IL-1 mediates TNF-induced osteoclastogenesis.
TNF-induced receptor activator NF-kappaB ligand (RANKL) synthesis by bone marrow stromal cells is a fundamental component of inflammatory osteolysis. We found that this process was abolished by IL-1 receptor antagonist (IL-1Ra) or in stromal cells derived from type I IL-1 receptor-deficient (IL-1RI-deficient) mice. Reflecting sequential signaling of the cytokines TNF and IL-1, TNF induces stromal cell expression of IL-1 and IL-1RI. These data suggest that TNF regulates RANKL expression via IL-1, and, therefore, IL-1 plays a role in TNF-induced periarticular osteolysis. Consistent with this posture, TNF-stimulated osteoclastogenesis in cultures consisting of WT marrow macrophages and stromal cells exposed to IL-1Ra or in cocultures established with IL-1RI-deficient stromal cells was reduced approximately 50%. The same magnitude of osteoclast inhibition occurred in IL-1RI-deficient mice following TNF administration in vivo. Like TNF, IL-1 directly targeted osteoclast precursors and promoted the osteoclast phenotype in a TNF-independent manner in the presence of permissive levels of RANKL. IL-1 is able to induce RANKL expression by stromal cells and directly stimulate osteoclast precursor differentiation under the aegis of p38 MAPK. Thus, IL-1 mediates the osteoclastogenic effect of TNF by enhancing stromal cell expression of RANKL and directly stimulating differentiation of osteoclast precursors.
Wei
Shi
S
Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Kitaura
Hideki
H
Zhou
Ping
P
Ross
F Patrick
FP
Teitelbaum
Steven L
SL
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology* / Q000502:physiology; D002352:Carrier Proteins; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D007375:Interleukin-1 / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000502:physiology; D008264:Macrophages / Q000502:physiology; D008562:Membrane Glycoproteins; D051379:Mice; D018345:Mice, Knockout; D010010:Osteoclasts / Q000502:physiology*; D010014:Osteolysis / Q000235:genetics / Q000523:psychology; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism; D053573:Receptors, Interleukin-1 Type I; D013234:Stem Cells / Q000502:physiology*; D017154:Stromal Cells; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D002352:Carrier Proteins; D007375:Interleukin-1; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D017472:Receptors, Interleukin-1; D053573:Receptors, Interleukin-1 Type I; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases