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.
Highlights
Rituximab (RTX) may favorably affect skin and lung fibrosis in patients with systemic sclerosis (SSc); the underlying molecular mechanisms remain unknown
Dkk-1 following RTX treatment (Dkk-)1 deficiency in the skin of patients with scleroderma is restored following B cell depletion therapy Dkk-1 was expressed in the epidermis, appendices, and fibroblasts in the dermis in all the biopsies obtained
Taking into account recently reported data indicating that transforming growth factor β (TGFβ) regulates Dkk-1 expression, we asked whether TGFβ skin expression is modified following B cell depletion therapy
Summary
Rituximab (RTX) may favorably affect skin and lung fibrosis in patients with systemic sclerosis (SSc); the underlying molecular mechanisms remain unknown. Daoussis et al Arthritis Research & Therapy (2016) 18:118 concept of B cell depletion therapy in SSc [9, 10] It is currently not known how RTX may mediate its potential beneficial effects in SSc. experimental evidence indicates that B cells are critically involved in the fibrotic process [11,12,13,14]. It was found that transforming growth factor β (TGFβ), the most potent profibrotic molecule that is crucially involved in the pathophysiology of SSc, downregulates Dkk-1 expression [20] These data have unraveled a previously unknown link between TGFβ and the Wnt pathway (TGFβ → downregulation of Dkk-1 → upregulation of the Wnt pathway → fibrosis) and have highlighted the role of Dkk-1 in the fibrotic process
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call