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ToxSci Advance Access originally published online on February 6, 2009
Toxicological Sciences 2009 108(2):330-343; doi:10.1093/toxsci/kfp021
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© The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Dioxin-Sensitive Proteins in Differentiating Osteoblasts: Effects on Bone Formation In Vitro

Donatella Carpi*, Merja Korkalainen{dagger}, Luisa Airoldi*, Roberto Fanelli*, Helen Hakansson{ddagger}, Virpi Muhonen§, Juha Tuukkanen§, Matti Viluksela{dagger} and Roberta Pastorelli*,1

* Department of Environmental Health Sciences, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy {dagger} Department of Environmental Health, National Public Health Institute, Kuopio, Finland {ddagger} Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden § Institute of Biomedicine, Department of Anatomy and Cell Biology, University of Oulu, Oulu, Finland

1 To whom correspondence should be addressed at Department of Environmental Health Sciences, Laboratory of Molecular Toxicology, Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156 Milan, Italy. Fax: +39-0239014735. E-mail: rpastorelli{at}marionegri.it.

Received September 12, 2008; accepted January 27, 2009


  Abstract

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an endocrine-disrupting environmental pollutant which affects bone tissue, although the mechanistic basis of this action is far from clear. We adopted a proteome approach to investigate the disturbance of osteogenesis evoked by TCDD in an in vitro osteoblast differentiation model of rat mesenchymal stem cells. Eighteen individual proteins showed a significant change in abundance as results of ten days of TCDD exposure, at which time mRNA changes in osteoblast differentiation markers were also observed. These proteins were mostly involved in cytoskeleton organization and biogenesis, actin filament-based processes, protein transport, and folding. The alteration in cell architecture and increase in cell adhesion were confirmed by confocal microscopy. The TCDD-induced decrease in the expression of calcium-binding proteins may interfere with osteoblast calcium deposition, which was in fact reduced by TCDD. This is the first report investigating, at the protein expression level, the effect of TCDD during osteoblastic differentiation. Interestingly, MetaCore pathway analysis grouped the majority of these proteins around two principal nodes (c-fos and c-myc) suggesting that they may participate in the transcriptional activation of key pathways in TCDD-driven inhibition of osteoblast differentiation. Our findings provide evidence of new molecular players in the effects of TCDD on bone development.

Key Words: osteoblasts; bone marrow stem cells; differentiation; tandem mass-spectrometry; dioxin; proteomics.


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