Endogenous IGFBP-3 regulates excess collagen expression in intestinal smooth muscle cells of Crohn's disease strictures
✍ Scribed by Robert S. Flynn; Sunila Mahavadi; Karnam S. Murthy; John R. Grider; John M. Kellum; Homayoon Akbari; John F. Kuemmerle
- Publisher
- John Wiley and Sons
- Year
- 2011
- Tongue
- English
- Weight
- 387 KB
- Volume
- 17
- Category
- Article
- ISSN
- 1078-0998
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✦ Synopsis
Background: Stricture formation occurs in %30% of patients with Crohn's disease (CD) and is a significant cause of morbidity. Strictures are characterized by intestinal smooth muscle cell hyperplasia, smooth muscle cell hypertrophy, and fibrosis due to excess net extracellular matrix production, including collagen. Transforming growth factor-b1 (TGF-b1) has profibrotic effects in many tissues due to its ability to regulate collagen expression and extracellular matrix dynamics. We previously showed that both insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) and TGF-b1 are expressed by normal human intestinal smooth muscle cells, bind to, and activate TGF-bRII/I receptors in these cells.
Methods: Smooth muscle cells isolated from the muscularis propria of patients were used to prepare RNA, protein lysates, or placed into primary culture. IGFBP-3, TGF-b1, and collagen IaI expression was measured with quantitative reverse-transcription polymerase chain reaction (RT-PCR) and protein levels by enzyme-linked immunosorbent assay (ELISA) or immunoblot.
Results: Expression and production of IGFBP-3, TGF-b1, and collagen IaI were significantly increased specifically in smooth muscle cells isolated from regions of strictured intestine in CD compared to nonstrictured histologically normal resection margin. IGFBP-3 and TGF-b1 regulated collagen IaI expression and production via a TGF-bRII/I-dependent and Smad2/3-dependent mechanism. Upregulated (excess) collagen IaI expression and production in smooth muscle cells of strictures and basal collagen IaI in smooth muscle cells of normal margin were inhibited by immunoneutralization of IGFBP-3 or TGF-b1.
Conclusions:
The findings indicate that upregulated endogenous IGFBP-3 and TGF-b1 expression regulates excess collagen IaI production and contributes to fibrosis and stricture formation in CD.