Abstract |
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.
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Authors | Shi Wei, Hideki Kitaura, Ping Zhou, F Patrick Ross, Steven L Teitelbaum |
Journal | The Journal of clinical investigation
(J Clin Invest)
Vol. 115
Issue 2
Pg. 282-90
(Feb 2005)
ISSN: 0021-9738 [Print] United States |
PMID | 15668736
(Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Carrier Proteins
- Interleukin-1
- Membrane Glycoproteins
- RANK Ligand
- Receptor Activator of Nuclear Factor-kappa B
- Receptors, Interleukin-1
- Receptors, Interleukin-1 Type I
- Tnfrsf11a protein, mouse
- Tnfsf11 protein, mouse
- Tumor Necrosis Factor-alpha
- p38 Mitogen-Activated Protein Kinases
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Topics |
- Animals
- Bone Marrow Cells
(cytology, physiology)
- Carrier Proteins
- Cell Differentiation
(genetics, physiology)
- Cells, Cultured
- Coculture Techniques
- Gene Expression Regulation
(genetics, physiology)
- Interleukin-1
(physiology)
- MAP Kinase Signaling System
(genetics, physiology)
- Macrophages
(physiology)
- Membrane Glycoproteins
- Mice
- Mice, Knockout
- Osteoclasts
(physiology)
- Osteolysis
(genetics, psychology)
- RANK Ligand
- Receptor Activator of Nuclear Factor-kappa B
- Receptors, Interleukin-1
(genetics, metabolism)
- Receptors, Interleukin-1 Type I
- Stem Cells
(physiology)
- Stromal Cells
- Tumor Necrosis Factor-alpha
(physiology)
- p38 Mitogen-Activated Protein Kinases
(metabolism)
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