Vitamin D reduces the expression of collagen and key profibrotic factors by inducing an antifibrotic phenotype in mesenchymal multipotent cells

Department of Internal Medicine, Charles Drew University of Medicine & Science, Los Angeles, California 90059, USA.
Journal of Endocrinology (Impact Factor: 3.72). 12/2008; 200(2):207-21. DOI: 10.1677/JOE-08-0241
Source: PubMed


Hypovitaminosis D is an important public health problem. Serum 25-hydroxyvitamin D (25-OHD) is now recognized as an independent predictor for cardiovascular and related diseases (CVD) as well as other chronic medical conditions. However, the biologic pathways through which these effects are mediated remain poorly understood. We hypothesized that exposing mesenchymal multipotent cells (MMCs) to the active form of vitamin D would increase the expression of selected antifibrotic factors that in turn would ameliorate the progression of chronic diseases. MMCs were primed with 5'-azacytidine to induce a fibrotic phenotype and then treated with active vitamin D (1,25D) or ethanol <0.1% as vehicle in a time course manner (30 min, 1, 5, and 24 h, and for 4 and 7 days). The addition of 1,25D to MMCs promotes: a) increased expression and nuclear translocation of the vitamin D receptor; b) decreased expression of TGFB1 and plasminogen activator inhibitor (SERPINE1), two well-known profibrotic factors; c) decreased expression of collagen I, III and other collagens isoforms; and d) increased expression of several antifibrotic factors such as BMP7 a TGFB1 antagonist, MMP8 a collagen breakdown inducer and follistatin, an inhibitor of the profibrotic factor myostatin. In conclusion, the addition of 1,25D to differentiated MMCs displays a decreased profibrotic signaling pathway and gene expression, leading to decrease in collagen deposition. 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 CVD and related fibrotic disorders.

