The role of S100A4 protein in rheumatoid arthritis

Authors: L. Ošlejšková;  L. Šenolt
Authors‘ workplace: Revmatologický ústav, 1. lékařská fakulta, Univerzita Karlova, Praha
Published in: Čes. Revmatol., 15, 2007, No. 3, p. 146-151.
Category: Overview Reports


S100A4 protein belongs to the large group of calcium binding protein family that consists of more than 25 low-weight molecules and appears to play regulatory roles in diverse biological activities. The S100A4 protein participates in the regulation of cell motility, proliferation and apoptosis, angiogenesis and remodeling of extracellular matrix. Functional role of S100A4 is associated with metastasis and the protein is suggested as a prognostic marker for various types of cancers. Increased expression of S100A4 mRNA was recently detected in proliferating synovial fibroblasts in rheumatoid arthritis (RA). Up-regulation of S100A4 protein in RA synovial tissue compared with osteoarthritic and control tissues have been also demonstrated. Moreover, the protein has been found at the sites of joint invasion. S100A4 is produced not only by synovial fibroblasts but also by several immune and vascular cells. Increased amount of bioactive S100A4 oligomer was determined not only locally at the inflammatory synovial tissue but also in plasma and synovial fluid. Consistently with the data in cancer studies, extracellular S100A4 oligomer can stimulate production of several matrix degrading enzymes – metaloproteinases and modulate biological function of the tumor suppressor protein p53 in synovial fibroblasts. Taken together, one can speculate that increased S100A4 protein might be implicated in the process of aggressive fibroblast behavior contributing to the pathogenesis of chronic autoimmune inflammatory rheumatic diseases.

Key words:
rheumatoid arthritis, S100A4, apoptosis, matrix degrading enzymes, synovial fibroblasts


1. Moore, B. W. A soluble protein characteristic of the nervous system. Biochem Biophys Res Commun 1965;19: 739–44.

2. Isobe T, Okuyama T. The amino-acid sequence of S-100 protein (PAP I-b protein) and its relation to the calcium-binding proteins. Eur J Biochem 1978;89:379–88.

3. Santamaria-Kisiel L, Rintala-Dempsey AC, Shaw GS. Calcium-dependent and-independent interactions of the S100 protein family. Biochem J 2006;396:201–14.

4. Heizmann CW, Cox JA. New perspectives on S100 proteins: a multi-functional Ca(2+)-, Zn(2+)- and Cu(2+)-binding protein family. Biometals 1998;11:383–97.

5. Strupat K, Rogniaux H, Van Dorsselaer A, Roth J, Vogl T. Calcium-induced noncovalently linked tetramers of MRP8 and MRP14 are confirmed by electrospray ionisation-mass analysis. J Am Soc Mass Spectrom 2000;11:780–788.

6. Vogl T, Leukert N, Barczyk K, Strupat K, Roth J. 2006. Biophysical characterization of S100A8 and S100A9 in the absence and presence of bivalent cations. Biochem Biophys Acta 1763:1298–306.

7. Moroz OV, Antson AA, Dodson EJ, et al. The structure of S100A12 in a hexameric form and its proposed role in receptor signalling. Acta Crystallogr D Biol Crystallogr 2002;58:407–13.

8. Klingelhofer J, Senolt L, Baslund B, et al. Up-regulation of metastasis-promoting S100A4 (Mts 1) in Rheumatoid Arthritis: putative involvement in the pathogenesis of RA. Arthritis Rheum 2007 Mar; 56:779–89.

9. Donato R. Intracellular and extracellular roles of S100 proteins. Microsc Res Tech 2003;60:540–51.

10. Huttunen HJ, Kuja-Panula J, Sorci G, Agneletti AL, Donato R, Rauvala H. 2000. Coregulation of neurite outgrowth and cell survival by amphoterin and S100 proteins through RAGE activation. J Biol Chem 275: 40096–40105.

11. Hofmann MA, Drury S, Fu C, Qu W, Taguchi A, Lu Y, et al. RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell 1999;97:889–901.

12. Robinson MJ, Tessier P, Poulsom R, Hogg N. The S100 family heterodimer, MRP-8/14, binds with high affinity to heparin and heparan sulfate glycosaminoglycans on endothelial cells. J Biol Chem 2002;277: 3658–65.

13. Marx J. Inflammation and cancer: the link grows stronger. Science 2004;306:966–8.

14. Lee WY, Su WC, Lin PW, Guo HR, Chang TW, Chen HH. Expression of S100A4 and Met: potential predictors for metastasis and survival in early stage breast cancer. Oncology 2004;66:429–38.

