The role of new pro-inflammatory and/or pro-fibrotic molecules in the pathogenesis of systemic sclerosis

Czech version

Authors: M. Tomčík
Authors‘ workplace: 1. lékařská fakulta Univerzity Karlovy v Praze
Published in: Čes. Revmatol., 22, 2014, No. 3, p. 127-142.
Category: The summary of the dissertation

Overview

Introduction:
Systemic sclerosis (SSc) is a generalized connective tissue disease affecting the skin and internal organs. The pathogenesis of SSc is characterized by inflammation, vasculopathy and fibrosis. To date, none of the tested drugs have demonstrated convincing efficacy in the treatment of SSc. S100A4 is involved in the regulation of cell motility, proliferation, apoptosis, angiogenesis and remodeling of the extracellular matrix. It was originally described as a promoter of metastasis in tumors, however, its pro-inflammatory properties have recently been demonstrated in inflammatory rheumatic diseases. The aim of this study was to assess the role of S100A4 in pathological activation of fibroblasts in SSc and in experimental models of dermal fibrosis.

Results:
The expression of S100A4 was increased in the skin of SSc patients, in SSc fibroblasts and in experimental fibrosis in a TGF-ß / Smad dependent manner. Overexpression of S100A4 or stimulation with recombinant S100A4 induced an activated phenotype in resting normal fibroblasts. In contrast, inhibition of S100A4 or its complete deficit abrogated the pro-fibrotic effects of TGF-ß and decreased the release of collagen. S100A4 knock-out mice (S100A4-/-) were protected from bleomycin-induced skin fibrosis with reduced dermal thickening, decreased hydroxyproline content and lower counts of activated fibroblasts, so called myofibroblasts. Similarly, deficiency of S100A4 also ameliorated fibrosis in the Tight skin-1 (Tsk-1) mouse model. Anti-fibrotic effects of the inactivation of S100A4 in both experimental models of dermal fibrosis were mediated by inhibition of TGF-ß / Smad signaling.

Conclusion:
Our results characterize S100A4 as a positive regulator of the stimmulatory effects of TGF-ß on fibroblasts in SSc. S100A4 is induced by TGF-ß and in turn amplifies the stimulatory effects of canonical TGF-ß / Smad signaling on collagen synthesis by SSc fibroblasts and on induction of fibrosis. Since S100A4 is essentially required for the pro-fibrotic effects of TGF-ß and neutralizing antibodies against S100A4 are currently evaluated in tumors, S100A4 might become a candidate molecule for novel anti-fibrotic therapies.

Key words:
S100A4, fibrosis, scleroderma, Smad3, fibroblasts

Sources

1. Abraham DJ, Varga J. Scleroderma: from cell and molecular mechanisms to disease models. Trends Immunol 2005; 26(11): 587–595.

2. Mayes MD, et al. Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum 2003; 48(8): 2246–2255.

3. LeRoy EC. Increased collagen synthesis by scleroderma skin fibroblasts in vitro: a possible defect in the regulation or activation of the scleroderma fibroblast. J Clin Invest 1974; 54(4): 880–889.

4. Pannu J, Trojanowska M. Recent advances in fibroblast signaling and biology in scleroderma. Curr Opin Rheumatol 2004; 16(6): 739–745.

5. Massague J, Gomis RR. The logic of TGFbeta signaling. FEBS Lett 2006; 580(12): 2811–2820.

6. Varga J, Bashey RI. Regulation of connective tissue synthesis in systemic sclerosis. Int Rev Immunol 1995; 12(2–4): 187–199.

7. Beyer C, et al. Animal models of systemic sclerosis: prospects and limitations. Arthritis Rheum 2010; 62(10): 2831–2844.

8. Yamamoto T, et al. Animal model of sclerotic skin. I: Local injections of bleomycin induce sclerotic skin mimicking scleroderma. J Invest Dermatol 1999; 112(4): 456–462.

9. Saito E., et al. CD19–dependent B lymphocyte signaling thresholds influence skin fibrosis and autoimmunity in the tight–skin mouse. J Clin Invest 2002; 109(11): 1453–1462.

10. Ebralidze A, 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(7): 1086–1093.

11. Moore BW. A soluble protein characteristic of the nervous system. Biochem Biophys Res Commun 1965; 19(6): 739–744.

12. Santamaria–Kisiel L, et al. Calcium–dependent and –independent interactions of the S100 protein family. Biochem J 2006; 396(2): 201–214.

13. Donato R. Intracellular and extracellular roles of S100 proteins. Microsc Res Tech 2003; 60(6): 540–551.

14. Ambartsumian N, et al. The metastasis–associated Mts1(S100A4) protein could act as an angiogenic factor. Oncogene 2001; 20(34): 4685–4695.

15. Senolt L, et al. S100A4 is expressed at site of invasion in rheumatoid arthritis synovium and modulates production of matrix metalloproteinases. Ann Rheum Dis 2006; 65(12): 1645–1648.

