ATF3 deficiency in chondrocytes alleviates osteoarthritis development

Takashi Iezaki, Kakeru Ozaki, Kazuya Fukasawa, Makoto Inoue, Shigetaka Kitajima, Takeshi Muneta, Shu Takeda, Hiroyuki Fujita, Yuki Onishi, Tetsuhiro Horie, Yukio Yoneda, Takeshi Takarada, Eiichi Hinoi

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Activating transcription factor 3 (Atf3) has been implicated in the pathogenesis of various diseases, including cancer and inflammation, as well as in the regulation of cell proliferation and differentiation. However, the involvement of Atf3 in developmental skeletogenesis and joint disease has not been well studied to date. Here, we show that Atf3 is a critical mediator of osteoarthritis (OA) development through its expression in chondrocytes. ATF3 expression was markedly up-regulated in the OA cartilage of both mice and humans. Conditional deletion of Atf3 in chondrocytes did not result in skeletal abnormalities or affect the chondrogenesis, but alleviated the development of OA generated by surgically inducing knee joint instability in mice. Inflammatory cytokines significantly up-regulated Atf3 expression through the nuclear factor-kB (NF-kB) pathway, while cytokine-induced interleukin-6 (Il6) expression was repressed, in ATF3-deleted murine and human chondrocytes. Mechanistically, Atf3 deficiency decreased cytokine-induced Il6 transcription in chondrocytes through repressing NF-kB signalling by the attenuation of the phosphorylation status of IkB and p65. These findings suggest that Atf3 is implicated in the pathogenesis of OA through modulation of inflammatory cytokine expression in chondrocytes, and the feed-forward loop of inflammatory cytokines/NF-kB/Atf3 in chondrocytes may be a novel therapeutic target for the treatment for OA.

Original languageEnglish
Pages (from-to)426-437
Number of pages12
JournalJournal of Pathology
Volume239
Issue number4
DOIs
Publication statusPublished - Aug 1 2016
Externally publishedYes

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Keywords

  • ATF3
  • chondrocyte
  • endochondral ossification
  • inflammatory cytokines
  • NF-kB
  • osteoarthritis

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Iezaki, T., Ozaki, K., Fukasawa, K., Inoue, M., Kitajima, S., Muneta, T., Takeda, S., Fujita, H., Onishi, Y., Horie, T., Yoneda, Y., Takarada, T., & Hinoi, E. (2016). ATF3 deficiency in chondrocytes alleviates osteoarthritis development. Journal of Pathology, 239(4), 426-437. https://doi.org/10.1002/path.4739