Arthritis Research & Therapy (Feb 2023)

Identification of anti-citrullinated osteopontin antibodies and increased inflammatory response by enhancement of osteopontin binding to fibroblast-like synoviocytes in rheumatoid arthritis

  • Akio Umemoto,
  • Takeshi Kuwada,
  • Koichi Murata,
  • Masahiro Shiokawa,
  • Sakiko Ota,
  • Yoshiki Murotani,
  • Akihiro Itamoto,
  • Kohei Nishitani,
  • Hiroyuki Yoshitomi,
  • Takayuki Fujii,
  • Akira Onishi,
  • Hideo Onizawa,
  • Kosaku Murakami,
  • Masao Tanaka,
  • Hiromu Ito,
  • Hiroshi Seno,
  • Akio Morinobu,
  • Shuichi Matsuda

DOI
https://doi.org/10.1186/s13075-023-03007-9
Journal volume & issue
Vol. 25, no. 1
pp. 1 – 12

Abstract

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Abstract Background Anti-citrullinated protein/peptide antibodies (ACPAs) are present in patients at onset and have important pathogenic roles during the course of rheumatoid arthritis (RA). The characteristics of several molecules recognized by ACPA have been studied in RA, but the positivity rate of autoantibodies against each antigen is not high, and the pathogenic mechanism of each antibody is not fully understood. We investigated the role of anti-citrullinated osteopontin (anti-cit-OPN) antibodies in RA pathogenesis. Methods Enzyme-linked immunosorbent assays on RA patients’ sera were used to detect autoantibodies against OPN. Fibroblast-like synoviocytes (FLS) isolated from RA patients were used to test the binding activity and inflammatory response of OPN mediated by anti-cit-OPN antibodies, and their effect was tested using an inflammatory arthritis mouse model immunized with cit-OPN. Anti-cit-OPN antibody positivity and clinical characteristics were investigated in the patients as well. Results Using sera from 224 RA patients, anti-cit-OPN antibodies were positive in approximately 44% of RA patients, while approximately 78% of patients were positive for the cyclic citrullinated peptide (CCP2) assay. IgG from patients with anti-cit-OPN antibody increased the binding activity of OPN to FLSs, which further increased matrix metalloproteinase and interleukin-6 production in TNF-stimulated FLSs. Mice immunized with cit-OPN antibodies experienced severe arthritis. Anti-cit-OPN antibodies in RA patients decreased the drug survival rate of tumor necrosis factor (TNF) inhibitors, while it did not decrease that of CTLA4-Ig. Conclusions Anti-cit-OPN antibodies were detected in patients with RA. IgG from patients with anti-cit-OPN antibodies aggravated RA, and anti-cit-OPN antibody was a marker of reduced the survival rate of TNF inhibitors in RA patients.

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