Inhibitory effects of insulin-like growth factor-1 and osteogenic protein-1 on fibronectin fragment- and interleukin-1beta-stimulated matrix metalloproteinase-13 expression in human chondrocytes.
Matrix metalloproteinase-13 (collagenase-3), a member of the family of matrix metalloproteinases (MMPs), plays a major pathological role in the cartilage destruction of arthritis. A dramatic up-regulation of MMP-13 by inflammatory cytokines such as interleukin (IL)-1beta or by fibronectin fragments has been observed in chondrocytes. In this study, we investigated the inhibitory effects of insulin-like growth factor-1 (IGF-1) and osteogenic protein-1 (OP-1) on the expression of MMP-13, which was induced by fibronectin fragment or IL-1beta in human immortalized or human primary chondrocytes. IGF-1 and OP-1 each significantly reduced the basal level as well as fibronectin fragment- or IL-1beta-stimulated transcription of the MMP-13 gene in a dose-dependent fashion with the corresponding decreases in the protein level of MMP-13. The most prominent suppressive effect was observed by the combination of IGF-1 and OP-1, which decreased the basal promoter activity by 60% and almost completely abrogated the fibronectin fragment-stimulated MMP-13 promoter activity. OP-1 was found to enhance mRNA levels of IGF-1 and the IGF-1 receptor, the latter of which appeared to be responsible for the combined effect of IGF-1 and OP-1. The suppressive effect of IGF-1 and OP-1 on MMP-13 expression was due in part to down-regulation of the expression of pro-inflammatory cytokines and the activity of their intermediate molecules, including NF-kappaB and AP-1 factors. We propose that IGF-1 and OP-1 could be key physiological regulators of MMP-13 gene expression and that the combination of IGF-1 and OP-1 may be useful in controlling the excess catabolic activity in arthritis.
Department of Biochemistry, Section of Rheumatology, Rush Medical College, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois 60612, USA.
Hee-Jeong
HJ
Im
Carol
C
Pacione
Susan
S
Chubinskaya
Andre J
AJ
Van Wijnen
Yubo
Y
Sun
Richard F
RF
Loeser
D015153:Blotting, Western; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism*; D017364:Collagenases / Q000096:biosynthesis* / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005353:Fibronectins / Q000737:chemistry*; D017353:Gene Deletion; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007375:Interleukin-1 / Q000737:chemistry*; D008156:Luciferases / Q000378:metabolism; D053509:Matrix Metalloproteinase 13; D008957:Models, Genetic; D010957:Plasmids / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013696:Temperature; D014162:Transfection; D016212:Transforming Growth Factor beta; D015854:Up-Regulation
C525819:BMP7 protein, human; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D017077:Culture Media, Conditioned; D005353:Fibronectins; D007375:Interleukin-1; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D012313:RNA; D007334:Insulin-Like Growth Factor I; D004247:DNA; D008156:Luciferases; D017526:Receptor, IGF Type 1; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13