Involvement of collagen-binding heat shock protein 47 in scleroderma-associated fibrosis

Abstract

Uncontrolled fibrosis of skin and internal organs is the main characteristic of scleroderma, and collagen is a major extracellular matrix protein that deposits in the fibrotic organs. As the chaperone of collagen, heat shock protein 47 (HSP47) is closely related with the development of fibrosis. To explore the potential function of HSP47 in the pathogenesis of scleroderma, the clinical, in vivo and in vitro studies were performed. In clinical, the increased mRNA level of HSP47 was observed in the skin fibroblasts and PBMC from scleroderma patients, and the enhanced protein level of HSP47 was also detected in the skin biopsy and plasma of the above patients. Unexpectedly, the enhanced levels of HSP47 were positively correlated with the presence of anti-centromere antibody in scleroderma patients. Moreover, a high expression of HSP47 was found in the skin lesion of BLM-induced scleroderma mouse model. Further in vitro studies demonstrated that HSP47 knockdown could block the intracellular and extracellular collagen over-productions induced by exogenous TGF-β. Therefore, the results in this study provide direct evidence that HSP47 is involved in the pathogenesis of scleroderma. The high expression of HSP47 can be detected in the circulatory system of scleroderma patients, indicating that HSP47 may become a pathological marker to assess the progression of scleroderma, and also explain the systemic fibrosis of scleroderma. Meanwhile, collagen over-expression is blocked by HSP47 knockdown, suggesting the possibility that HSP47 can be a potential therapeutic target for scleroderma.

Keywords

systemic sclerosis / fibrosis / collagen / heat shock protein 47 / anti-centromere antibody / therapeutic target

References

[1] Abraham DJ, Krieg T, Distler J, Distler O (2009) Overview of pathogenesis of systemic sclerosis. Rheumatology 48(Suppl 3): iii3-7

[2] Bhattacharyya S, Wei J, Varga J (2012) Understanding fibrosis in systemic sclerosis: shifting paradigms, emerging opportunities. Nat Rev Rheumatol 8: 42-54

[3] Bournia VK, Vlachoyiannopoulos PG, Selmi C, Moutsopoulos HM, Gershwin ME (2009) Recent advances in the treatment of systemic sclerosis. Clin Rev Allergy Immunol 36: 176-200

[4] Broen JC, Coenen MJ, Radstake TR (2012) Genetics of systemic sclerosis: an update. Curr Rheumatol Rep 14: 11-21

[5] Denton CP, Black CM, Abraham DJ (2006) Mechanisms and consequences of fibrosis in systemic sclerosis. Nat Clin Pract Rheumatol 2: 134-144

[6] Derk CT, Jimenez SA (2003) Systemic sclerosis: current views of its pathogenesis. Autoimmun Rev 2: 181-191

[7] Fujimoto M, Hamaguchi Y, Yazawa N, Komura K, Takehara K, Sato S (2004) Autoantibodies to a collagen-specific molecular chaperone, heat-shock protein 47, in systemic sclerosis. Clin Exp Immunol 138: 534-539

[8] Hagiwara S, Iwasaka H, Matsumoto S, Noguchi T, Yoshioka H (2007) Coexpression of HSP47 gene and type I and type III collagen genes in LPS-induced pulmonary fibrosis in rats. Lung 185: 31-37

[9] Hirayoshi K, Kudo H, Takechi H, Nakai A, Iwamatsu A, Yamada KM, Nagata K (1991) HSP47: a tissue-specific, transformation-sensitive, collagen-binding heat shock protein of chicken embryo fibroblasts. Mol Cell Biol 11: 4036-4044

[10] Hunzelmann N, Brinckmann J (2010) What are the new milestones in the pathogenesis of systemic sclerosis? Ann Rheum Dis 69 (Suppl 1): i52-56

[11] Ishida Y, Kubota H, Yamamoto A, Kitamura A, Bachinger HP, Nagata K (2006) Type I collagen in Hsp47-null cells is aggregated in endoplasmic reticulum and deficient in N-propeptide processing and fibrillogenesis. Mol Biol Cell 17: 2346-2355

