Interleukin-33 is expressed in differentiated osteoblasts and blocks osteoclast formation from bone marrow precursor cells

J Bone Miner Res. 2011 Apr;26(4):704-17. doi: 10.1002/jbmr.269.


Since the hematopoetic system is located within the bone marrow, it is not surprising that recent evidence has demonstrated the existence of molecular interactions between bone and immune cells. While interleukin 1 (IL-1) and IL-18, two cytokines of the IL-1 family, have been shown to regulate differentiation and activity of bone cells, the role of IL-33, another IL-1 family member, has not been addressed yet. Since we observed that the expression of IL-33 increases during osteoblast differentiation, we analyzed its possible influence on bone formation and observed that IL-33 did not affect matrix mineralization but enhanced the expression of Tnfsf11, the gene encoding RANKL. This finding led us to analyze the skeletal phenotype of Il1rl1-deficient mice, which lack the IL-33 receptor ST2. Unexpectedly, these mice displayed normal bone formation but increased bone resorption, thereby resulting in low trabecular bone mass. Since this finding suggested a negative influence of IL-33 on osteoclastogenesis, we next analyzed osteoclast differentiation from bone marrow precursor cells and observed that IL-33 completely abolished the generation of TRACP(+) multinucleated osteoclasts, even in the presence of RANKL and macrophage colony-stimulating factor (M-CSF). Although our molecular studies revealed that IL-33 treatment of bone marrow cells caused a shift toward other hematopoetic lineages, we further observed a direct negative influence of IL-33 on the osteoclastogenic differentiation of RAW264.7 macrophages, where IL-33 repressed the expression of Nfatc1, which encodes one of the key transciption factors of osteoclast differentiation. Taken together, these findings have uncovered a previously unknown function of IL-33 as an inhibitor of bone resorption.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acid Phosphatase / metabolism
  • Animals
  • Basophils / cytology
  • Basophils / metabolism
  • Bone Marrow Cells / cytology*
  • Bone Marrow Cells / drug effects
  • Bone Resorption / metabolism
  • Bone and Bones / pathology
  • Calcitriol / pharmacology
  • Cell Count
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology*
  • Cell Line, Tumor
  • Cells, Cultured
  • Eosinophils / cytology
  • Eosinophils / metabolism
  • Gene Expression / drug effects
  • Gene Expression / genetics
  • Granulocyte-Macrophage Colony-Stimulating Factor / genetics
  • Interleukin-1 Receptor-Like 1 Protein
  • Interleukin-33
  • Interleukins / pharmacology
  • Interleukins / physiology*
  • Isoenzymes / metabolism
  • Macrophage Colony-Stimulating Factor / pharmacology
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Osteoblasts / cytology
  • Osteoblasts / drug effects
  • Osteoblasts / metabolism*
  • Osteoclasts / cytology*
  • Osteoclasts / metabolism
  • Osteoclasts / pathology
  • RANK Ligand / genetics
  • RANK Ligand / pharmacology
  • Receptors, Interleukin / genetics
  • Stromal Cells / cytology
  • Stromal Cells / physiology
  • Tartrate-Resistant Acid Phosphatase


  • Il1rl1 protein, mouse
  • Il33 protein, mouse
  • Interleukin-1 Receptor-Like 1 Protein
  • Interleukin-33
  • Interleukins
  • Isoenzymes
  • RANK Ligand
  • Receptors, Interleukin
  • Tnfsf11 protein, mouse
  • Macrophage Colony-Stimulating Factor
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Acid Phosphatase
  • Tartrate-Resistant Acid Phosphatase
  • Calcitriol