Inhibitory effects of insulin-like growth factor-1 and osteogenic protein-1 on fibronectin fragment- and interleukin-1β-stimulated matrix metalloproteinase-13 expression in human chondrocytes

Hee Jeong Im, Carol Pacione, Susan Chubinskaya, Andre J van Wijnen, Yubo Sun, Richard F. Loeser

Research output: Contribution to journalArticle

116 Citations (Scopus)

Abstract

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)-1β 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-1β 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-1β-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 downregulation of the expression of pro-inflammatory cytokines and the activity of their intermediate molecules, including NF-κB 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.

Original languageEnglish (US)
Pages (from-to)25386-25394
Number of pages9
JournalJournal of Biological Chemistry
Volume278
Issue number28
DOIs
StatePublished - Jul 11 2003
Externally publishedYes

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Bone Morphogenetic Protein 7
Matrix Metalloproteinase 13
Somatomedins
Chondrocytes
Interleukin-1
Fibronectins
Arthritis
Cytokines
Somatomedin Receptors
Transcription Factor AP-1
Cartilage
Transcription
Matrix Metalloproteinases
Gene expression
Up-Regulation
Down-Regulation
Genes
Gene Expression

ASJC Scopus subject areas

  • Biochemistry

Cite this

Inhibitory effects of insulin-like growth factor-1 and osteogenic protein-1 on fibronectin fragment- and interleukin-1β-stimulated matrix metalloproteinase-13 expression in human chondrocytes. / Im, Hee Jeong; Pacione, Carol; Chubinskaya, Susan; van Wijnen, Andre J; Sun, Yubo; Loeser, Richard F.

In: Journal of Biological Chemistry, Vol. 278, No. 28, 11.07.2003, p. 25386-25394.

Research output: Contribution to journalArticle

Im, Hee Jeong ; Pacione, Carol ; Chubinskaya, Susan ; van Wijnen, Andre J ; Sun, Yubo ; Loeser, Richard F. / Inhibitory effects of insulin-like growth factor-1 and osteogenic protein-1 on fibronectin fragment- and interleukin-1β-stimulated matrix metalloproteinase-13 expression in human chondrocytes. In: Journal of Biological Chemistry. 2003 ; Vol. 278, No. 28. pp. 25386-25394.
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abstract = "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)-1β 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-1β 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-1β-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 downregulation of the expression of pro-inflammatory cytokines and the activity of their intermediate molecules, including NF-κB 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.",
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