title: Effect of natural uranium on the UMR-106 osteoblastic cell line: impairment of the autophagic process as an underlying mechanism of uranium toxicity.
abstract: Natural uranium (U), which is present in our environment, exerts a chemical toxicity, particularly in bone where it accumulates. Generally, U is found at oxidation state +VI in its oxocationic form [Formula: see text] in aqueous media. Although U(VI) has been reported to induce cell death in osteoblasts, the cells in charge of bone formation, the molecular mechanism for U(VI) effects in these cells remains poorly understood. The objective of our study was to explore U(VI) effect at doses ranging from 5 to 600 µM, on mineralization and autophagy induction in the UMR-106 model osteoblastic cell line and to determine U(VI) speciation after cellular uptake. Our results indicate that U(VI) affects mineralization function, even at subtoxic concentrations (<100 µM). The combination of thermodynamic modeling of U with EXAFS data in the culture medium and in the cells clearly indicates the biotransformation of U(VI) carbonate species into a meta-autunite phase upon uptake by osteoblasts. We next assessed U(VI) effect at 100 and 300 µM on autophagy, a survival process triggered by various stresses such as metal exposure. We observed that U(VI) was able to rapidly activate autophagy but an inhibition of the autophagic flux was observed after 24 h. Thus, our results indicate that U(VI) perturbs osteoblastic functions by reducing mineralization capacity. Our study identifies for the first time U(VI) in the form of meta-autunite in mammalian cells. In addition, U(VI)-mediated inhibition of the autophagic flux may be one of the underlying mechanisms leading to the decreased mineralization and the toxicity observed in osteoblasts.
authors: UMR E-4320 TIRO-MATOs CEA/DRF/BIAM, Faculté de Médecine, Université Nice Sophia Antipolis, Avenue de Valombrose, 06107, Nice Cedex 2, France. pierrefi@unice.fr.
authors: Valérie
authors: V
authors: Pierrefite-Carle
authors: UMR E-4320 TIRO-MATOs CEA/DRF/BIAM, Faculté de Médecine, Université Nice Sophia Antipolis, Avenue de Valombrose, 06107, Nice Cedex 2, France.
authors: Sabine
authors: S
authors: Santucci-Darmanin
authors: UMR E-4320 TIRO-MATOs CEA/DRF/BIAM, Faculté de Médecine, Université Nice Sophia Antipolis, Avenue de Valombrose, 06107, Nice Cedex 2, France.|Service de Rhumatologie, CHU de Nice, Nice, France.
authors: Véronique
authors: V
authors: Breuil
authors: UMR E-4320 TIRO-MATOs CEA/DRF/BIAM, Faculté de Médecine, Université Nice Sophia Antipolis, Avenue de Valombrose, 06107, Nice Cedex 2, France.
authors: Tatiana
authors: T
authors: Gritsaenko
authors: CEA/DRF/BIAM, Bagnols sur Cèze, France.
authors: Claude
authors: C
authors: Vidaud
authors: Institut de Chimie de Nice, UMR 7272, Université de Nice Sophia Antipolis, Nice, France.
authors: Gaelle
authors: G
authors: Creff
authors: Synchrotron SOLEIL L'Orme des Merisiers, Saint-Aubin, BP 48, 91192, Gif-sur-Yvette Cedex, France.
authors: Pier Lorenzo
authors: PL
authors: Solari
authors: Centre Commun de Microscopie Appliquée, Université Nice Sophia Antipolis, Nice, France.
authors: Sophie
authors: S
authors: Pagnotta
authors: UMR E-4320 TIRO-MATOs CEA/DRF/BIAM, Faculté de Médecine, Université Nice Sophia Antipolis, Avenue de Valombrose, 06107, Nice Cedex 2, France.
authors: Rasha
authors: R
authors: Al-Sahlanee
authors: Institut de Chimie de Nice, UMR 7272, Université de Nice Sophia Antipolis, Nice, France.
authors: Christophe Den
authors: CD
authors: Auwer
authors: UMR E-4320 TIRO-MATOs CEA/DRF/BIAM, Faculté de Médecine, Université Nice Sophia Antipolis, Avenue de Valombrose, 06107, Nice Cedex 2, France.
authors: Georges F
authors: GF
authors: Carle
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D002113:Calcification, Physiologic / Q000187:drug effects*; D002460:Cell Line; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012516:Osteosarcoma / Q000378:metabolism; D051381:Rats; D013816:Thermodynamics; D014501:Uranium / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D014501:Uranium
keywords: Autophagy; Mineralization; Osteoblast; Uranium