Alteration of matrix metalloproteinase-3 O-glycan structure as a biomarker for disease activity of rheumatoid arthritis

Masaru Takeshita, Atsushi Kuno, Katsuya Suzuki, Atsushi Matsuda, Hiroko Shimazaki, Tomomi Nakagawa, Yuki Otomo, Yasuaki Kabe, Makoto Suematsu, Hisashi Narimatsu, Tsutomu Takeuchi

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Background: Nearly all secreted proteins are glycosylated, and serum glycoproteins that exhibit disease-associated glycosylation changes have potential to be biomarkers. In rheumatoid arthritis (RA), C-reactive protein (CRP), and matrix metalloproteinase-3 (MMP-3) are widely used as serologic biomarkers, but they lack sufficient specificity or precision. We performed comparative glycosylation profiling of MMP-3 using a recently developed antibody-overlay lectin microarray technology that allows semicomprehensive and quantitative analysis of specific protein glycosylation to develop an RA-specific disease activity biomarker. Methods: Serum was taken from patients with RA (n = 24) whose disease activity was scored using composite measures, and MMP-3 was immunoprecipitated and subjected to lectin microarray analysis. A disease activity index (DAI) based on lectin signal was developed and validated using another cohort (n = 60). Synovial fluid MMP-3 in patients with RA and patients with osteoarthritis (OA) was also analyzed. Results: Intense signals were observed on a sialic acid-binding lectin (Agrocybe cylindracea galectin [ACG]) and O-glycan-binding lectins (Jacalin, Agaricus bisporus agglutinin [ABA], and Amaranthus caudatus agglutinin [ACA]) by applying subnanogram levels of serum MMP-3. ACG, ABA, and ACA revealed differences in MMP-3 quantity, and Jacalin revealed differences in MMP-3 quality. The resultant index, ACG/Jacalin, correlated well with disease activity. Further validation using another cohort confirmed that this index correlated well with several DAIs and their components, and reflected DAI changes following RA treatment, with correlations greater than those for MMP-3 and CRP. Furthermore, MMP-3, which generated a high ACG/Jacalin score, accumulated in synovial fluid of patients with RA but not in that of patients with OA. Sialidase digestion revealed that the difference in quality was derived from O-glycan α-2,6-sialylation. Conclusions: This is the first report of a glycoprotein biomarker using glycan change at a local lesion to assess disease activity in autoimmune diseases. Differences in the degree of serum MMP-3 α-2,6-sialylation may be a useful index for estimating disease activity.

Original languageEnglish
Article number112
JournalArthritis Research and Therapy
Volume18
Issue number1
DOIs
Publication statusPublished - 2016 May 21

Fingerprint

Matrix Metalloproteinase 3
Polysaccharides
Rheumatoid Arthritis
Biomarkers
Agrocybe
Galectins
Agglutinins
Lectins
Glycosylation
Amaranthus
Synovial Fluid
Osteoarthritis
C-Reactive Protein
Glycoproteins
Serum
Agaricus
Matrix Metalloproteinase 2
Neuraminidase
N-Acetylneuraminic Acid
Microarray Analysis

Keywords

  • Biomarker
  • Glycoprotein
  • MMP-3
  • Rheumatoid arthritis

ASJC Scopus subject areas

  • Rheumatology
  • Immunology
  • Immunology and Allergy

Cite this

Alteration of matrix metalloproteinase-3 O-glycan structure as a biomarker for disease activity of rheumatoid arthritis. / Takeshita, Masaru; Kuno, Atsushi; Suzuki, Katsuya; Matsuda, Atsushi; Shimazaki, Hiroko; Nakagawa, Tomomi; Otomo, Yuki; Kabe, Yasuaki; Suematsu, Makoto; Narimatsu, Hisashi; Takeuchi, Tsutomu.

In: Arthritis Research and Therapy, Vol. 18, No. 1, 112, 21.05.2016.

Research output: Contribution to journalArticle

Takeshita, Masaru ; Kuno, Atsushi ; Suzuki, Katsuya ; Matsuda, Atsushi ; Shimazaki, Hiroko ; Nakagawa, Tomomi ; Otomo, Yuki ; Kabe, Yasuaki ; Suematsu, Makoto ; Narimatsu, Hisashi ; Takeuchi, Tsutomu. / Alteration of matrix metalloproteinase-3 O-glycan structure as a biomarker for disease activity of rheumatoid arthritis. In: Arthritis Research and Therapy. 2016 ; Vol. 18, No. 1.
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AU - Shimazaki, Hiroko

AU - Nakagawa, Tomomi

AU - Otomo, Yuki

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