Calgizzarin (S100A11): a novel inflammatory mediator associated with disease activity of rheumatoid arthritis

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Abstract

Background

Calgizzarin (S100A11) is a member of the S100 protein family that acts in different tumors by regulating a number of biologic functions. Recent data suggest its association with low-grade inflammation in osteoarthritis (OA). The aim of our study is to compare S100A11 expression in the synovial tissues, synovial fluid and serum of patients with rheumatoid arthritis (RA) and osteoarthritis (OA) and to characterize the potential association between S100A11 and disease activity.

Methods

S100A11 protein expression was detected in synovial tissue from patients with RA ( n = 6) and patients with OA ( n = 6) by immunohistochemistry and immunofluorescence. Serum and synovial fluid S100A11 levels were measured by ELISA in patients with RA ( n = 40) and patients with OA ( n = 34). Disease activity scores in 28 joints based on C-reactive protein (DAS28-CRP) were used to assess disease activity. Cytokine content in peripheral blood mononuclear cells (PBMCs), synovial fibroblasts (SFs) and synovial fluid was analysed by ELISA, western blotting or cytometric bead array.

Results

S100A11 expression was significantly up-regulated in the synovial lining and sublining layers ( p < 0.01) and vessels ( p < 0.05) of patients with RA compared to patients with OA, and was associated with fibroblasts and T cells. S100A11 was significantly increased in synovial fluid ( p < 0.0001) but not in serum ( p = 0.158) from patients with RA compared to patients with OA when adjusted for age and sex. Synovial fluid S100A11 correlated with DAS28 ( r = 0.350, p = 0.027), serum CRP ( r = 0.463, p = 0.003), synovial fluid leukocyte count ( r = 0.677, p < 0.001), anti-cyclic citrullinated peptide antibodies (anti-CCP) ( r = 0.424, p = 0.006) and IL-6 ( r = 0.578, p = 0.002) and IL-8 ( r = 0.740, p < 0.001) in synovial fluid from patients with RA. PBMCs and SFs isolated from patients with RA synthesized and spontaneously secreted higher levels of S100A11 in comparison with PBMCs and SFs from patients with OA ( p = 0.011 and 0.03, respectively). S100A11 stimulated the production of the pro-inflammatory cytokine IL-6 by PBMCs ( p < 0.05) and SFs ( p < 0.01).

Conclusions

Our data provide the first evidence of S100A11 up-regulation and its association with inflammation and disease activity in patients with RA.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-017-1288-y) contains supplementary material, which is available to authorized users.

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Most cited references 32

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The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis.

D McShane, D. Bloch, Emma Healey … (1988)

The revised criteria for the classification of rheumatoid arthritis (RA) were formulated from a computerized analysis of 262 contemporary, consecutively studied patients with RA and 262 control subjects with rheumatic diseases other than RA (non-RA). The new criteria are as follows: 1) morning stiffness in and around joints lasting at least 1 hour before maximal improvement; 2) soft tissue swelling (arthritis) of 3 or more joint areas observed by a physician; 3) swelling (arthritis) of the proximal interphalangeal, metacarpophalangeal, or wrist joints; 4) symmetric swelling (arthritis); 5) rheumatoid nodules; 6) the presence of rheumatoid factor; and 7) radiographic erosions and/or periarticular osteopenia in hand and/or wrist joints. Criteria 1 through 4 must have been present for at least 6 weeks. Rheumatoid arthritis is defined by the presence of 4 or more criteria, and no further qualifications (classic, definite, or probable) or list of exclusions are required. In addition, a "classification tree" schema is presented which performs equally as well as the traditional (4 of 7) format. The new criteria demonstrated 91-94% sensitivity and 89% specificity for RA when compared with non-RA rheumatic disease control subjects.

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A review of the S100 proteins in cancer.

I Salama Benarroch, F. Mihaimeed, Donald J L Jones … (2008)

In the quest to reduce mortality and morbidity from cancer, there is continued effort to identify novel biomarkers to aid in the early detection and the accurate prediction of tumour behaviour. One group of proteins that is emerging as a potentially important group of markers in multiple tumour types is the S100 family. This review summarises the biological and clinical relevance of these proteins in relation to different tumour types. A literature search was performed using the PubMed database and the reference lists of relevant articles. Single case studies were excluded and only reports with a clinical relevance from 1961 to 2007 were included. The search yielded over 1000 published articles and reports. Important reports and studies were reviewed, screened and tracked for further relevant publications. Only the most relevant publications are discussed with relation to individual members of the S100 family. There is increasing evidence that altered expression of S100 family members is seen in many cancers including breast, lung, bladder, kidney, thyroid, gastric, prostate and oral cancers. S100 proteins are commonly up-regulated in tumours and this is often associated with tumour progression. In contrast S100A2, S100A11 and S100A9 have been documented as tumour suppressors in some cancers but as tumour promoters in others. This demonstrates the complexity of the family and variability of their functions. Although the precise roles of these proteins in cancer is still to be discovered many of the family are associated with promoting metastases through interactions with matrix metalloproteinases or by acting as chemoattractants. There is also evidence that some members can regulate transcription factors such as p53. S100B already has a role in a clinical setting in the diagnosis and therapeutic monitoring of malignant melanoma. As our understanding of this family develops it is likely that many more members will aid the diagnosis, monitoring and potential treatment of cancers in the future.

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RNA released from necrotic synovial fluid cells activates rheumatoid arthritis synovial fibroblasts via Toll-like receptor 3.

