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

Abstract

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.

Vitamin D Deficiency in a Cohort of Patients with Systemic Scleroderma from the South of Spain

“…Recently it was found that progression of fibrosis may be influenced by vitamin D deficiency decreasing the expression of antifibrotic factors 6 ; moreover, if the study conclusions warrant levels of vitamin D > 30 ng/ml, we will need to administer vitamin D in higher than the usual doses.…”

Disturbances of parathyroid hormone–vitamin D axis in non-cholestatic chronic liver disease: a cross-sectional study

“…It is notable that activities such as regulation of synthesis of metalloproteinase and their inhibitors, activation of fibroblasts, and collagen synthesis are also considered as properties of vitamin D [9][10][11]. These evidences bring this hypothesis in mind that vitamin D can have a role in progression of hepatic damage and CLD.…”

Vitamin D and the Cardiovascular System

“…The role of this paracrine production of 1,25(OH)D in these tissues is not well understood, but a variety of in vitro studies indicated that this process may be involved in a wide range of physiologic functions, including regulation of cytokines, inflammatory and/or fibrotic pathways, the renin-angiotensin system, vascular and cardiac cell function, immune response modulation, cell growth and differentiation, and others (7)(8)(9)(10)(11)(12)(13)(14)(15). Several of the biologic pathways through which the effects of 1,25(OH)D are mediated remain poorly understood but may account for its role in cardiovascular health (Figure 1).…”