IL-7 induces bone loss in vivo by induction of receptor activator of nuclear factor kappa B ligand and tumor necrosis factor alpha from T cells.
IL-7, a powerful lymphopoietic cytokine, is elevated in rheumatoid arthritis (RA) and known to induce bone loss when administered in vivo. IL-7 has been suggested to induce bone loss, in part, by stimulating the proliferation of B220(+) cells, a population capable of acting as early osteoclast (OC) precursors. However, the mechanism by which IL-7 leads to differentiation of precursors into mature OCs remains unknown. We previously reported that, in vitro, IL-7 up-regulated T cell cytokines including receptor activator of nuclear factor kappaB ligand (RANKL). To demonstrate the importance of T cells to the bone-wasting effect of IL-7 in vivo, we have now examined IL-7-induced bone loss in T cell-deficient nude mice. We show that T cell-replete mice undergo significant osteoclastic bone loss after IL-7 administration, concurrent with induction of RANKL and tumor necrosis factor alpha (TNF-alpha) secretion by splenic T cells. In contrast, nude mice were resistant to IL-7-induced bone loss and showed no detectable increase in either RANKL or TNF-alpha, despite an up-regulation of B220(+) cells. Importantly, T cell adoptive transfer into nude mice restored IL-7-induced bone loss, and RANKL and TNF-alpha secretion, demonstrating that T cells are essential mediators of IL-7-induced bone loss in vivo.
Toraldo
Gianluca
G
Division of Bone and Mineral Diseases, Washington University School of Medicine and Barnes-Jewish Hospital, St. Louis, MO 63110, USA.
Roggia
Cristiana
C
Qian
Wei-Ping
WP
Pacifici
Roberto
R
Weitzmann
M Neale
MN
D019264:Adoptive Transfer; D000818:Animals; D001862:Bone Resorption / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D006023:Glycoproteins / Q000378:metabolism; D015851:Interleukin-7 / Q000494:pharmacology*; D017710:Lymphocyte Transfusion; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism*; D010010:Osteoclasts / Q000276:immunology; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
D002352:Carrier Proteins; D006023:Glycoproteins; D015851:Interleukin-7; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505687:Tnfrsf11a protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D014409:Tumor Necrosis Factor-alpha