16. Novitskaya V, et al. Oligomeric forms of the metastasis–related Mts1 (S100A4) protein stimulate neuronal differentiation in cultures of rat hippocampal neurons. J Biol Chem 2000; 275(52): 41278–41286.

17. Kimura K, et al. Clinical significance of S100A4 and E-cadherin-related adhesion molecules in non–small cell lung cancer. Int J Oncol 2000; 16(6): 1125–1131.

18. Saleem M, et al. Prognostic significance of metastasis–associated protein S100A4 (Mts1) in prostate cancer progression and chemoprevention regimens in an autochthonous mouse model. Clin Cancer Res 2005; 11(1): 147–153.

19. Davies BR, et al. Expression of S100A4 protein is associated with metastasis and reduced survival in human bladder cancer.J Pathol 2002; 196(3): 292–299.

20. Rosty C, et al. Overexpression of S100A4 in pancreatic ductal adenocarcinomas is associated with poor differentiation and DNA hypomethylation. Am J Pathol 2002; 160(1): 45–50.

21. Yonemura Y, et al. Inverse expression of S100A4 and E-cadherin is associated with metastatic potential in gastric cancer. Clin Cancer Res 2000; 6(11): 4234–4242.

22. Andersen K, et al. Expression of S100A4 combined with reduced E–cadherin expression predicts patient outcome in malignant melanoma. Mod Pathol 2004; 17(8): 990–997.

23. Boye K, et al. Nuclear S100A4 is a novel prognostic marker in colorectal cancer. Eur J Cancer 2010; 46(16): 2919–2925.

24. Boye K, Maelandsmo GM. S100A4 and metastasis: a small actor playing many roles. Am J Pathol 2010; 176(2): 528–535.

25. Schneider M, et al. S100A4: a common mediator of epithelial-mesenchymal transition, fibrosis and regeneration in diseases?J Mol Med (Berl) 2008; 86(5): 507–522.

26. Cerezo LA, et al. The metastasis promoting protein S100A4 is increased in idiopathic inflammatory myopathies. Rheumatology (Oxford) 2011; 50(10): 1766–1772.

27. Zibert JR, et al. Significance of the S100A4 protein in psoriasis. J Invest Dermatol 2010; 130(1): 150–160.

28. LeRoy EC, Medsger TA, Jr. Criteria for the classification of early systemic sclerosis. J Rheumatol 2001; 28(7): 1573–1576.

29. EL Naamam C, et al. Cancer predisposition in mice deficient for the metastasis-associated Mts1(S100A4) gene. Oncogene 2004; 23(20): 3670–3680.

30. Woessner JF, Jr. The determination of hydroxyproline in tissue and protein samples containing small proportions of this imino acid. Arch Biochem Biophys 1961; 93: 440–447.

31. Xie R., et al. S100A4 mediates endometrial cancer invasion and is a target of TGF–beta1 signaling. Lab Invest 2009; 89(8): 937–947.

32. Kawakita T., et al. Activation of Smad–mediated TGF–beta signaling triggers epithelial-mesenchymal transitions in murine cloned corneal progenitor cells. J Cell Physiol 2013; 228(1): 225–234.

33. Beyer C., et al. Hypoxia. Hypoxia in the pathogenesis of systemic sclerosis. Arthritis Res Ther 2009; 11(2): 220.

34. Distler J.H., et al. Hypoxia-induced increase in the production of extracellular matrix proteins in systemic sclerosis. Arthritis Rheum 2007; 56(12): 4203–4215.

35. Copple BL. Hypoxia stimulates hepatocyte epithelial to mesenchymal transition by hypoxia–inducible factor and transforming growth factor-beta-dependent mechanisms. Liver Int. 2010; 30(5): 669–682.

36. Matsuura I., et al. Functional interaction between Smad3 and S100A4 (metastatin-1) for TGF-beta-mediated cancer cell invasiveness. Biochem J 2010; 426(3): 327–335.

37. Green MC, et al. Tight-skin, a new mutation of the mouse causing excessive growth of connective tissue and skeleton. Am J Pathol 1976; 82(3): 493–512.

38. Lawson WE, et al. Characterization of fibroblast–specific protein 1 in pulmonary fibrosis. Am J Respir Crit Care Med 2005; 171(8): 899–907.

39. Zeisberg EM, et al. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat Med 2007; 13(8): 952–961.

40. Sack U, et al. S100A4-induced cell motility and metastasis is restricted by the Wnt/beta-catenin pathway inhibitor calcimycin in colon cancer cells. Mol Biol Cell. 2011; 22(18): 3344–3354.

41. Valentini G., et al. Assessment of disease activity. Clin Exp Rheumatol. 2003; 21(3 Suppl 29): S39–41.

Labels

Dermatology & STDs Paediatric rheumatology Rheumatology

Inflammatory back pain – significance in screening and diagnosis of spondyloarthritis

Article was published in

Czech Rheumatology

2014 Issue 3