Combination of tumor necrosis factor α and interleukin-6 induces mouse osteoclast-like cells with bone resorption activity both in vitro and in vivo

Kazuhiro Yokota, Kojiro Sato, Takashi Miyazaki, Hideki Kitaura, Hisako Kayama, Fumihiko Miyoshi, Yasuto Araki, Yuji Akiyama, Kiyoshi Takeda, Toshihide Mimura

Research output: Contribution to journalArticlepeer-review

78 Citations (Scopus)

Abstract

Objective: To clarify the function of osteoclast-like multinuclear cells differentiated from bone marrowderived macrophages (BMMs) by a combination of tumor necrosis factor a (TNFa) and interleukin-6 (IL-6), and to investigate the molecular mechanisms underlying the differentiation. Methods: BMMs were stimulated by TNFα and/or IL-6. The cells were then compared with conventional osteoclasts differentiated in vitro by RANKL. An in vitro pit formation assay on dentine slices and an in vivo resorption assay of calvarial bones were performed. We also evaluated the activities and expression levels of NF-κB, c-Fos, and NF-ATc1, which are essential to the differentiation of conventional osteoclasts. Small interfering RNA was used to knock down c-Fos. The effects of genetic ablation of STAT-3 and pharmacologic inhibitors of NF-AT, JAK, and ERK were also studied. Results: Osteoclast-like cell differentiation depended on TNFα and IL-6 and was not inhibited by osteoprotegerin. These differentiated cells were associated with both in vitro and in vivo bone resorption activity. TNFα and IL-6 had a synergistic effect on the activity and expression of c-Fos. Knockdown of c-Fos inhibited the expression of NF-ATc1 and the differentiation of osteoclast-like cells. All of these inhibitors blocked differentiation of the cells in vitro, but surprisingly, the conditional knockout of STAT-3 did not. Tofacitinib also inhibited the bone destruction caused by TNFα and IL-6 in vivo. Conclusion: Our results demonstrate that a combination of the inflammatory cytokines TNFα and IL-6 can induce osteoclast-like cells that have in vitro and in vivo bone-resorptive activity.

Original languageEnglish
Pages (from-to)121-129
Number of pages9
JournalArthritis and Rheumatology
Volume66
Issue number1
DOIs
Publication statusPublished - 2014 Jan

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology

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