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VITAMIN D: A NOVEL

THERAPEUTIC APPROACH FOR
KELOID, AN IN VITRO ANALYSIS
G.Y. Zhang; T. Cheng; Q. Luan; T. Liao; C.L. Nie; X.
Zheng; X.G. Xie; W.Y. Gao

Posted: 05/12/2011; The British Journal of
Dermatology. 2011;164(4):729-737. © 2011 Blackwell
Publishing

bone remodelling. Recent studies also suggest a beneficial role of vitamin D in slowing the progression of tissue fibrosis. hormone secretion. However. their effects on dermal fibrosis and keloids are unknown .BACKGROUND  Vitamin D and its metabolites play an important role in calcium homeostasis. cell proliferation and differentiation.

25D) in the pathogenesis of tissue fibrosis by keloid fibroblasts (KFs) .OBJECTIVES  To investigate the effect of 1.25-dihydroxyvitamin D3 (1.

Collagen synthesis was evaluated by measuring Hproline incorporation. KF phenotypes and protein production were analysed by real-time reverse transcriptase-polymerase chain reaction. The effect of 1. Western blot. immunofluorescence and multiplex enzyme-linked immunosorbent assay techniques.METHODS  KFs were cultured and exposed to different concentrations of 1.25D in the presence or absence of transforming growth factor (TGF)-β1. 5-diphenyltetrazolium bromide.25D on cell proliferation and viability was evaluated by Formazan assay. proliferating cell nuclear antigen expression and the colorimetric conversion of 3-[4. . 5-dimethylthiazol2-yl]-2.

Incubation of KFs with 1. Fibroblasts transfected with a vitamin D response element reporter construct and exposed to the active vitamin D metabolite 1.25D suppressed TGF-β1-induced collagen type I.RESULTS   We confirmed the presence of vitamin D receptors (VDRs) in cultured keloid fibroblasts.25D also modulated plasminogen activator inhibitor-1 and matrix metalloproteinase-9 expression induced by TGF-β1. .25D induced hepatocyte growth factor mRNA expression and protein secretion in keloid fibroblasts. Interestingly. fibronectin and α-smooth muscle actin expression.25D showed increased promoter activity indicating VDR functionality in these cells. 1. 1.

CONCLUSIONS   This study highlights key mechanistic pathways through which vitamin D decreases fibrosis. and provides a rationale for studies to test vitamin D supplementation as a preventive and/or early treatment strategy for keloid and related fibrotic disorders. .

consistent with its role as a nuclear receptor. e.25D . systemic sclerosis. we demonstrated VDR expression in normal skin and keloid-derived fibroblasts. In the present study. Furthermore. and that it is functional as KFs transfected with a VDRE fused to a luciferase reporter showed increased expression of the transfected gene when exposed to 1. we found that VDR localizes to the nucleus. the real role of vitamin D in skin remains largely unexplored We hypothesized that vitamin D influences profibrogenic processes by targeting normal fibroblasts and KFs.g.DISCUSSION   Although clinical research has shown that vitamin D can inhibit the formation of skin fibrosis.

another important observation relates to the fact that 1.25D. TGF-β1 increased secretion of matrix proteins collagen type I. not unexpectedly. . These observations are important for the following reasons. FN and α-SMA and these effects were significantly inhibited by 1.25D was capable of inhibiting the TGF-β1-mediated tissue remodelling responses in KFs. much of the work on the role of vitamin D in TGF-β1-related fibrosis has been studied. in cells or organs known to be vitamin D targets. they confirm that KFs are indeed capable of recognizing 1. Secondly. As expected. Although quite limited.25D through functional VDRs. Firstly.

a potent collagen breakdown inducer.and decreased the PAI-1 expression. This demonstrates that modulating PAI-1 may contribute to the process of keloid formation and tissue fibrosis via enhancing the antiproteolytic activity of the ECM metabolism equilibrium towards a state of impaired degration .ultraviolet radiation-induced skin fibrosis. and viral myocarditis Incubation with 1. which cleaves collagen at a single site and renders it susceptible to degradation by other MMPs and proteases leading to a reversion of early fibrosis.  Activation of vitamin D pathways has been observed to decrease matrix expression and/or affect TGF-β1 signalling in experimental renal fibrosis.25D increased the expression of MMP-9.

which was confirmed by previous research.  HGF has recently been confirmed as an antifibrotic cytokine that prevents the genesis and progression of fibrotic lesions in keloids 1.25D also regulated HGF production by TGF-β1 in KFs.This establishes that HGF may act as a downstream effect that mediates the action of 1.25D ameliorates skin tissue fibrosis .25D in the keloid. These observations provide significant insights into understanding the mechanism by which 1.

such interaction between VDR and Smad3 results in an enhancement of TGF-β1 signalling.  One intriguing observation is that VDR interacts directly with Smad3. and therefore cannot account for an inhibitory effect of 1. the observation in the current study of the antifibrotic effect in keloid by the active form of vitamin D suggests a potential therapeutic effect for keloid .25D on TGF-β1 action Thus. However. thereby regulating TGFβ1/Smad signalling.

on the basis of our in vitro evidence we can state that 1.25D still need to be explored in KFs . the precise molecular mechanisms of the effects of 1.25D-targeted inhibition of ECM and induced HGF secretion may be an appropriate therapeutic strategy for the management of keloid. In conclusion. However.