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ToxSci Advance Access originally published online on August 14, 2008
Toxicological Sciences 2008 106(1):223-232; doi:10.1093/toxsci/kfn169
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Retinoic Acid Receptor Gamma-Induced Misregulation of Chondrogenesis in the Murine Limb Bud In Vitro

Eugene Galdones and Barbara F. Hales1

Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada H3G 1Y6

1 To whom correspondence should be addressed at Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir-William-Osler, Room 110, Montréal, Québec, Canada H3G 1Y6. Fax: (514) 398-7120. E-mail: barbara.hales{at}mcgill.ca.

Received June 18, 2008; accepted August 8, 2008


  Abstract

Vitamin A derivatives modulate gene expression through retinoic acid and rexinoid receptor (RAR/RXR) heterodimers and are indispensable for limb development. Of particular interest, RAR{gamma} is highly expressed in cartilage, a target affected following retinoid-induced limb insult. The goal of this study was to examine how selective activation of RAR{gamma} affects limb development. Forelimbs from E12.5 CD-1 mice were cultured for 6 days in the presence of all-trans RA (pan-RAR agonist; 0.1 or 1.0µM) or BMS-189961 (BMS961, RAR{gamma}-selective agonist; 0.01 or 0.1µM) and limb morphology assessed. Untreated limbs developed normal cartilage elements whereas pan-RAR or RAR{gamma} agonist-treated limbs exhibited reductive effects on chondrogenesis. Retinoid activity was assessed using RAREβ2 (retinoic acid response element β2)-lacZ reporter limbs; after 3 h of treatment, both drugs increased retinoid activity proximally. To elucidate the expression profiles of a subset of genes important for development, limbs were cultured for 3 h and cRNA hybridized to osteogenesis-focused microarrays. Two genes, matrix GLA protein (Mgp; chondrogenesis inhibitor) and growth differentiation factor-10 (Gdf10/Bmp3b) were induced by RA and BMS-189961. Real-time PCR was done to validate our results and whole mount in situ hybridizations against Mgp and Gdf10 localized their upregulation to areas of cartilage and programmed cell death, respectively. Thus, our results illustrate the importance of RAR{gamma} in mediating the retinoid-induced upregulation of Mgp and Gdf10; determining their roles in chondrogenesis and cell death will help further unravel mechanisms underlying retinoid teratogenicity.

Key Words: matrix GLA protein; growth differentiation factor 10; retinoic acid receptor gamma; retinoic acid; limb development; chondrogenesis.


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