PMID- 27209430 OWN - NLM STAT- MEDLINE DCOM- 20171108 LR - 20181113 IS - 1478-6362 (Electronic) IS - 1478-6354 (Print) IS - 1478-6354 (Linking) VI - 18 IP - 1 DP - 2016 May 21 TI - Alteration of matrix metalloproteinase-3 O-glycan structure as a biomarker for disease activity of rheumatoid arthritis. PG - 112 LID - 10.1186/s13075-016-1013-2 [doi] LID - 112 AB - 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 alpha-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 alpha-2,6-sialylation may be a useful index for estimating disease activity. FAU - Takeshita, Masaru AU - Takeshita M AD - Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan. FAU - Kuno, Atsushi AU - Kuno A AD - Research Center for Medical Glycoscience (RCMG), National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Umezono, Tsukuba, Ibaraki, 305-8568, Japan. AD - Center for Systems Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan. FAU - Suzuki, Katsuya AU - Suzuki K AD - Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan. FAU - Matsuda, Atsushi AU - Matsuda A AD - Research Center for Medical Glycoscience (RCMG), National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Umezono, Tsukuba, Ibaraki, 305-8568, Japan. AD - Center for Systems Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan. FAU - Shimazaki, Hiroko AU - Shimazaki H AD - Research Center for Medical Glycoscience (RCMG), National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Umezono, Tsukuba, Ibaraki, 305-8568, Japan. FAU - Nakagawa, Tomomi AU - Nakagawa T AD - Department of Biochemistry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan. FAU - Otomo, Yuki AU - Otomo Y AD - Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan. FAU - Kabe, Yasuaki AU - Kabe Y AD - Department of Biochemistry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan. FAU - Suematsu, Makoto AU - Suematsu M AD - Department of Biochemistry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan. FAU - Narimatsu, Hisashi AU - Narimatsu H AD - Research Center for Medical Glycoscience (RCMG), National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Umezono, Tsukuba, Ibaraki, 305-8568, Japan. FAU - Takeuchi, Tsutomu AU - Takeuchi T AD - Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan. tsutake@z5.keio.jp. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160521 PL - England TA - Arthritis Res Ther JT - Arthritis research & therapy JID - 101154438 RN - 0 (Biomarkers) RN - EC 3.4.24.17 (MMP3 protein, human) RN - EC 3.4.24.17 (Matrix Metalloproteinase 3) SB - IM MH - Aged MH - Arthritis, Rheumatoid/*enzymology MH - Biomarkers/*analysis MH - Blotting, Western MH - Female MH - Glycosylation MH - Humans MH - Immunoprecipitation MH - Male MH - Matrix Metalloproteinase 3/analysis/chemistry/*metabolism MH - Middle Aged MH - Protein Array Analysis/*methods MH - Synovial Fluid/chemistry/metabolism PMC - PMC4875599 OTO - NOTNLM OT - Biomarker OT - Glycoprotein OT - MMP-3 OT - Rheumatoid arthritis EDAT- 2016/05/23 06:00 MHDA- 2017/11/09 06:00 PMCR- 2016/05/21 CRDT- 2016/05/23 06:00 PHST- 2016/02/24 00:00 [received] PHST- 2016/05/04 00:00 [accepted] PHST- 2016/05/23 06:00 [entrez] PHST- 2016/05/23 06:00 [pubmed] PHST- 2017/11/09 06:00 [medline] PHST- 2016/05/21 00:00 [pmc-release] AID - 10.1186/s13075-016-1013-2 [pii] AID - 1013 [pii] AID - 10.1186/s13075-016-1013-2 [doi] PST - epublish SO - Arthritis Res Ther. 2016 May 21;18(1):112. doi: 10.1186/s13075-016-1013-2.