Background Activated wingless-type MMTV integration site (Wnt)/β-catenin signaling pathway contributes fibrotic process in scleroderma. It affects the transformation of fibroblasts into activated fibroblasts (myofibroblasts) and also the transformation of non-fibroblastic cells to fibroblastic cells. Paricalcitol inhibits connection of T-cell factor (TCF-4) from transcription factors to the β-catenin as competitively through vitamin D receptor (VDR) and thus inhibits the activity of the Wnt/β-catenin signaling pathway.
Objectives The aim of our study is to determine prophylactic and therapeutic efficacy of inhibition of Wnt/β-catenin signaling pathway with paricalcitol which is synthetic vitamin D analog, in experimental scleroderma models created with bleomycin (BLM).
Methods 60 Balb/c female mice were taken to this study. 6 groups were formed as early stage groups (groups [Control group], II [placebo group] and III [paricalcitol group]) and late-stage groups (group IV [Control group], V [placebo group] VI [paricalcitol group]). Phosphate buffered saline (PBS) was applied subcutaneously to the control group of mice (group I) and (group IV) from shaved upper back region. 100 mg BLM (dissolved in 100 mL PBS) was applied subcutaneously and daily to mice in group of II and III along 3 weeks, in the group of V and VI along 6 weeks. In addition to BLM, paricalcitol (0.3 mg/kg) was injected to dorsal front of neck subcutaneously and daily to third group (prophylactic paricalcitol group) mice during first three week and to 6th group (therapeutic paricalcitol group) mice group from 21th day until the end of 6th week.
Mice were sacrificed by decapitation 24 hours after the last treatment (the first three groups at the end of the third week and the remaining three groups at the end of 6th week). Tissue samples were harvested for subsequent a pathological and real-time polymerase chain reaction (RT-PCR) analysis. Tissue TGF-β1, axin-1 and Wnt-2 mRNA expressions were determined by RT-PCR.
Results Repeated BLM applications increased the dermal inflammatory cell infiltration (Figure 1A) and dermal thickness (Figure 1B), and led to dermal fibrosis, in both early and late stages. Similarly, TGF-β1, axin-1 and wnt-2 expressions were significantly increased in the sham groups compared to the own control group (p<0.05 for all). Contrarily, prophylactic and therapeutic paricalcitol applications decreased the TGF-β1, axin-1 and Wnt-2 mRNA expressions compared to the own sham group (p<0.05 for all). In addition, the regressions in dermal necro-inflammation and dermal fibrosis on pathological views were also observed in the paricalcitol applied groups (Figure 1).
Conclusions In the BLM-induced dermal fibrosis model, increased axin-1 and wnt-2 mRNA expressions suggest that Wnt/β-catenin signaling pathway is active in dermal fibrosis. Moreover, paricalcitol has anti-fibrotic potential and this effect may be associated on Wnt/β-catenin signaling pathway.
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He W, et al. J Am Soc Nephrol 2011;22:90-103.
Disclosure of Interest None declared
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