Gastroenterology
Volume 138, Issue 1 , Pages 285-293 , January 2010

Endogenous IGF-I and αVβ3 Integrin Ligands Regulate Increased Smooth Muscle Hyperplasia in Stricturing Crohn's Disease

  • Robert S. Flynn

      Affiliations

    • Department of Medicine, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia
    • ,
  • Karnam S. Murthy

      Affiliations

    • Department of Medicine, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia
    • Department of Physiology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia
    • ,
  • John R. Grider

      Affiliations

    • Department of Medicine, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia
    • Department of Physiology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia
    • ,
  • John M. Kellum

      Affiliations

    • Department of Surgery, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia
    • ,
  • John F. Kuemmerle

      Affiliations

    • Department of Medicine, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia
    • Department of Physiology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia
    • Corresponding Author InformationReprint requests Address requests for reprints to: John F. Kuemmerle, MD, Division of Gastroenterology, Medical College of Virginia Campus, Virginia Commonwealth University, PO Box 980341, Richmond, Virginia 23298-0341. fax: (804) 828-2500

Received 17 February 2009 ,Accepted 3 September 2009.

References 

  1. Ruthruff B. Clinical review of Crohn's disease. J Am Acad Nurse Pract. 2007;19:392–397
  2. Loftus EV. Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology. 2004;126:1504–1517
  3. Gelbmann CM, Mestermann S, Gross V, et al. Strictures in Crohn's disease are characterised by an accumulation of mast cells colocalised with laminin but not with fibronectin or vitronectin. Gut. 1999;45:210–217
  4. Lee EY, Stenson WF, DeSchryver-Kecskemeti K. Thickening of muscularis mucosae in Crohn's disease. Mod Pathol. 1991;4:87–90
  5. Williams KL, Fuller CR, Fagin J, et al. Mesenchymal IGF-I overexpression: paracrine effects in the intestine, distinct from endocrine actions. Am J Physiol Gastrointest Liver Physiol. 2002;283:G875–G885
  6. Kuemmerle JF. Autocrine regulation of growth in cultured human intestinal muscle by growth factors. Gastroenterology. 1997;113:817–824
  7. Sjogren K, Liu JL, Blad K, et al. Liver-derived insulin-like growth factor I (IGF-I) is the principal source of IGF-I in blood but is not required for postnatal body growth in mice. Proc Natl Acad Sci U S A. 1999;96:7088–7092
  8. Wang J, Niu W, Nikiforov Y, et al. Targeted overexpression of IGF-I evokes distinct patterns of organ remodeling in smooth muscle cell tissue beds of transgenic mice. J Clin Invest. 1997;100:1425–1439
  9. Ohneda K, Ulshen MH, Fuller CR, et al. Enhanced growth of small bowel in transgenic mice expressing human insulin-like growth factor I. Gastroenterology. 1997;112:444–454
  10. Kuemmerle JF. Occupation of αvβ3-integrin by endogenous ligands modulates IGF-I receptor activation and proliferation of human intestinal smooth muscle. Am J Physiol Gastrointest Liver Physiol. 2006;290:G1194–G1202
  11. Clemmons DR, Horvitz G, Engleman W, et al. Synthetic αVβ3 antagonists inhibit insulin-like growth factor-I-stimulated smooth muscle cell migration and replication. Endocrinology. 1999;140:4616–4621
  12. Maile LA, Clemmons DR. The αVβ3 integrin regulates insulin-like growth factor I (IGF-I) receptor phosphorylation by altering the rate of recruitment of the Src-homology 2-containing phosphotyrosine phosphatase-2 to the activated IGF-I receptor. Endocrinology. 2002;143:4259–4264
  13. Nichols TC, du Laney T, Zheng B, et al. Reduction in atherosclerotic lesion size in pigs by αVβ3 inhibitors is associated with inhibition of insulin-like growth factor-I-mediated signaling. Circ Res. 1999;85:1040–1045
  14. Taylor CV, Letarte M, Lye SJ. The expression of integrins and cadherins in normal human uterus and uterine leiomyomas. Am J Obstet Gynecol. 1996;175:411–419
  15. Kuemmerle JF. Endogenous IGF-I protects human intestinal smooth muscle cells from apoptosis by regulation of GSK-3 β activity. Am J Physiol Gastrointest Liver Physiol. 2005;288:G101–G110
  16. Kuemmerle JF. IGF-I elicits growth of human intestinal smooth muscle cells by activation of PI3K, PDK-1, and p70S6 kinase. Am J Physiol Gastrointest Liver Physiol. 2003;284:G411–G422
  17. Kuemmerle JF, Bushman TL. IGF-I stimulates intestinal muscle cell growth by activating distinct PI 3-kinase and MAP kinase pathways. Am J Physiol. 1998;275:G151–G158
  18. Zimmermann EM, Li L, Hou YT, et al. Insulin-like growth factor I and insulin-like growth factor binding protein 5 in Crohn's disease. Am J Physiol Gastrointest Liver Physiol. 2001;280:G1022–G1029
