorption involves the activation of T cell s and the T-cell-dependent augmentation of osteoclastogenesis, (C) 2000 by The American Society of Hematology.