BACKGROUND & AIMS: Insulin-like growth factor-I (IGF-I) regulates human intestinal smooth muscle growth by stimulating proliferation and inhibiting apoptosis. IGF-I-stimulated growth is augmented when alphaVbeta3 integrin is occupied by its ligands, fibronectin and vitronectin. Increased IGF-I expression and muscle cell hyperplasia are features of stricturing Crohn's disease (CD); however, the role of IGF-I in stricture formation is unknown. The aim was to identify the functional role of endogenous IGF-I and alphaVbeta3 integrin ligands in regulating muscle cell hyperplasia in stricturing CD. METHODS: Smooth muscle cells were isolated from muscularis propria of stricturing CD or normal margins. Quantitative polymerase chain reaction, immunoblot analysis, and enzyme-linked immunosorbent assay were used to measure fibronectin, vitronectin, alphaVbeta3 integrin, and IGF-I levels. Activation of the IGF-I receptor, Erk1/2, p70S6 kinase, and GSK-3beta was measured by immunoblot. Proliferation was quantified by Ki67 immunostaining and [(3)H]thymidine incorporation. Apoptosis was measured from caspase-3 cleavage and nucleosome accumulation. RESULTS: IGF-I, vitronectin, and fibronectin RNA and protein levels were increased 1.8- to 3.4-fold in muscle cells from strictures over normal margins. Basal IGF-I receptor phosphorylation was increased 320% in strictured over normal muscle, and basal Erk1/2, p70S6 kinase, and GSK-3beta phosphorylation were increased 205%-292% in strictures. In muscle cells from strictures, Ki67 immunoreactivity and [(3)H]thymidine incorporation were increased and apoptosis was decreased compared with normal margins. Antagonists of the IGF-I receptor or alphaVbeta3 integrin reversed these changes. CONCLUSIONS: Smooth muscle cell hyperplasia in stricturing CD is regulated by increased endogenous IGF-I and alphaVbeta3 integrin ligands that regulate augmented proliferation and diminished apoptosis. Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
BACKGROUND & AIMS:Insulin-like growth factor-I (IGF-I) regulates human intestinal smooth muscle growth by stimulating proliferation and inhibiting apoptosis. IGF-I-stimulated growth is augmented when alphaVbeta3 integrin is occupied by its ligands, fibronectin and vitronectin. Increased IGF-I expression and muscle cell hyperplasia are features of stricturing Crohn's disease (CD); however, the role of IGF-I in stricture formation is unknown. The aim was to identify the functional role of endogenous IGF-I and alphaVbeta3 integrin ligands in regulating muscle cell hyperplasia in stricturing CD. METHODS: Smooth muscle cells were isolated from muscularis propria of stricturing CD or normal margins. Quantitative polymerase chain reaction, immunoblot analysis, and enzyme-linked immunosorbent assay were used to measure fibronectin, vitronectin, alphaVbeta3 integrin, and IGF-I levels. Activation of the IGF-I receptor, Erk1/2, p70S6 kinase, and GSK-3beta was measured by immunoblot. Proliferation was quantified by Ki67 immunostaining and [(3)H]thymidine incorporation. Apoptosis was measured from caspase-3 cleavage and nucleosome accumulation. RESULTS:IGF-I, vitronectin, and fibronectin RNA and protein levels were increased 1.8- to 3.4-fold in muscle cells from strictures over normal margins. Basal IGF-I receptor phosphorylation was increased 320% in strictured over normal muscle, and basal Erk1/2, p70S6 kinase, and GSK-3beta phosphorylation were increased 205%-292% in strictures. In muscle cells from strictures, Ki67 immunoreactivity and [(3)H]thymidine incorporation were increased and apoptosis was decreased compared with normal margins. Antagonists of the IGF-I receptor or alphaVbeta3 integrin reversed these changes. CONCLUSIONS: Smooth muscle cell hyperplasia in stricturing CD is regulated by increased endogenous IGF-I and alphaVbeta3 integrin ligands that regulate augmented proliferation and diminished apoptosis. Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
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