Up‐regulation of metastasis‐promoting S100A4 (Mts‐1) in rheumatoid arthritis: Putative involvement in the pathogenesis of rheumatoid arthritis

Abstract

Objective. To examine the involvement of the metastasis-inducing protein S100A4 (Mts-1) in the pathogenesis of rheumatoid arthritis (RA).Methods. Synovial tissue, synovial fluid, and plasma were obtained from RA and osteoarthritis (OA) patients who were undergoing joint surgery. Immunohistochemical and immunofluorescence analyses and enzyme-linked immunosorbent assays were used to determine the locations and concentrations of S100A4. The conformational structure of S100A4 in plasma and synovial fluid was determined after fractionation by size-exclusion chromatography, protein separation by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and Western blot analysis. Expression of various S100 proteins in RA synovium was determined by immunofluorescence and double-staining using specific anti-S100 antibodies.Results. We found an up-regulation of S100A4 in cells infiltrating RA synovial tissue. Most cell types identified by cell-specific markers (fibroblasts, immune cells, and vascular cells) contributed to the production of S100A4 in RA synovial tissue. The pattern of S100A4 expression differed significantly from that of the proinflammatory proteins S100A9 and S100A12, which were restricted to phagocytes and granulocytes. The upregulation of S100A4 in RA synovial tissue was consistent with the high concentrations of the protein in RA versus OA plasma (mean 1,100 versus 211 ng/ml) and synovial fluid (mean 1,980 versus 247 ng/ml). Moreover, we found that S100A4 in RA plasma and synovial fluid was present in bioactive multimeric (M-S100A4) conformations, whereas in OA, the majority of extracellular S100A4 was detected as the less active dimeric form. Consistent with our observations in tumor models, extracellular S100A4 stabilized the p53 tumor suppressor in RA synovial fibroblast-like cells and affected the regulation of p53 target genes, including Bcl-2, p21 WAF , and Hdm-2, as well as matrix metalloproteinases.Conclusion. Overexpression of S100A4 in RA synovial tissue and its release as M-S100A4 can influence p53 function and modulate the expression of several genes that are potentially implicated in the disease process. Thus, S100A4 might play an important role in the pathogenesis of RA and might represent a new target for the treatment of RA.

S100A4 amplifies TGF-β-induced fibroblast activation in systemic sclerosis

“…The expression of S100A4 was strongly increased in fibrotic skin, particularly in fibroblasts, perivascular inflammatory infiltrates and in the basal layer of epidermis. Our data are in line with recent findings in other autoimmune inflammatory diseases, such as RA,5 inflammatory myopathies10 or psoriasis,16 where S100A4 was found to be expressed in macrophages, granulocytes, mast cells, fibroblasts, pericytes, endothelial cells, dendritic cells and T cells, but not B cells or stem cells. We did not observe any differences in S100A4 expression patients with limited versus diffuse cutaneous SSc, or correlations with disease duration or activity.…”

“…Intracellular S100A4 regulates several processes that are fundamental for cell homeostasis and differentiation such as gene transcription, cytoskeletal rearrangement and cell proliferation 4. When secreted into extracellular space, S100A4 exerts cytokine-like effects and regulates remodelling of ECM,5 angiogenesis6 and cell survival 7. S100A4 has been extensively studied in tumours and described to promote tumour progression and metastasis 3 8.…”

“…However, more recently, it became apparent that S100A4 is also implicated in pathogenesis of non-malignant human disorders. Of particular interest, S100A4 has been described to be involved in the pathogenesis of rheumatoid arthritis (RA)5 9 and inflammatory myopathies 10. In RA, increased expression of S100A4 might contribute to the aggressive phenotype of RA synovial fibroblasts 11.…”

Cell death in rheumatoid arthritis

“…In this study, blocking of IL-15 increased apoptosis along with a suppression of Bcl-2. The reason as to why Bcl-2 levels are elevated in RA-FLS remains elusive but some recent findings suggest that the S100 protein Mts-1 (S100A4) is expressed at increased levels in the RA synovium and involved in the up-regulation of Bcl-2 [18].…”

The metastasis associated protein S100A4: a potential novel link to inflammation and consequent aggressive behaviour of rheumatoid arthritis synovial fibroblasts

“…Certain conditions, particularly the extracellular milieu, contribute to the formation of oligomers and multimers of some S100 proteins. For example, S100A8/S100A9 forms heterotetramers,6 7 S100A12 hexamers,6 8 and S100A4 forms tetramers and higher 9. Interaction of S100 proteins with several target proteins might explain their implication in a wide range of cellular events.…”