Session Title: Osteoarthritis and Joint Biology – Basic Science Poster II
Session Type: ACR Poster Session C
Session Time: 9:00AM-11:00AM
Background/Purpose: 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. It is interesting that the pathological features of bone lesions in NOMID / CINCA are similar to those found in patients with fibrous dysplasia, a skeletal disease caused by the gain-of function mutation of the GNAS gene that leads to aberrant activation of the canonical Wnt signal. Since the importance of the Wnt signal in human skeletal development is evidenced by the existence of human diseases caused by abnormalities associated with Wnt receptors, we explored the potential role of IL-1β on the expression of WNT genes and the Wnt antagonist Dickkopf-1 (DKK1).
Methods: The expression of WNT2, 3, 4, 5A, 11 and DKK1 mRNA in fibroblast-like synoviocytes (FLS) was quantified by quantitative PCR. The concentration of DKK1 in supernatant from FLS was determined by ELISA. Additionally, we used TCF reporter transfected in U2OS cell, a cell line that does not express DKK1, 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. Recombinant WNT3A or Lithium chloride (LiCl) was used to activate Wnt signal. Anti-DKK1 antibodies were used to neutralize DKK1 in supernatant from FLS culture.
Results: The mRNA expression of both canonical and non-canonical WNT genes as well as DKK1 was detected in FLS. FLS secreted DKK1 comparable to bone marrow-derived mesenchymal stromal cell. 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. Moreover, the supernatant from FLS cultures significantly suppressed the TCF activity induced by WNT3A or LiCl in a dose dependent manner. IL-1β induced WNT2 and 5A, whereas significantly reduced DKK1 in FLS. Furthermore, the supernatant of FLS cultured with IL-1β showed a reduced inhibitory effect on TCF activity compared with the supernatant of untreated FLS.
Conclusion: FLS suppress Wnt signal via DKK1 production, and that IL-1β reduce DKK1 production from the cells and, thereby, activation Wnt signal. Therefore, it is possible that the overproduction of IL-1β in patients with NOMID/CINCA aberrantly activates the Wnt signal and leads to abnormalities in cartilage and bone differentiation. Our data, consistently with a previous report about fibrous dysplasia, suggest that two distinct genetic mutations in two different diseases lead to similar abnormal activation of the Wnt signal, and, consequently, similar bone lesions.
To cite this abstract in AMA style:Yamasaki S, Yoshida Y, Oi K, Kuranobu T, Nojima T, Ida H, Sugiyama E. IL-1β Inhibits the Expression of Dickkopf-1, an Antagonist of the Wnt-β-Catenin Signaling Pathway: A Possible Role of Inflammasome in Dysregulation of Endochondral Ossification [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/il-1%ce%b2-inhibits-the-expression-of-dickkopf-1-an-antagonist-of-the-wnt-%ce%b2-catenin-signaling-pathway-a-possible-role-of-inflammasome-in-dysregulation-of-endochondral-ossification/. Accessed July 15, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/il-1%ce%b2-inhibits-the-expression-of-dickkopf-1-an-antagonist-of-the-wnt-%ce%b2-catenin-signaling-pathway-a-possible-role-of-inflammasome-in-dysregulation-of-endochondral-ossification/