15. Gupta S, Hussain T, MacLennan GT, Fu P, Patel J, Mukhtar H. Differential expression of S100A2 and S100A4 during progression of human prostate adenocarcinoma. J Clin Oncol 2003;21:106–12.

16. Ambartsumian NS, Grigorian MS, Larsen IF, Karlstrom O, Sidenius N, Rygaard J, et al. Metastasis of mammary carcinomas in GRS/A hybrid mice transgenic for the mts1 gene. Oncogene 1996; 13: 1621–30.

17. Senolt L, Grigorian M, Lukanidin E, et al. S100A4 (Mts1): is there any relation to the pathogenesis of rheumatoid arthritis? Autoimmun Rev 2006;5:129–31.

18. Senolt L, Grigorian M, Lukanidin E, Simmen B, Michel BA, Pavelka K, et al. S100A4 is expressed at site of invasion in rheumatoid arthritis synovium and modulates production of matrix metalloproteinases. Ann Rheum Dis 2006;65:1645–8.

19. Ebralidze A, Tulchinsky E, Grigorian M, et al. Isolation and characterization of a gene specifically expressed in different metastatic cells and whose deduced gene product has a high degree of homology to a Ca2+-binding protein family. Genes Dev 1989;3: 1086–93.

20. Takenaga K, Nakamura Y, Sakiyama S, Hasegawa Y, Sato K, Endo H. Binding of pEL98 protein, an S100-related calcium-binding protein, to nonmuscle tropomyosin. J Cell Biol 1994;124:757–68.

21. Gibbs FE, Barraclough R, Platt-Higgins A,et al. Immunocytochemical distribution of the calcium-binding protein p9Ka in normal rat tissues: variation in the cellular location in different tissues. J Histochem Cytochem 1995;43:169–80.

22. Grigorian M, Tulchinsky E, Burrone O, Tarabykina S, Georgiev G, Lukanidin E. Modulation of mts1 expression in mouse and human normal and tumor cells. Electrophoresis 1994;15:463–8.

23. Mazzucchelli L. Protein S100A4: too long overlooked by pathologists? Am J Pathol 2002;160:7–13.

24. Wang G, Rudland PS, White MR, Barraclough R. Interaction in vivo and in vitro of the metastasis-inducing S100 protein, S100A4 (p9Ka) with S100A1. J Biol Chem 2000;275:11141–6.

25. Tarabykina S, Kriajevska M, Scott DJ, Hill TJ, Lafitte D,et al. Heterocomplex formation between metastasis-related protein S100A4 (Mts1) and S100A1 as revealed by the yeast two-hybrid system. FEBS Lett 2000;475:187–91.

26. Kriajevska MV, Cardenas MN, Grigorian MS, Ambartsumian NS, Georgiev GP and Lukanidin EM. Non-muscle myosin heavy chain as a possible target for protein encoded by metastasis-related mts-1 gene. J Biol Chem 1994;269:19679–82.

27. Kriajevska M, Fischer-Larsen M, Moertz E, et al. Liprin beta 1, a member of the family of LAR transmembrane tyrosine phosphatase-interacting proteins, is a new target for the metastasis-associated protein S100A4 (Mts1). J Biol Chem 2002;277:5229–35.

28. Grigorian M, Andresen S, Tulchinsky E, Kriajevska M, Carlberg C, Kruse C, Cohn M, Ambartsumian N, Christensen A, Selivanova G, Lukanidin E. Tumor suppressor p53 protein is a new target for the metastasis-associated Mts1/S100A4 protein: functional consequences of their interaction. J Biol Chem 2001;276: 22699–708.

29. Davies BR, Davies MP, Gibbs FE, Barraclough R, Rudland PS. Induction of the metastatic phenotype by transfection of a benign rat mammary epithelial cell line with the gene for p9Ka, a rat calcium-binding protein, but not with the oncogene EJ-ras-1. Oncogene 1993;8:999–1008.

30. Novitskaya V, Grigorian M, Kriajevska M, Tarabykina S, Bronstein I, Berezin V, Bock E, Lukanidin E. Oligomeric forms of the metastasis-related Mts1 (S100A4) protein stimulate neuronal differentiation in cultures of rat hippocampal neurons J Biol Chem 2000;275: 41278-86.

31. Belot N, Pochet R, Heizmann CW, Kiss R, Decaestecker C. Extracellular S100A4 stimulates the migration rate of astrocytic tumor cells by modifying the organization of their actin cytoskeleton. Biochim Biophys Acta 2002;1600:74–83.