Steffen Gay, Fabia Brentano, Diego Kyburz … (2005)

To assess the expression of Toll-like receptor 3 (TLR-3) protein in synovial tissues and cultured synovial fibroblasts obtained from patients with rheumatoid arthritis (RA) and osteoarthritis (OA) and to investigate the consequences of stimulation of cultured synovial fibroblasts with TLR-3 ligands. TLR-3 expression in synovial tissues was determined by immunohistochemistry and immunofluorescence, and expression in cultured RA synovial fibroblasts (RASFs) was determined by fluorescence-activated cell sorting and real-time polymerase chain reaction techniques. TLR-3 signaling was assessed by incubating RASFs with poly(I-C), lipopolysaccharide, palmitoyl-3-cysteine-serine-lysine-4, or necrotic synovial fluid cells from RA patients in the presence or absence of hydroxychloroquine or Benzonase. Subsequent determination of interferon-beta (IFNbeta), CXCL10, CCL5, and interleukin-6 (IL-6) protein production in the culture supernatants was performed by enzyme-linked immunosorbent assays. TLR-3 protein expression was found to be higher in RA synovial tissues than in OA synovial tissues. TLR-3 expression was localized predominantly in the synovial lining, with a majority of the TLR-3-expressing cells coexpressing fibroblast markers. Stimulation of cultured RASFs with the TLR-3 ligand poly(I-C) resulted in the production of high levels of IFNbeta, CXCL10, CCL5, and IL-6 protein. Similarly, coincubation of RASFs with necrotic synovial fluid cells from patients with RA resulted in up-regulation of these cytokines and chemokines in a TLR-3-dependent manner. Our findings demonstrate the expression of TLR-3 in RA synovial tissue and the activation of RASFs in vitro by the TLR-3 ligand poly(I-C) as well as by necrotic RA synovial fluid cells, and indicate that RNA released from necrotic cells might act as an endogenous TLR-3 ligand for the stimulation of proinflammatory gene expression in RASFs.

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Author and article information

Contributors

Lucie Andrés Cerezo:

ORCID: http://orcid.org/0000-0003-1664-5834

lucie.andres.cerezo@gmail.com

Barbora Šumová: sumova@revma.cz

Klára Prajzlerová: prajzlerova@revma.cz

David Veigl: dveigl@yahoo.com

Dres Damgaard: dres.damg@gmail.com

Claus Henrik Nielsen: claus.henrik.nielsen@regionh.dk

Karel Pavelka: pavelka@revma.cz

Jiří Vencovský: vencovsky@revma.cz

Ladislav Šenolt: +420 234075232 , senolt@revma.cz

Journal

Journal ID (nlm-ta): Arthritis Res Ther

Journal ID (iso-abbrev): Arthritis Res. Ther

Title: Arthritis Research & Therapy

Publisher: BioMed Central (London )

ISSN (Print): 1478-6354

ISSN (Electronic): 1478-6362

Publication date (Electronic): 26 April 2017

Publication date PMC-release: 26 April 2017

Publication date (Print): 2017

Volume: 19

Electronic Location Identifier: 79

Affiliations

[1 ]ISNI 0000 0000 8694 9225, GRID grid.418965.7, , Institute of Rheumatology, ; Na Slupi 4, 12850 Prague, Czech Republic

[2 ]ISNI 0000 0004 1937 116X, GRID grid.4491.8, Department of Rheumatology, 1st Faculty of Medicine, , Charles University, ; Prague, Czech Republic

[3 ]ISNI 0000 0004 1937 116X, GRID grid.4491.8, First Orthopaedic Clinic, 1st Faculty of Medicine, , Charles University, ; Prague, Czech Republic

[4 ]ISNI 0000 0004 0646 7373, GRID grid.4973.9, Institute for Inflammation Research, Center for Rheumatology and Spine Diseases, , Copenhagen University Hospital, ; Rigshospitalet, Copenhagen, Denmark

Author information

Lucie Andrés Cerezo http://orcid.org/0000-0003-1664-5834

Article

Publisher ID: 1288

DOI: 10.1186/s13075-017-1288-y

PMC ID: 5405489

PubMed ID: 28446208

SO-VID: e45b9202-a2f9-47c1-bf8b-a3645124a36d

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 29 October 2016

Date accepted : 31 March 2017

Funding

Funded by: Agency for Healthcare Research of the Czech Republic

Award ID: 15-34065A

Award Recipient : Lucie Andrés Cerezo

Funded by: FundRef http://dx.doi.org/10.13039/501100003243, Ministerstvo Zdravotnictví Ceské Republiky;

Award ID: 023728

Custom metadata

ScienceOpen disciplines: Orthopedics

Keywords: calgizzarin,s100 proteins,rheumatoid arthritis,inflammation,disease activity

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ScienceOpen disciplines: Orthopedics

Keywords: calgizzarin, s100 proteins, rheumatoid arthritis, inflammation, disease activity

Calgizzarin (S100A11): a novel inflammatory mediator associated with disease activity of rheumatoid arthritis

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Abstract

Background

Methods

Results

Conclusions

Electronic supplementary material

Related collections

Biomarkers for Inflammatory Lung Disease

Most cited references 32

The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis.

A review of the S100 proteins in cancer.

RNA released from necrotic synovial fluid cells activates rheumatoid arthritis synovial fibroblasts via Toll-like receptor 3.

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