Interleukin-1 receptor-associated kinase-4 (IRAK4) promotes inflammatory osteolysis by activating osteoclasts and inhibiting formation of foreign body giant cells

Eri Katsuyama, Hiroya Miyamoto, Tami Kobayashi, Yuiko Sato, Wu Hao, Hiroya Kanagawa, Atsuhiro Fujie, Toshimi Tando, Ryuichi Watanabe, Mayu Morita, Kana Miyamoto, Yasuo Niki, Hideo Morioka, Morio Matsumoto, Yoshiaki Toyama, Takeshi Miyamoto

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15 Citations (Scopus)

Abstract

Formation of foreign body giant cells (FBGCs) occurs following implantation of medical devices such as artificial joints and is implicated in implant failure associated with inflammation or microbial infection. Two major macrophage subpopulations, M1 and M2, play different roles in inflammation and wound healing, respectively. Therefore, M1/M2 polarization is crucial for the development of various inflammation-related diseases. Here, we show that FBGCs do not resorb bone but rather express M2 macrophage-like wound healing and inflammation-terminating molecules in vitro. We also found that FBGC formation was significantly inhibited by inflammatory cytokines or infection mimetics in vitro . Interleukin-1 receptor-associated kinase-4 (IRAK4) deficiency did not alter osteoclast formation in vitro, and IRAK4-deficient mice showed normal bone mineral density in vivo. However, IRAK4-deficient mice were protected from excessive osteoclastogenesis induced by IL-1β in vitro or by LPS, an infection mimetic of Gram-negative bacteria, in vivo. Furthermore, IRAK4 deficiency restored FBGC formation and expression of M2 macrophage markers inhibited by inflammatory cytokines in vitro or by LPS in vivo. Our results demonstrate that osteoclasts and FBGCs are reciprocally regulated and identify IRAK4 as a potential therapeutic target to inhibit stimulated osteoclastogenesis and rescue inhibited FBGC formation under inflammatory and infectious conditions without altering physiological bone resorption.

Original languageEnglish
Pages (from-to)716-726
Number of pages11
JournalJournal of Biological Chemistry
Volume290
Issue number2
DOIs
Publication statusPublished - 2015 Jan 9

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ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Katsuyama, E., Miyamoto, H., Kobayashi, T., Sato, Y., Hao, W., Kanagawa, H., Fujie, A., Tando, T., Watanabe, R., Morita, M., Miyamoto, K., Niki, Y., Morioka, H., Matsumoto, M., Toyama, Y., & Miyamoto, T. (2015). Interleukin-1 receptor-associated kinase-4 (IRAK4) promotes inflammatory osteolysis by activating osteoclasts and inhibiting formation of foreign body giant cells. Journal of Biological Chemistry, 290(2), 716-726. https://doi.org/10.1074/jbc.M114.568360