Vitamin D reduces the expression of collagen and key profibrotic factors by inducing an antifibrotic phenotype in mesenchymal multipotent cells.
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.
Artaza
Jorge N
JN
Department of Internal Medicine, Charles Drew University of Medicine & Science, Los Angeles, California 90059, USA. jorgeartaza@cdrewu.edu
Norris
Keith C
KC
D000818:Animals; D055419:Bone Morphogenetic Protein 7 / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000187:drug effects*; D000431:Ethanol / Q000494:pharmacology; D005136:Eye Proteins / Q000187:drug effects; D005355:Fibrosis / Q000188:drug therapy*; D038681:Follistatin / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects*; D020784:Matrix Metalloproteinase 8 / Q000187:drug effects; D059630:Mesenchymal Stem Cells; D051379:Mice; D008809:Mice, Inbred C3H; D009414:Nerve Growth Factors / Q000187:drug effects; D018167:Receptors, Calcitriol / Q000187:drug effects; D015843:Serpins / Q000187:drug effects; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000187:drug effects; D014807:Vitamin D / Q000494:pharmacology*; D000099174:Pigment Epithelium-Derived Factor
D055419:Bone Morphogenetic Protein 7; D003094:Collagen; D000431:Ethanol; D005136:Eye Proteins; D038681:Follistatin; D020784:Matrix Metalloproteinase 8; D009414:Nerve Growth Factors; D018167:Receptors, Calcitriol; D015843:Serpins; D053773:Transforming Growth Factor beta1; D014807:Vitamin D; D000099174:Pigment Epithelium-Derived Factor; C508961:Tgfb1 protein, mouse; C525820:bmp7 protein, mouse