[12] Jercan O, Penescu M, Malaescu DG (2012) Immunoexpression of alpha-SMA and CD68 in native kidney biopsies. Rom J Morphol Embryol= Revue roumaine de morphologie et embryologie 53: 1037-1042

[13] Kach J, Sandbo N, Sethakorn N, Williams J, Reed EB, La J, Tian X, Brain SD, Rajendran K, Krishnan R (2013) Regulation of myofibroblast differentiation and bleomycin-induced pulmonary fibrosis by adrenomedullin. Am J Physiol Lung Cell Mol Physiol 304: L757-764

[14] Kakugawa T, Mukae H, Hayashi T, Ishii H, Abe K, Fujii T, Oku H, Miyazaki M, Kadota J, Kohno S (2004) Pirfenidone attenuates expression of HSP47 in murine bleomycin-induced pulmonary fibrosis. Eur Respir J 24: 57-65

[15] Kakugawa T, Mukae H, Hishikawa Y, Ishii H, Sakamoto N, Ishimatsu Y, Fujii T, Koji T, Kohno S (2010) Localization of HSP47 mRNA in murine bleomycin-induced pulmonary fibrosis. Virchows Archiv Int J Pathol 456: 309-315

[16] Krieg T, Abraham D, Lafyatis R (2007) Fibrosis in connective tissue disease: the role of the myofibroblast and fibroblast-epithelial cell interactions. Arthritis Res Therapy 9(Suppl 2): S4

[17] Kurkinen M, Taylor A, Garrels JI, Hogan BL (1984) Cell surfaceassociated proteins which bind native type IV collagen or gelatin. J Biol Chem 259: 5915-5922

[18] Kuroda K, Tsukifuji R, Shinkai H (1998) Increased expression of heat-shock protein 47 is associated with overproduction of type I procollagen in systemic sclerosis skin fibroblasts. J Investig Dermatol 111: 1023-1028

[19] Leask A (2012) Emerging targets for the treatment of scleroderma. Expert Opin Emerg Drugs 17: 173-179

[20] Leask A, Abraham DJ (2004) TGF-beta signaling and the fibrotic response. FASEB J 18: 816-827

[21] Martin JE, Bossini-Castillo L, Martin J (2012) Unraveling the genetic component of systemic sclerosis. Hum Genet 131: 1023-1037

[22] Masi AT (1980) Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum 23: 581-590

[23] Masuda H, Fukumoto M, Hirayoshi K, Nagata K (1994) Coexpression of the collagen-binding stress protein HSP47 gene and the alpha 1(I) and alpha 1(III) collagen genes in carbon tetrachlorideinduced rat liver fibrosis. J Clin Investig 94: 2481-2488

[24] Mehra S, Walker J, Patterson K, Fritzler MJ (2013) Autoantibodies in systemic sclerosis. Autoimmun Rev 12: 340-354

[25] Nagata K (1998) Expression and function of heat shock protein 47: a collagen-specific molecular chaperone in the endoplasmic reticulum. Matrix Biol J Int Soc Matrix Biol 16: 379-386

[26] Nishino T, Miyazaki M, Abe K, Furusu A, Mishima Y, Harada T, Ozono Y, Koji T, Kohno S (2003) Antisense oligonucleotides against collagen-binding stress protein HSP47 suppress peritoneal fibrosis in rats. Kidney Int 64: 887-896

[27] Ohba S, Wang ZL, Baba TT, Nemoto TK, Inokuchi T (2003) Antisense oligonucleotide against 47-kDa heat shock protein (Hsp47) inhibits wound-induced enhancement of collagen production. Arch Oral Biol 48: 627-633

[28] Quan TE, Cowper S, Wu SP, Bockenstedt LK, Bucala R (2004) Circulating fibrocytes: collagen-secreting cells of the peripheral blood. Int J Biochem Cell Biol 36: 598-606

