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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.

journal_name

Toxicol Lett

journal_title

Toxicology letters

authors

Lizotte J,Abed E,Signor C,Malu DT,Cuevas J,Kevorkova O,Sanchez-Dardon J,Satoskar A,Scorza T,Jumarie C,Moreau R

doi

10.1016/j.toxlet.2012.10.006

subject

Has Abstract

pub_date

2012-12-17 00:00:00

pages

167-73

issue

eissn

0378-4274

issn

1879-3169

pii

S0378-4274(12)01337-9

journal_volume

215

pub_type

杂志文章

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Expression of macrophage migration inhibitory factor by osteoblastic cells: protection against cadmium toxicity.