B cell depletion therapy upregulates Dkk-1 skin expression in patients with systemic sclerosis: association with enhanced resolution of skin fibrosis

Abstract

BackgroundRituximab (RTX) may favorably affect skin and lung fibrosis in patients with systemic sclerosis (SSc); however, the underlying molecular mechanisms remain unknown. We aimed to explore the hypothesis that RTX may mediate its antifibrotic effects by regulating the expression of Dickkopf-1 (Dkk-1), an inhibitor of the Wnt pathway.MethodsFourteen patients with SSc and five healthy subjects were recruited. Dkk-1 expression was immunohistochemically assessed in skin biopsies obtained from 11 patients with SSc (8 treated with RTX and 3 with standard treatment), whereas DKK1 gene expression was assessed in 3 patients prior to and following RTX administration.ResultsIn baseline biopsies obtained from all patients with SSc but not in healthy subjects, Dkk-1 was undetectable in skin fibroblasts. Following RTX treatment, four out of eight patients had obvious upregulation of Dkk-1 skin expression. Similarly, RTX treatment correlated with a significant 4.8-fold upregulation of DKK1 gene expression (p = 0.030). In contrast, TGFβ expression in the upper dermis was significantly attenuated following treatment. Moreover, this decreased expression of TGFβ in the skin was significantly more pronounced in the subgroup of patients with Dkk-1 upregulation. In this subgroup TGFβ was downregulated by 50.88 % in contrast to only 15.98 % in patients who did not have Dkk-1 upregulation (p = 0.022).ConclusionsThis is the first study demonstrating a link between B cell depletion and skin Dkk-1 upregulation in patients with SSc. RTX-mediated B cell depletion may mechanistically function via the recently established TGFβ-Dkk-1 axis in improving skin fibrosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1017-y) contains supplementary material, which is available to authorized users.

Dkk1: A key molecule in joint remodelling and fibrosis

“…Our group investigated the hypothesis that Rituximab (RTX) exerts its antifibrotic effects through inhibition of the Wnt/β-catenin signaling. 68 We found that Dkk-1 was clearly expressed in skin biopsies obtained from healthy subjects; however, it was absent in all baseline biopsies obtained from patients with SSc. However, following RTX treatment, half of the patients exhibited Dkk-1 expression in the follow up skin biopsies; upregulation of Dkk-1 expression highly associated with enhanced resolution of skin fibrosis.…”

Wenyang Huazhuo Tongluo formula inhibits fibrosis via suppressing Wnt/β-catenin signaling pathway in a Bleomycin-induced systemic sclerosis mouse model

“…Therefore, Wnt/β-catenin signaling pathway may be acted as an important target for the treatment of SSc fibrosis. It may be one of effective ways to treat SSc fibrosis by regulating Wnt/β-catenin signaling pathway and its target genes [ 24 ]. In our previous study, we had found WYHZTL formula could inhibit the expression of cyclin D1 and survivin in skin fibroblasts of SSc patients [ 29 ].…”

“…On the contrary, Dkk1 inhibited Wnt/β-catenin signaling pathway by binding to LRP5 and LRP6, the Wnt receptor complex [ 22 ]. Akhmetshina et al [ 23 , 24 ] found that DKK1 expression was absent in SSc dermal fibroblasts and also significantly reduced in pulmonary fibrosis. The animal experiments showed that DKK1 overexpression inhibited Bleomycin-induced fibrosis [ 18 ].…”

Pharmacological Treatment of Fibrosis: a Systematic Review of Clinical Trials

“…Immunomodulatory monoclonal antibodies have shown promising potential for the treatment of systemic sclerosis. Targeting CD20 + cells with rituximab (RTX) resulted in the overexpression of the Wnt pathway inhibitor Dickkopf-1 in systemic sclerosis patients [86]. Moreover, RTX-treated patients showed a marked reduction in dermal TGF-β (subtype not specified) expression; histological analysis highlighted enhanced resolution of skin fibrosis following treatment, indicating that RTX-mediated B cell depletion might be an efficient strategy for the treatment of fibrotic conditions with an autoimmune aetiology.…”