32. Ambartsumian N, Klingelhofer J, Grigorian M, Christensen C, Kriajevska M, Tulchinsky E, Georgiev G, Berezin V, Bock E, Rygaard J, Cao R, Cao Y, Lukanidin E. The metastasis-associated Mts1(S100A4) protein could act as an angiogenic factor. Oncogene 2001;20: 4685–95.

33. Schmidt-Hansen B., ÖrnĆs D., Grigorian M., Tulchinsky E, Lukanidin E, Ambartsumian N. Extracellular S100A4 (mts1) stimulates invasive growth of mouse endothelial cells and modulates MMP-13 matrix metalloproteinase activity. Oncogene 2004;23:5487–95.

34. Duarte WR, Shibata T, Takenaga K, et al. S100A4: a novel negative regulator of mineralization and osteoblast differentiation. J Bone Miner Res 2003;18:493–501.

35. Kriajevska M, Tarabykina S, Bronstein I, et al. Metastasis-associated Mts1 (S100A4) protein modulates protein kinase C phosphorylation of the heavy chain of nonmuscle myosin. J Biol Chem 1998;273:9852–6.

36. Kriajevska M, Bronstein IB, Scott DJ, et al. Metastasis-associated protein Mts1 (S100A4) inhibits CK2-mediated phosphorylation and self-assembly of the heavy chain of nonmuscle myosin Biochim Biophys Acta 2000;1498: 252–63.

37. Kimura K, Endo Y, Yonemura Y, et al. Clinical significance of S100A4 and E-cadherin-related adhesion molecules in non-small cell lung cancer. Int J Oncol 2000;16: 1125–31.

38. Keirsebilck A, Bonne S, Bruyneel E, et al. E-cadherin and metastasin (mts-1/S100A4) expression levels are inversely regulated in two tumor cell families. Cancer Res 1998;58:4587–91.

39. Parker C, Lakshmi MS, Piura B, Sherbet GV. Metastasis-associated mts1 gene expression correlates with increased p53 detection in the B16 murine melanoma. DNA Cell Biol 1994;13:343–51.

40. EL Naaman C, Grum-Schwensen B, Mansouri A, et al. Cancer predisposition in mice deficient for the metastasis-associated Mts1(S100A4) gene. Oncogene 2004;23: 3670 –80.

41. Schmidt-Hansen B, Klingelhöfer J, Grum-Schwensen B, Christensen A, Andresen A, Kruse C, Ambartsumian N, Lukanidin E, Grigorian M. Functional significance of S100A4 (Mts1) in tumor-stroma interplay. J Biol Chem 2004;279:24498–504.

42. Roberts DD. Regulation of tumor growth and metastasis by thrombospondin-1. FASEB J 1996;10:1183–91.

43. Michael S. Pepper. Role of the Matrix Metalloproteinase and Plasminogen Activator–Plasmin Systems in Angiogenesis. Arterioscler Thromb Vasc Biol 2001;21:1104–17.

44. Bjornland K, Winberg JO, Odegaard OT, et al. S100A4 involvement in metastasis: deregulation of matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases in osteosarcoma cells transfected with an anti-S100A4 ribozyme. Cancer Res 1999;59:4702–8.

45. Saleem M, Kweon MH, Johnson JJ, et al. S100A4 accelerates tumorigenesis and invasion of human prostate cancer through the transcriptional regulation of matrix metalloproteinase 9. Proc Natl Acad Sci U S A. 2006;103: 14825–30.

46. Helfman DM, Kim EJ, Lukanidin E, Grigorian M. The metastasis associated protein S100A4: role in tumour progression and metastasis. Br J Cancer 2005;92:1955–8.

47. Stanczyk J, Ospelt C, Gay RE, Gay S. Synovial cell activation. Curr Opin Rheumatol. 2006;18:262–7.

48. Huber LC, Distler O, Tarner I, Gay RE, Gay S, Pap T. Synovial fibroblasts: key players in rheumatoid arthritis. Rheumatology (Oxford). 2006;45:669–75.

49. Masuda K, Masuda R, Neidhart M, Simmen BR, et al. Molecular profile of synovial fibroblasts in rheumatoid arthritis depends on the stage of proliferation. Arthritis Res 2002; 4(5):R8.

50. Yammani RR, Carlson CS, Bresnick AR, Loeser RF. Increase in production of matrix metalloproteinase 13 by human articular chondrocytes due to stimulation with S100A4: Role of the receptor for advanced glycation end products. Arthritis Rheum 2006;54:2901–11.

Dermatology & STDs Paediatric rheumatology Rheumatology
Forgotten password

Don‘t have an account?  Create new account

Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.


Don‘t have an account?  Create new account