[29] Quan TE, Cowper SE, Bucala R (2006) The role of circulating fibrocytes in fibrosis. Curr Rheumatol Rep 8: 145-150

[30] Rabquer BJ, Koch AE (2012) Angiogenesis and vasculopathy in systemic sclerosis: evolving concepts. Curr Rheumatol Rep 14: 56-63

[31] Razzaque MS, Hossain MA, Kohno S, Taguchi T (1998) Bleomycininduced pulmonary fibrosis in rat is associated with increased expression of collagen-binding heat shock protein (HSP) 47. Virchows Arch Int J Pathol 432: 455-460

[32] Saga S, Nagata K, Chen WT, Yamada KM (1987) pH-dependent function, purification, and intracellular location of a major collagen-binding glycoprotein. J Cell Biol 105: 517-527

[33] Sapadin AN, Fleischmajer R (2002) Treatment of scleroderma. Arch Dermatol 138: 99-105

[34] Sasaki H, Sato T, Yamauchi N, Okamoto T, Kobayashi D, Iyama S, Kato J, Matsunaga T, Takimoto R, Takayama T (2002) Induction of heat shock protein 47 synthesis by TGF-beta and IL-1 beta via enhancement of the heat shock element binding activity of heat shock transcription factor 1. J Immun 168: 5178-5183

[35] Verrecchia F, Mauviel A, Farge D (2006) Transforming growth factorbeta signaling through the Smad proteins: role in systemic sclerosis. Autoimmun Rev 5: 563-569

[36] Wang JC, Lai S, Guo X, Zhang X, de Crombrugghe B, Sonnylal S, Arnett FC, Zhou X (2010) Attenuation of fibrosis in vitro and in vivo with SPARC siRNA. Arthritis Res Therapy 12: R60

[37] Wang JC, Sonnylal S, Arnett FC, De Crombrugghe B, Zhou X (2011) Attenuation of expression of extracellular matrix genes with siRNAs to Sparc and Ctgf in skin fibroblasts of CTGF transgenic mice. Int J Immunopathol Pharmacol 24: 595-601

[38] Wu T, Chu H, Tu W, Song M, Chen D, Yuan J, Yu L, Ma Y, Liu Q, Jin L (2014) Dissection of the mechanism of traditional Chinese medical prescription-Yiqihuoxue formula as an effective antifibrotic treatment for systemic sclerosis. BMC Complement Altern Med 14: 224

[39] Xiao HB, Liu RH, Ling GH, Xiao L, Xia YC, Liu FY, Li J, Liu YH, Chen QK, Lv JL (2012) HSP47 regulates ECM accumulation in renal proximal tubular cells induced by TGF-beta1 through ERK1/ 2 and JNK MAPK pathways. Am J Physiol Renal Physiol 303: F757-765

[40] Yan JD, Yang S, Zhang J, Zhu TH (2009) BMP6 reverses TGFbeta1- induced changes in HK-2 cells: implications for the treatment of renal fibrosis. Acta Pharmacol Sin 30: 994-1000

[41] Yokota S, Kubota H, Matsuoka Y, Naitoh M, Hirata D, Minota S, Takahashi H, Fujii N, Nagata K (2003) Prevalence of HSP47 antigen and autoantibodies to HSP47 in the sera of patients with mixed connective tissue disease. Biochem Biophys Res Commun 303: 413-418

[42] Yoshizaki A, Yanaba K, Yoshizaki A, Iwata Y, Komura K, Ogawa F, Takenaka M, Shimizu K, Asano Y, Hasegawa M (2010) Treatment with rapamycin prevents fibrosis in tight-skin and bleomycin-induced mouse models of systemic sclerosis. Arthritis Rheum 62: 2476-2487

[43] Zandman-Goddard G, Tweezer-Zaks N, Shoenfeld Y (2005) New therapeutic strategies for systemic sclerosis—a critical analysis of the literature. Clin Dev Immunol 12: 165-173

RIGHTS & PERMISSIONS

2014 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.