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Blood, 1 September 2000, Vol. 96, No. 5, pp. 1873-1878
IMMUNOBIOLOGY
Interleukin-7 stimulates osteoclast formation by up-regulating
the T-cell production of soluble osteoclastogenic cytokines
M. Neale Weitzmann,
Simone Cenci,
Leonard Rifas,
Christopher Brown, and
Roberto Pacifici
From the Division of Bone and Mineral Diseases,
Washington University School of Medicine and Barnes-Jewish Hospital, St
Louis, MO, and Division of Hematology, University of Calgary, Calgary,
Canada.
In unstimulated conditions osteoclast renewal occurs as a result of
the stromal cell production of the key osteoclastogenic factors,
receptor activator of NFkB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). Inflammation is known to cause increased osteoclastogenesis; however, the mechanisms responsible for
this phenomenon are poorly understood. We now show that
interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF ),
cytokines 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 both RANKL and M-CSF,
saturating concentrations of osteoprotegerin failed to inhibit
approximately 40% of the OC formation, suggesting that IL-7 acts via
both RANKL-dependent and RANKL-independent pathways. Despite the
identification of T-cell-secreted M-CSF, this cytokine was not
essential for either RANKL-dependent or -independent OC formation,
suggesting that T cells secrete other cytokines capable of substituting
for M-CSF action. On the basis of our data, we propose a novel
mechanism for inflammatory bone loss in which induction of IL-7 from
stromal cells by IL-1 and TNF leads to the production of soluble
osteoclastogenic cytokines by T cells. Thus, the mechanism by which
IL-7 causes bone resorption involves the activation of T cells
and the T-cell-dependent augmentation of osteoclastogenesis.
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