Chondroitin sulphate decreases collagen synthesis in normal and scleroderma fibroblasts through a Smad-independent TGF-beta pathway--implication of C-Krox and Sp1.
Despite several investigations, the transcriptional mechanisms which regulate the expression of both type I collagen genes (COL1A1 and COL1A2) in either physiological or pathological situations, such as scleroderma, are not completely known. In this study, we determined the effects of both native ichtyan chondroïtin sulphate (CS) and its derived hydrolytic fragments (CSf) on human normal (NF) and scleroderma (SF) fibroblasts. Here, we demonstrate for the first time that CS and CSf exert an inhibitory effect on type I collagen protein synthesis and decrease the corresponding mRNA steady-state levels of COL1A1 and COL1A2 in NF and SF. These glycosaminoglycan molecules repress COL1A1 gene transcription through a -112/-61 bp sequence upstream the start site of transcription and imply hc-Krox and Sp1 transcription factors. In addition, CS and CSf induced a down-regulation of TbetaRI expression. As a conclusion, our findings highlight a possible new role for CS and CSf as anti-fibrotic molecules and could help in elucidating the mechanisms of action by which CS and CSf exert their inhibitory effect on type I collagen synthesis.
Renard
Emmanuelle
E
Laboratoire de Biochimie du Tissu Conjonctif, Université de Caen/Basse-Normandie, IFR 146 ICORE, Faculté de Médecine, CHU niveau 3, Caen, France.
Chadjichristos
Christos
C
Kypriotou
Magdalini
M
Beauchef
Gallic
G
Bordat
Pascal
P
Dompmartin
Anne
A
Widom
Russell L
RL
Boumediene
Karim
K
Pujol
Jean-Pierre
JP
Galéra
Philippe
P
D020029:Base Pairing; D001483:Base Sequence; D002809:Chondroitin Sulfates / Q000494:pharmacology*; D003094:Collagen / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D024061:Collagen Type III / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012594:Scleroderma, Localized / Q000378:metabolism* / Q000473:pathology; D051785:Smad Proteins / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D051705:Sp3 Transcription Factor / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
C439971:COL3A1 protein, human; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D024061:Collagen Type III; D004268:DNA-Binding Proteins; D010446:Peptide Fragments; D012333:RNA, Messenger; D051785:Smad Proteins; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C484225:ZBTB7B protein, human; D051705:Sp3 Transcription Factor; D002809:Chondroitin Sulfates; D003094:Collagen