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

Haiyan Chu,Wenzhen Tu,Yanyun Ma,Qingmei Liu,Shuai Jiang,Sidi Chen,Jiucun Wang,Li Jin,Wenyu Wu,Ting Wu,Xiaodong Zhou

doi:10.1007/s13238-015-0171-3

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.

Highlights

Systemic sclerosis is a complex autoimmune disease in which excessive accumulation of extracellular matrix (ECM) in the skin and internal organs is a major pathological finding
Since heat shock protein 47 (HSP47) is pivotal for the production of collagen, which closely related to fibrosis development of SSc, our aim was to explore the role of HSP47 in the regulation of collagen protein expression during fibrosis development of SSc and whether HSP47 would be a new serum marker to assess the fibrosis activity of the disease
The uncontrolled synthesis and excessive deposition of collagen are the main characteristics of fibrotic disorders

Summary

Introduction

Systemic sclerosis (scleroderma, SSc) is a complex autoimmune disease in which excessive accumulation of extracellular matrix (ECM) in the skin and internal organs is a major pathological finding. The etiology of this disease remains unknown, a number of therapeutic approaches are available for treating scleroderma, including circulation improvement, blocking production of certain pro-inflammatory and pro-fibrotic cytokines, as well as fibrosis prevention and treatment (Bournia et al, 2009; Sapadin and Fleischmajer, 2002), due to vascular, immunologic and fibrotic alterations in SSc (Denton et al, 2006). None of these treatments are consistently effective in attenuating fibrosis (Leask, 2012; Martin et al, 2012; Zandman-Goddard et al, 2005). After the triple helix collagen formation, HSP47 and the triple helix proceed to the Golgi, where HSP47 dissociates from the procollagen in the cis-Golgi complex (Nagata, 1998)

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