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IL-1 mediates TNF-induced osteoclastogenesis.

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.
AuthorsShi Wei, Hideki Kitaura, Ping Zhou, F Patrick Ross, Steven L Teitelbaum
JournalThe Journal of clinical investigation (J Clin Invest) Vol. 115 Issue 2 Pg. 282-90 (Feb 2005) ISSN: 0021-9738 [Print] United States
PMID15668736 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
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
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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