Up-regulation of metastasis-promoting S100A4 (Mts-1) in rheumatoid arthritis: putative involvement in the pathogenesis of rheumatoid arthritis.
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 up-regulation 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.


CONCLUSIONS
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.
Klingelhöfer
Jörg
J
Danish Cancer Society, Copenhagen, Denmark.
Senolt
Ladislav
L
Baslund
Bo
B
Nielsen
Gitte Helle
GH
Skibshøj
Inge
I
Pavelka
Karel
K
Neidhart
Michel
M
Gay
Steffen
S
Ambartsumian
Noona
N
Hansen
Birgitte Schmidt
BS
Petersen
Jørgen
J
Lukanidin
Eugene
E
Grigorian
Mariam
M
D017209:Apoptosis; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000503:physiopathology*; D040502:Calgranulin B / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D006801:Humans; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000067616:S100A12 Protein; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
D040502:Calgranulin B; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; D000067616:S100A12 Protein; C090441:S100A12 protein, human; D016159:Tumor Suppressor Protein p53; C077591:S100A4 protein, human