Collagen triple helix repeat containing-1 exerts antifibrotic effects on human skin fibroblast and bleomycin-induced dermal fibrosis models

Abstract

BACKGROUND: Systemic scleroderma (SSc) is an acquired disorder characterized by excessive deposition of extracellular matrix in the skin and internal organs. So far, the molecular mechanisms underpinning the pathogenesis of SSc have remained unknown. Collagen triple helix repeat containing-1 (CTHRC1) has been indicated to be a cell type-specific inhibitor of transforming growth factor-β (TGF-β), which could have the potential for extensive clinical application owing to its ability to reduce collagen deposition. Our previous studies showed that CTHRC1 inhibited TGF-β1-induced collagen type I synthesis in keloid fibroblasts. In our present research, we attempted to probe the role of CTHRC1 in dermal fibrosis in bleomycin (BLM)-treated mice. METHODS: CTHRC1 and TGF-β1 expression was detected in dermal tissues from patients with SSc and BLM-treated mice by immunohistochemistry. A 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay was used to assess TGF-β1-induced proliferation of human dermal fibroblasts. Collagen expression and fibroblast synthesis were evaluated by quantitative real-time polymerase chain reaction and the 3H-proline incorporation. Masson's trichrome staining and western blotting were carried out to analyze the deposits and protein levels of type I collagen, respectively. RESULTS: Compared with those in normal tissues, the levels of CTHRC1 and TGF-β1 were elevated in dermal tissues from patients with SSc and in skin tissues from BLM-treated mice, respectively. Furthermore, recombinant CTHRC1 was found to inhibit TGF-β1-stimulated collagen deposition by fibroblasts. Finally, the in vivo experiments showed that CTHRC1 alleviated BLM-induced dermal fibrotic changes. CONCLUSIONS: CTHRC1 can inhibit human dermal fibroblast collagen deposition and can also exert protective effects against BLM-induced dermal fibrosis in mice. This research provides an indication that CTHRC1 may be a promising treatment choice for dermal fibrosis in SSc patients.