Download full-text


Available from: Keith C Norris, Jan 13, 2014
  • Source
    • "Various mechanisms have been proposed to explain the role of VDR signaling in fibrosis regulation, but it is still poorly understood. The activation of this pathway has been shown to inhibit myofibroblast activation [25], to induce differentiation of mesenchymal precursors into a non-fibrogenic phenotype [26] and to reduce inflammation through NF-κB sequestration [16]. These mechanisms are not mutually exclusive and might work together. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Fibrosis is a significant health problem associated with a chronic inflammatory reaction. The precise mechanisms involved in the fibrotic process are still poorly understood. However, given that inflammation is a major causative factor, immunomodulation is a possible therapeutic approach to reduce fibrosis. The vitamin D receptor (VDR) that is present in all hematopoietic cells has been associated with immunomodulation. We investigated whether the intraperitoneal administration of paricalcitol, a specific activator of the VDR, modulates peritoneal dialysis fluid (PDF)-induced peritoneal fibrosis. We characterized the inflammatory process in the peritoneal cavity of mice treated or not treated with paricalcitol and analyzed the ensuing fibrosis. The treatment reduced peritoneal IL-17 levels, which strongly correlated with a significantly lower peritoneal fibrotic response. In vitro studies demonstrate that both CD4+ and CD8+ regulatory T cells appear to impact the regulation of IL-17. Paricalcitol treatment resulted in a significantly increased frequency of CD8+ T cells showing a regulatory phenotype. The frequency of CD4+ Tregs tends to be increased, but it did not achieve statistical significance. However, paricalcitol treatment increased the number of CD4+ and CD8+ Treg cells in vivo. In conclusion, the activation of immunological regulatory mechanisms by VDR signaling could prevent or reduce fibrosis, as shown in peritoneal fibrosis induced by PDF exposure in mice.
    PLoS ONE 10/2014; 9(10):e108477. DOI:10.1371/journal.pone.0108477 · 3.23 Impact Factor
  • Source
    • "Vitamin D and liver fibrosis 1a,25(OH) 2 D has anti-fibrotic effects in lung fibroblasts and mesenchymal multipotent cells in vitro [60] [61], as well as antiproliferative and anti-fibrotic effects in both in vitro and in vivo rat models of liver fibrosis. VDR is expressed by hepatic stellate cells (HSC) and this expression is upregulated by 1a,25(OH) 2 D. In addition, 1a,25(OH) 2 D suppresses HSC proliferation, and expression of cyclin D1, tissue inhibitor of metalloproteinase 1 and collagen Ia1 in vitro. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Vitamin D is synthesized predominantly in the liver and functions as an important secosteroid hormone with pleiotropic effects. While its key regulatory role in calcium and bone homeostasis is well established, recently there is increasing recognition that vitamin D also regulates cell proliferation and differentiation, and has immunomodulatory, anti-inflammatory and anti-fibrotic properties. These non-skeletal effects are relevant in the pathogenesis and treatment of many causes of chronic liver disease. Vitamin D deficiency is frequently present in chronic liver disease and may predict non-response to antiviral therapy in chronic hepatitis C. Small studies suggest that vitamin D supplementation improves sustained viral response rates, while 1α-hydroxylase polymorphisms and vitamin D-binding protein are also implicated in therapeutic outcomes. Vitamin D deficiency also closely relates to the severity of non-alcoholic fatty liver disease (NAFLD) and is implicated in the pathogenesis of insulin resistance, a key factor in the development of NAFLD. In preclinical studies, phototherapy and vitamin D supplementation ameliorate NAFLD histopathology, while vitamin D is a powerful anti-fibrotic against thioacetamide liver injury. In liver transplant recipients severe vitamin D deficiency predicts, and vitamin D supplementation prevents, acute cellular rejection. The role of vitamin D in the activation and regulation of both innate and adaptive immune systems may explain its importance in the above liver diseases. Further prospective studies are therefore warranted to investigate the therapeutic impact of vitamin D supplementation in chronic liver disease.
    Journal of Hepatology 05/2012; 57(4):897-909. DOI:10.1016/j.jhep.2012.04.033 · 11.34 Impact Factor
  • Source
    • "It has been reported that VD3 (the active form of vitamin D) significantly promoted apoptosis in the undifferentiated gastric cancer cell line HGC-27 [8]. Vitamin D may prevent gastric cancers from progressing by modulating the extracellular microenvironment, as vitamin D has been shown to alter the expression of multiple genes in the extracelluar matrix remodeling [38,39]. VD3 can inhibit Wnt signaling by interrupting the crosstalk between tumor epithelial cells and its microenvironment [40]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Results from large epidemiologic studies on the association between vitamin D and gastric cancer are controversial. Vitamin D significantly promotes apoptosis in the undifferentiated gastric cancer cell, but the prognostic effects of its levels are unknown. 197 gastric carcinoma patients who received treatment in the cancer centre of Sun Yat-sen University from January 2002 to January 2006 were involved in the study. The stored blood drawn before any treatment was assayed for 25-hydroxyvitamin D levels. The clinicopathologic data were collected to examine the prognostic effects of vitamin D. The mean vitamin D levels of the 197 gastric patients was 49.85 ± 23.68 nmol/L, among whom 114(57.9%) were deficient in Vitamin D(< 50 nmol/L), 67(34%) were insufficient (50-75 nmol/L) and 16(8.1%) were sufficient (> 75 nmol/L). Clinical stage (P = 0.004) and lymph node metastasis classification (P = 0.009) were inversely associated with vitamin D levels. The patients with high vitamin D levels group (≥ 50 nmol/L) had a higher overall survival compared with the low vitamin D levels group (< 50 nmol/L)(P = 0.018). Multivariate analysis indicated that vitamin D levels were an independent prognostic factor of gastric cancer (P = 0.019). Vitamin D deficiency may be associated with poor prognosis in gastric cancer.
    Journal of Translational Medicine 01/2012; 10(1):16. DOI:10.1186/1479-5876-10-16 · 3.93 Impact Factor
Show more