Hazelgrove KB, Flynn RS, Qiao LY, Grider JR, Kuemmerle JF. Endogenous IGF-I and ␣v3 integrin ligands regulate increased smooth muscle growth in TNBS-induced colitis. Am J Physiol Gastrointest Liver Physiol 296: G1230 -G1237, 2009. First published April 9, 2009 doi:10.1152/ajpgi.90508.2008.-Endogenous insulinlike growth factor-I (IGF-I) regulates intestinal smooth muscle growth by concomitantly stimulating proliferation and inhibiting apoptosis. IGF-I-stimulated growth is augmented by the ␣v3 integrin ligands vitronectin and fibronectin. IGF-I expression in smooth muscle is increased in both TNBS-induced colitis and Crohn's disease. We hypothesized that intestinal inflammation increased vitronectin and fibronectin expression by smooth muscle and, along with IGF-I upregulation, increased intestinal muscle growth. Intestinal smooth muscle cells were examined 7 days following the induction of TNBS-induced colitis. Although ␣ v3 integrin expression was not altered by TNBSinduced colitis, vitronectin and fibronectin levels were increased by 80 Ϯ 10% and 90 Ϯ 15%, above control levels, respectively. Basal IGF-I receptor phosphorylation in inflamed muscle from TNBStreated rats was increased by 86 Ϯ 8% over vehicle-treated controls. Basal ERK1/2, p70S6 kinase, and GSK-3 phosphorylation in muscle cells of TNBS-treated rats were also increased by 140 -180%. TNBS treatment increased basal muscle cell proliferation by 130 Ϯ 15% and decreased apoptosis by 20 Ϯ 2% compared with that in vehicletreated controls. The changes in proliferation and apoptosis were reversed by an IGF-I receptor tyrosine kinase inhibitor or an ␣v3 integrin antagonist. The results suggest that smooth muscle hyperplasia in TNBS-induced colitis partly results from the upregulation of endogenous IGF-I and ligands of ␣ v3 integrin that mediate increased smooth muscle cell proliferation and decreased apoptosis. This paper has identified one mechanism regulating smooth muscle hyperplasia, a feature of stricture formation that occurs in the chronically inflamed intestine of TNBS-induced colitis and potentially Crohn's disease.
Background & Aims-Strictures occur in ~30% of patients with Crohn's disease and are characterized by intestinal smooth muscle hyperplasia, hypertrophy, and fibrosis due to excess extracellular matrix production including collagen. Insulin-like Growth Factor-I (IGF-I) expression is increased in smooth muscle cells of the muscularis propria in Crohn's disease and in animal models of Crohn's disease, including TNBS-induced colitis. While upregulated IGF-I is conjectured to cause smooth muscle cell growth and collagen production in the inflamed intestine, its role in the development of fibrosis has not been directly demonstrated.
The igf1 gene is alternatively spliced as IGF-IEa and IGF-IEc variants in humans. In fibrostenotic Crohn's disease, the fibrogenic cytokine TGF-β1 induces IGF-IEa expression and IGF-I production in intestinal smooth muscle and results in muscle hyperplasia and collagen I production that contribute to stricture formation. Mechano-growth factor (MGF) derived from IGF-IEc induces skeletal and cardiac muscle hypertrophy following stress. We hypothesized that increased IGF-IEc expression and MGF production mediated smooth muscle hypertrophy also characteristic of fibrostenotic Crohn's disease. IGF-IEc transcripts and MGF protein were increased in muscle cells isolated from fibrostenotic intestine under regulation by endogenous TGF-β1. Erk5 and MEF2C were phosphorylated in vivo in fibrostenotic muscle; both were phosphorylated and colocalized to nucleus in response to synthetic MGF in vitro. Smooth muscle-specific protein expression of α-smooth muscle actin, γ-smooth muscle actin, and smoothelin was increased in affected intestine. Erk5 inhibition or MEF2C siRNA blocked smooth muscle-specific gene expression and hypertrophy induced by synthetic MGF. Conditioned media of cultured fibrostenotic muscle induced muscle hypertrophy that was inhibited by immunoneutralization of endogenous MGF or pro-IGF-IEc. The results indicate that TGF-β1-dependent IGF-IEc expression and MGF production in patients with fibrostenotic Crohn's disease regulates smooth muscle cell hypertrophy a critical factor that contributes to intestinal stricture formation.
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