Proteoglycans decorin and biglycan differentially modulate TGF-beta-mediated fibrotic responses in the lung.
Transforming growth factor (TGF)-beta is a key cytokine in the pathogenesis of pulmonary fibrosis, and pharmacological interference with TGF-beta can ameliorate the fibrotic tissue response. The small proteoglycans decorin and biglycan are able to bind and inhibit TGF-beta activity in vitro. Although decorin has anti-TGF-beta properties in vivo, little is known about the physiological role of biglycan in vivo. Adenoviral gene transfer was used to overexpress active TGF-beta, decorin, and biglycan in cell culture and in murine lungs. Both proteoglycans were able to interfere with TGF-beta bioactivity in vitro in a dose-dependant manner. In vivo, overexpression of TGF-beta resulted in marked lung fibrosis, which was significantly reduced by concomitant overexpression of decorin. Biglycan, however, had no significant effect on lung fibrosis induced by TGF-beta. The data suggest that differences in tissue distribution are responsible for the different effects on TGF-beta bioactivity in vivo, indicating that decorin, but not biglycan, has potential therapeutic value in fibrotic disorders of the lung.
Kolb
M
M
Department of Pathology and Molecular Medicine and Centre for Gene Therapeutics, McMaster University, 1200 Main St., West Hamilton, Ontario, Canada L8N 3Z5.
Margetts
P J
PJ
Sime
P J
PJ
Gauldie
J
J
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D058578:Biglycan; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002460:Cell Line; D058575:Decorin; D004305:Dose-Response Relationship, Drug; D016326:Extracellular Matrix Proteins; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D006909:Hydroxyproline / Q000378:metabolism; D007150:Immunohistochemistry; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D011509:Proteoglycans / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D014018:Tissue Distribution; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D016896:Treatment Outcome
C546884:BGN protein, human; C546885:Bgn protein, mouse; D058578:Biglycan; C546878:DCN protein, human; C546879:Dcn protein, mouse; D058575:Decorin; D016326:Extracellular Matrix Proteins; D011509:Proteoglycans; D016212:Transforming Growth Factor beta; D006909:Hydroxyproline