Elevated levels of Interleukin (IL)-33 induce bone pathology but absence of IL-33 does not negatively impact normal bone homeostasis

Cytokine. 2016 Mar;79:66-73. doi: 10.1016/j.cyto.2015.12.011. Epub 2016 Jan 6.


Interleukin (IL)-33 is a member of the IL-1 family. IL-33 effects are mediated through its receptor, ST2 and IL-1RAcP, and its signaling induces the production of a number of pro-inflammatory mediators, including TNFα, IL-1β, IL-6, and IFN-γ. There are conflicting reports on the role of IL-33 in bone homeostasis, with some demonstrating a bone protective role for IL-33 whilst others show that IL-33 induces inflammatory arthritis with concurrent bone destruction. To better clarify the role IL-33 plays in bone biology in vivo, we studied IL-33 KO mice as well as mice in which the cytokine form of IL-33 was overexpressed. Mid-femur cortical bone mineral density (BMD) and bone strength were similar in the IL-33 KO mice compared to WT animals during the first 8months of life. However, in the absence of IL-33, we observed higher BMD in lumbar vertebrae and distal femur in female mice. In contrast, overexpression of IL-33 resulted in a marked and rapid reduction of bone volume, mineral density and strength. Moreover, this was associated with a robust increase in inflammatory cytokines (including IL-6 and IFN-γ), suggesting the bone pathology could be a direct effect of IL-33 or an indirect effect due to the induction of other mediators. Furthermore, the detrimental bone effects were accompanied by increases in osteoclast number and the bone resorption marker of C-terminal telopeptide collagen-I (CTX-I). Together, these results demonstrate that absence of IL-33 has no negative consequences in normal bone homeostasis while high levels of circulating IL-33 contributes to pathological bone loss.

Keywords: Aging; Biomechanics; Bone; Genetic deficient mice; IL-33.

MeSH terms

  • Animals
  • Bone Density / genetics
  • Bone Density / physiology*
  • Bone Resorption / metabolism*
  • Collagen Type I / metabolism
  • Cytokines / metabolism
  • Female
  • Femur / physiology*
  • Interleukin-33 / biosynthesis
  • Interleukin-33 / genetics*
  • Interleukin-33 / metabolism*
  • Lumbar Vertebrae / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Osteoclasts / cytology
  • Peptides / metabolism


  • Collagen Type I
  • Cytokines
  • Il33 protein, mouse
  • Interleukin-33
  • Peptides
  • collagen type I trimeric cross-linked peptide