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Rheumatology Advance Access published online on January 31, 2008
Rheumatology, doi:10.1093/rheumatology/kem323
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

17β-Oestradiol up-regulates the expression of a functional UDP-glucose dehydrogenase in articular chondrocytes: comparison with effects of cytokines and growth factors

L. Maneix1, G. Beauchef1, A. Servent1, Y. Wegrowski2, F. X. Maquart2, N. Boujrad3, G. Flouriot3, J. P. Pujol1, K. Boumediene1, P. Galéra1 and S. Moslemi1

1Laboratory of Extracellular Matrix and Pathology, Faculty of Medicine, IFR 146 ICORE, University of Caener-Low Normandy, Caen, 2Laboratory of Medical Biochemistry and Molecular Biology, CNRS UMR 6198, Faculty of Medicine, University of Reims, Reims and 3Laboratory of Molecular Endocrinology of the Reproduction, CNRS UMR 6026, University of Rennes I, Rennes, France.

Correspondence to: S. Moslemi, Laboratory of Extracellular Matrix and Pathology, Faculty of Medicine, University of Caen-Low Normandy, 14032 Caen Cedex, France. E-mail: safa.moslemi{at}unicaen.fr


  Abstract

Objectives. To investigate the mechanisms by which cytokines and 17β-oestradiol (17β-E2) modulate gene expression and activity of uridine diphosphoglucose dehydrogenase (UGDH), a key enzyme of GAG synthesis in articular chondrocytes.

Methods. Rabbit articular chondrocytes (RAC) from 3-week-old animals were incubated for 24 h with TGF-β, insulin like growth factor-I (IGF-I), IL-1β, IL-6 and 17β-E2. GAG synthesis was measured by [35S]-sulphate labelling and the expression of the UGDH gene was estimated by both real-time polymerase chain reaction and western blotting, whereas the enzyme activity was assayed by a spectrophotometric procedure. In addition, the transcriptional activity of several UGDH gene promoter constructs was determined in RAC transiently transfected with wild-type or deleted human oestrogen receptor-{alpha} gene (hER{alpha}66 or hER{alpha}46, respectively).

Results. 17β-E2 and its receptor hER{alpha}66 enhanced GAG neosynthesis in rabbit articular chondrocytes, as did TGF-β1 whereas IL-1β decreased this synthesis. 17β-E2 was found to exert positive regulatory effects at mRNA, protein and UGDH activity levels. In addition, the receptor hER{alpha}66, but not hER{alpha}46, increased the transcriptional activity of the UGDH gene. In contrast, no clear correlation between transcription, translation and activity of the UGDH was found under the effects of the cytokines studied. However, TGF-β enhanced the enzyme activity, whereas IL-1β, IL-6 and IGF-I were without significant effect.

Conclusions. 17β-E2 enhanced GAG synthesis in chondrocytes via up-regulation of the UGDH gene expression and enzyme activity. These data provide insights into the molecular mechanisms involved in the regulation of the UGDH gene and offer new approaches to investigate its potential alteration in joint diseases.

KEY WORDS: UDP-glucose dehydrogenase, Glycosaminoglycan synthesis, 17β-oestradiol, Oestrogen receptor, Cytokines, Cartilage, Chondrocytes

Submitted 3 August 2007; revised version accepted 1 November 2007.
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