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IL-1β Enhances Wnt Signal by Inhibiting DKK1

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Abstract

Aberrant endochondral bone formation in the physis is a unique bone lesion in neonatal-onset multisystem inflammatory disease (NOMID), also called chronic infantile neurologic cutaneous articular (CINCA), the most severe of the cryopyrin-associated periodic syndrome (CAPS) diseases, which are interleukin-1β (IL-1β)-related monogenic autoinflammatory diseases. The wingless (Wnt) pathway plays an important role in osteoblast differentiation. In this study, we explored the potential role of IL-1β on the expression of WNT genes and the Wnt antagonist Dickkopf-1 (DKK1). The expression of WNT and DKK1 in fibroblast-like synoviocytes (FLS), which are articular resident cells, was quantified by quantitative PCR and enzyme-linked immunosorbent assay. Additionally, we used T cell factor (TCF) reporter assays to evaluate the activity of the canonical Wnt signal pathway in the presence or absence of the supernatant of cultured FLS treated with or without IL-1β and IL-6. Anti-DKK1 antibodies were used to neutralize DKK1. The expression of both canonical and non-canonical WNT genes as well as DKK1 was observed in FLS. The supernatant of cultured FLS suppressed the luciferase activity of the TCF reporter, and this effect was reduced by its pre-treatment with an anti-DKK1 antibody. Both IL-1β and IL-6 significantly reduced DKK1 production. Furthermore, the supernatant of FLS cultured with IL-1β or IL-6 showed a reduced inhibitory effect on Wnt signaling, compared with the supernatant of untreated FLS. These data suggest that IL-1β, like IL-6, dampens DKK1 production, and thereby promotes Wnt signal activation. Therefore, increased levels of IL-1β may contribute to the dysregulation of endochondral ossification in NOMID/CINCA.

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Funding

This study was funded by JSPS KAKENHI [grant numbers 26461463 and 23591439].

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Authors and Affiliations

  1. Department of Clinical Immunology and Rheumatology, Hiroshima University Hospital, 1-2-3 Kasumi, Minami, Hiroshima, 734-8551, Japan

    Yusuke Yoshida, Katsuhiro Oi, Tatsuomi Kuranobu, Takaki Nojima & Eiji Sugiyama

  2. Division of Respirology, Neurology and Rheumatology, Department of Medicine, Kurume University School of Medicine, 67 Asahi, Kurume, Fukuoka, 830-0011, Japan

    Satoshi Yamasaki & Hiroaki Ida

  3. Division of Rheumatology, Kurume University Medical Center, 155-1 Kokubu, Kurume, Fukuoka, 839-0863, Japan

    Satoshi Yamasaki

  4. Department of Orthopedic Surgery, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami, Hiroshima, 734-8551, Japan

    Shigeru Miyaki

  5. Department of Regenerative Medicine, Hiroshima University Hospital, 1-2-3 Kasumi, Minami, Hiroshima, 734-8551, Japan

    Shigeru Miyaki

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  1. Yusuke Yoshida
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  2. Satoshi Yamasaki
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Corresponding author

Correspondence to Satoshi Yamasaki.

Ethics declarations

RA-FLS purchased from Articular Engineering were isolated from synovial tissues harvested from post-mortem donors with a clinical diagnosis of RA with anonymous informed written consent from the donor or a nearest relative. The company obtained the synovial tissues according to the legal and ethical requirements of the country of collection (approval of an ethics committee, institutional review board, or state license). OA-FLS and normal FLS were obtained from human knee joints at the time of autopsy from donors, with the approval of the Scripps Human Subjects Committee. Synovial tissue samples were obtained from patients with RA with approval of the Ethics Committee of the Nagasaki University (Nagasaki, Japan).

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The authors declare that they have no conflict of interest.

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Yoshida, Y., Yamasaki, S., Oi, K. et al. IL-1β Enhances Wnt Signal by Inhibiting DKK1. Inflammation 41, 1945–1954 (2018). https://doi.org/10.1007/s10753-018-0838-z

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