Physiological and clinically attainable concentrations of 1,25-dihydroxyvitamin D3 suppress proliferation and extracellular matrix protein expression in mouse pancreatic stellate cells

Background/objectives: Vitamin D is an antiproliferative and differentiation-promoting secosteroid hormone with pleiotropic homeostatic functions in bone and extraskeletal tissues. Signaling of vitamin D is mediated via its ubiquitously expressed nuclear receptor, the vitamin D receptor (VDR). Pancreatic stellate cells have recently been identified as targets of vitamin D action. Our aim was to elucidate the effectiveness of the most potent endogenous vitamin D metabolite, 1,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3] on the proliferation and extracellular matrix (ECM) protein expression in pancreatic stellate cells (PSCs) using concentrations of the compound from the physiological and clinically attainable range in humans. Methods: Culture-activated mouse PSCs were exposed to 1,25(OH)(2)D-3 concentrations ranging from 0.1 nM to 10 nM for 7 days and subjected to calorimetric crystal violet assay for cell growth assessment and to Western blot and immunohistochemical analyses of VDR, fibronectin and collagen I using protein-specific antibodies. Immunohistochemical localization of VDR was performed on mouse pancreatic tissue and on a set of human specimens obtained at pancreatic surgery. Results: A low basal level of VDR was detected in PSCs that was strongly induced in the presence of ligand. Cell growth was suppressed dose-dependently by 1,25(OH)(2)D-3, the mean percentages of inhibition ranging from 24% at the physiological 0.1 nM concentration to around 60% at 10 nM. Significant 48% and 40% reductions in fibronectin expression were seen at 0.5 nM and I nM 1,25(OH)(2)D-3. A minor decrease in collagen I expression was detected at 5 nM. VDR was predominantly localized in the islets of Langerhans in mouse and human tissues. In the latter VDR was expressed also in the exocrine tissue showing individual variation in its cellular distribution. Conclusions: Mouse PSCs express VDR protein and are sensitive 1,25(OH)(2)D-3 target cells with low levels of 1,25(OH)(2)D-3 exerting antiproliferative and antifibrotic effects on activated PSCs in vitro. Copyright (C) 2015, LAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.