Bone marrow Th17 TNFα cells induce osteoclast differentiation, and link bone destruction to IBD

Gut. 2015 Jul;64(7):1072-81. doi: 10.1136/gutjnl-2014-306947. Epub 2014 Oct 8.


Objective: Under both physiological and pathological conditions, bone volume is determined by the rate of bone formation by osteoblasts and bone resorption by osteoclasts. Excessive bone loss is a common complication of human IBD whose mechanisms are not yet completely understood. Despite the role of activated CD4(+) T cells in inflammatory bone loss, the nature of the T cell subsets involved in this process in vivo remains unknown. The aim of the present study was to identify the CD4(+) T cell subsets involved in the process of osteoclastogenesis in vivo, as well as their mechanism of action.

Design: CD4(+) T cells were studied in IL10-/- mice and Rag1-/- mice adoptively transferred with naive CD4(+)CD45RB(high) T cells, representing two well-characterised animal models of IBD and in patients with Crohn's disease. They were phenotypically and functionally characterised by flow cytometric and gene expression analysis, as well as in in vitro cocultures with osteoclast precursors.

Results: In mice, we identified bone marrow (BM) CD4(+) T cells producing interleukin (IL)-17 and tumour necrosis factor (TNF)-α as an osteoclastogenic T cell subset referred to as Th17 TNF-α(+) cells. During chronic inflammation, these cells migrate to the BM where they survive in an IL-7-dependent manner and where they promote the recruitment of inflammatory monocytes, the main osteoclast progenitors. A population equivalent to the Th17 TNF-α(+) cells was also detected in patients with Crohn's disease.

Conclusions: Our results highlight the osteoclastogenic function of the Th17 TNF-α(+) cells that contribute to bone loss in vivo in IBD.


Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity / physiology
  • Animals
  • Bone Diseases / immunology
  • Bone Diseases / physiopathology*
  • Bone Marrow Cells / immunology
  • Bone Marrow Cells / metabolism
  • Bone Marrow Cells / physiology*
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Differentiation
  • Crohn Disease / immunology
  • Crohn Disease / physiopathology
  • Disease Models, Animal
  • Humans
  • Immunohistochemistry
  • Inflammatory Bowel Diseases / immunology
  • Inflammatory Bowel Diseases / physiopathology*
  • Interleukin-7 / physiology
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Osteoclasts / immunology
  • Osteoclasts / physiology*
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocyte Subsets / physiology*
  • Th17 Cells / immunology
  • Th17 Cells / physiology*
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Necrosis Factor-alpha / physiology


  • Interleukin-7
  • Tumor Necrosis Factor-alpha