  19. Kuemmerle JF. Endogenous IGF-I promotes survival of human intestinal muscle cells by Akt-dependent inhibition of GSK-3β activity. Mol Biol Cell. 2002;13:165a
  20. Kuemmerle JF, Zhou H. Insulin-like growth factor-binding protein-5 (IGFBP-5) stimulates growth and IGF-I secretion in human intestinal smooth muscle by Ras-dependent activation of p38 MAP kinase and Erk1/2 pathways. J Biol Chem. 2002;277:20563–20571
  21. Teng B, Murthy KS, Kuemmerle JF, et al. Expression of endothelial nitric oxide synthase in human and rabbit gastrointestinal smooth muscle cells. Am J Physiol. 1998;275:G342–G351
  22. Qiao LY, Gulick MA, Bowers J, et al. Differential changes in brain-derived neurotrophic factor and extracellular signal-regulated kinase in rat primary afferent pathways with colitis. Neurogastroenterol Motil. 2008;20:928–938
  23. Kuemmerle JF, Murthy KS. Coupling of the insulin-like growth factor-I receptor tyrosine kinase to Gi2 in human intestinal smooth muscle: Gβγ-dependent mitogen-activated protein kinase activation and growth. J Biol Chem. 2001;276:7187–7194
  24. Clemmons DR, Maile LA. Minireview: integral membrane proteins that function coordinately with the insulin-like growth factor I receptor to regulate intracellular signaling. Endocrinology. 2003;144:1664–1670
  25. Danen EH, Sonnenberg A. Integrins in regulation of tissue development and function. J Pathol. 2003;201:632–641
  26. Moiseeva EP. Adhesion receptors of vascular smooth muscle cells and their functions. Cardiovasc Res. 2001;52:372–386
  27. Jones JI, Prevette T, Gockerman A, et al. Ligand occupancy of the αVβ3 integrin is necessary for smooth muscle cells to migrate in response to insulin-like growth factor. Proc Natl Acad Sci U S A. 1996;93:2482–2487
  28. Parrizas M, Gazit A, Levitzki A, et al. Specific inhibition of insulin-like growth factor-1 and insulin receptor tyrosine kinase activity and biological function by tyrphostins. Endocrinology. 1997;138:1427–1433
  29. Katsanos KH, Tsatsoulis A, Christodoulou D, et al. Reduced serum insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 levels in adults with inflammatory bowel disease. Growth Horm IGF Res. 2001;11:364–367
  30. Zeeh JM, Riley NE, Hoffmann P, et al. Expression of insulin-like growth factor binding proteins and collagen in experimental colitis in rats. Eur J Gastroenterol Hepatol. 2001;13:851–858
  31. Zimmermann EM, Sartor RB, McCall RD, et al. Insulin-like growth factor I and interleukin 1 β messenger RNA in a rat model of granulomatous enterocolitis and hepatitis. Gastroenterology. 1993;105:399–409
  32. Rico-Bautista E, Flores-Morales A, Fernandez-Perez L. Suppressor of cytokine signaling (SOCS) 2, a protein with multiple functions. Cytokine Growth Factor Rev. 2006;17:431–439
  33. Theiss AL, Fuller CR, Simmons JG, et al. Growth hormone reduces the severity of fibrosis associated with chronic intestinal inflammation. Gastroenterology. 2005;129:204–219
  34. Graham MF, Diegelmann RF, Elson CO, et al. Collagen content and types in the intestinal strictures of Crohn's disease. Gastroenterology. 1988;94:257–265
  35. Kuemmerle JF. Endogenous IGF-I regulates IGF-binding protein production in human intestinal smooth muscle cells. Am J Physiol Gastrointest Liver Physiol. 2000;278:G710–G717
  36. Flynn RS, Kuemmerle JF. Endogenous IGFBP-3 activates TGF-β receptors and regulates type I collagen expression and production in human intestinal smooth muscle cells in Crohn's Disease. Gastroenterology. 2008;132:
  37. Graham MF, Bryson GR, Diegelmann RF. Transforming growth factor β 1 selectively augments collagen synthesis by human intestinal smooth muscle cells. Gastroenterology. 1990;99:447–453
  38. Chidlow JH, Langston W, Greer JJ, et al. Differential angiogenic regulation of experimental colitis. Am J Pathol. 2006;169:2014–2030
  39. Chidlow JH, Shukla D, Grisham MB, et al. Pathogenic angiogenesis in IBD and experimental colitis: new ideas and therapeutic avenues. Am J Physiol Gastrointest Liver Physiol. 2007;293:G5–G18
  40. Danese S, Sans M, de la Motte C, et al. Angiogenesis as a novel component of inflammatory bowel disease pathogenesis. Gastroenterology. 2006;130:2060–2073
  41. Danese S, Sans M, Spencer DM, et al. Angiogenesis blockade as a new therapeutic approach to experimental colitis. Gut. 2007;56:855–862

 Conflicts of interest The authors disclose no conflicts.

 Funding Supported by grant DK49691 from the National Institutes of Diabetes and Digestive and Kidney Diseases.

PII: S0016-5085(09)01566-2

doi: 10.1053/j.gastro.2009.09.003

Gastroenterology
Volume 138, Issue 1 , Pages 285-293 , January 2010

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