How do glucocorticoids compare to oligo decoys as inhibitors of collagen synthesis and potential toxicity of these therapeutics?
This article demonstrates how glucocorticoids decrease collagen synthesis. The parameters used to assess procollagen synthesis in our laboratory will be compared to those used by others. This article will note all the pertinent literature on the molecular mechanisms of this down regulation of procollagen synthesis. For example, what are the effects of glucocorticoids at the levels of transcription and translation of collagen mRNAs? Finally, we will define a molecular mechanism to inhibit Type I collagen synthesis by decreasing the binding of the TGF-beta activator protein complex to the TGF-beta element in the distal promoter of the proalpha1 Type I collagen gene, preventing the 2:1 ratio of alpha1 to alpha2 chains in the processed Type I collagen molecule. We will next ask "How do sense oligo decoys decrease Type I collagen synthesis at the in vivo and at the cell levels?" In primary fibrotic cell culture, the double-stranded phosphorothioate oligodeoxynucleotide decoys were more effective than their sense single-stranded counterparts. The molecular mechanism for the decrease in Type I collagen synthesis is the same as glucocorticoids, that is by decreasing the binding of the TGF-beta activator protein complex to the TGF-beta element in the distal promoter of the proalpha1 Type I collagen gene for the transcription of the proalpha1 mRNAs. The reason for using sense oligo decoys as anti-fibrotic agents as compared to the anti-fibrotic glucocorticoids, is that presently marketed and FDA approved glucocorticoids have many untoward side effects which the sense oligo decoys do not have.
Cutroneo
Kenneth R
KR
Department of Biochemistry, College of Medicine and the Cell and Molecular Biology Program, University of Vermont, Burlington, Vermont 05405, USA. kenneth.cutroneo@uvm.edu
Sterling
Kenneth M
KM
D001667:Binding, Competitive; D003094:Collagen / Q000096:biosynthesis / Q000235:genetics*; D024042:Collagen Type I / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D003907:Dexamethasone / Q000494:pharmacology; D015536:Down-Regulation / Q000235:genetics; D005347:Fibroblasts / Q000187:drug effects; D005355:Fibrosis / Q000188:drug therapy; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D006801:Humans; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D011401:Promoter Regions, Genetic; D020218:Response Elements; D016212:Transforming Growth Factor beta / Q000378:metabolism
D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D005938:Glucocorticoids; D009838:Oligodeoxyribonucleotides; D016212:Transforming Growth Factor beta; D003907:Dexamethasone; D003094:Collagen