IL-1 mediates TNF-induced osteoclastogenesis

J Clin Invest. 2005 Feb;115(2):282-90. doi: 10.1172/JCI23394.

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Bone Marrow Cells / cytology*
  • Bone Marrow Cells / physiology
  • Carrier Proteins
  • Cell Differentiation / genetics
  • Cell Differentiation / physiology*
  • Cells, Cultured
  • Coculture Techniques
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / physiology
  • Interleukin-1 / physiology*
  • MAP Kinase Signaling System / genetics
  • MAP Kinase Signaling System / physiology
  • Macrophages / physiology
  • Membrane Glycoproteins
  • Mice
  • Mice, Knockout
  • Osteoclasts / physiology*
  • Osteolysis / genetics
  • Osteolysis / psychology
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Receptors, Interleukin-1 / genetics
  • Receptors, Interleukin-1 / metabolism
  • Receptors, Interleukin-1 Type I
  • Stem Cells / physiology*
  • Stromal Cells
  • Tumor Necrosis Factor-alpha / physiology*
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • 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