title: Expression of macrophage migration inhibitory factor by osteoblastic cells: protection against cadmium toxicity.
abstract: Exposition to cadmium (Cd) has been linked to bone metabolism alterations and occurrence of osteoporosis. Despite its known renal toxicity which indirectly disrupts bone metabolism through impairment of vitamin D synthesis, increasing evidence argues for the direct action of Cd on bone-forming osteoblasts. Indeed, accumulation of Cd in osteoblasts and metal-induced cell death has been documented but little is known about the intracellular mechanisms of protection against this stress. In this work, we investigated the protection afforded by thiol-containing proteins against Cd cytotoxicity in MC3T3 osteoblastic cells. Viability of MC3T3 cells was reduced by Cd in a concentration-dependent manner with a LC(50) of 7.6±1.1μM. Depletion of glutathione by l-buthionine sulphoximine (BSO) increased cell sensitivity to Cd cytotoxicity, suggesting the involvement of thiol-containing peptides as a mechanism of protection. Accordingly, Cd was shown to promote progressive depletion of reduced thiol content and to stimulate the production of reactive oxygen species (ROS). Interestingly, low non cytotoxic concentrations of Cd increased the gene expression of macrophage migration inhibitory factor (MIF), also a thiol-containing protein. Inhibition of the transcription factor NFκB prevented Cd-dependent upregulation of MIF expression and consequently, increased Cd cytotoxicity in osteoblasts. Moreover, MIF deficient mouse osteoblasts were more sensitive to Cd cytotoxicity than the corresponding control cells. By gel-filtration chromatography, we demonstrated that MIF acts as a thiol-containing protein and thereby promotes Cd complexation. In accordance with its binding ability, addition of recombinant MIF to the culture medium reduced Cd cytotoxicity. Overall, upregulation of MIF expression by Cd may protect against the cytotoxicity of this metal in the osteoblasts.
authors.affiliation: Laboratoire du Métabolisme Osseux, Centre BioMed, Département des Sciences Biologiques, Université du Québec à Montréal, Montréal, Québec H3C 3P8, Canada. jeromelizotte@hotmail.com
authors.forename: Jérôme
authors.initials: J
authors.lastname: Lizotte
authors.forename: Elie
authors.initials: E
authors.lastname: Abed
authors.forename: Céline
authors.initials: C
authors.lastname: Signor
authors.forename: Diane Tshikudi
authors.initials: DT
authors.lastname: Malu
authors.forename: Jorge
authors.initials: J
authors.lastname: Cuevas
authors.forename: Olha
authors.initials: O
authors.lastname: Kevorkova
authors.forename: Jaime
authors.initials: J
authors.lastname: Sanchez-Dardon
authors.forename: Abhay
authors.initials: A
authors.lastname: Satoskar
authors.forename: Tatiana
authors.initials: T
authors.lastname: Scorza
authors.forename: Catherine
authors.initials: C
authors.lastname: Jumarie
authors.forename: Robert
authors.initials: R
authors.lastname: Moreau
mesh_terms: D016475:3T3 Cells; D000818:Animals; D002104:Cadmium / Q000633:toxicity*; D004785:Environmental Pollutants / Q000633:toxicity; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism*; D015398:Signal Transduction; D013450:Sulfones / Q000494:pharmacology
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D004785:Environmental Pollutants; D008263:Macrophage Migration-Inhibitory Factors; D016328:NF-kappa B; D009570:Nitriles; D013450:Sulfones; D002104:Cadmium; D048049:Extracellular Signal-Regulated MAP Kinases; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse