This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ellison, J. A. Articles by del Zoppo, G. J. Search for Related Content PubMed PubMed Citation Articles by Ellison, J. A. Articles by del Zoppo, G. J.

(Stroke. 1998;29:1698-1707.)
© 1998 American Heart Association, Inc.

Original Contributions

Osteopontin and its Integrin Receptor _vß₃ Are Upregulated During Formation of the Glial Scar After Focal Stroke

Julie A. Ellison, PhD; James J. Velier, PhD; Patricia Spera, PhD; Zdenka L. Jonak, PhD; Xinkang Wang, PhD; Frank C. Barone, PhD; Giora Z. Feuerstein, MD

From the Departments of Cardiovascular Pharmacology and Molecular and Cellular Immunology (Z.L.J.), SmithKline Beecham Pharmaceuticals, King of Prussia, Pa.

Correspondence to Giora Z. Feuerstein, MD, Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, 709 Swedeland Rd, PO Box 1539, UW2523, King of Prussia, PA 19406. E-mail G_Z_Feuerstein{at}SBPHRD.COM

Background and Purpose—Microglia and astrocytes in the peri-infarct region are activated in response to focal stroke. A critical function of activated glia is formation of a protective barrier that ultimately forms a new glial-limiting membrane. Osteopontin, a provisional matrix protein expressed during wound healing, is induced after focal stroke. The present study was performed to determine the spatial and temporal expression of osteopontin and its integrin receptor _vß₃ during formation of the peri-infarct gliotic barrier and subsequent formation of a new glial-limiting membrane.

Methods—Spontaneously hypertensive rats (n=19) were subjected to permanent occlusion of the middle cerebral artery and killed 3, 6, and 24 hours and 2, 5, and 15 days after occlusion. The spatial and temporal expression of osteopontin mRNA was determined by in situ hybridization, and that of osteopontin ligand and its integrin receptor _vß₃ was determined by immunohistochemistry.

Results—Osteopontin mRNA was expressed de novo in the peri-infarct region from 3 to 48 hours; by 5 days osteopontin mRNA expression was restricted to the infarct. Osteopontin protein was expressed by peri-infarct microglia beginning at 24 hours and by microglia/macrophages at 48 hours in the infarct. Integrin receptor _vß₃ was expressed in peri-infarct astrocytes at 5 and 15 days.

Conclusions—Early microglial/macrophage expression of osteopontin mRNA defines the borders and final infarct area at 24 hours. At 5 days osteopontin ligand is at a distance from the peri-infarct astrocytes expressing integrin receptor _vß₃. By 15 days astrocytes expressing integrin receptor _vß₃ are localized in an osteopontin-rich region concomitant with formation of the new glial-limiting membrane. The de novo expression and interaction of osteopontin ligand with its receptor integrin _vß₃ suggest a role in wound healing after focal stroke.

Editorial Comment

Takeo Abumiya, MD, Guest Editor; Gregory J. del Zoppo, MD,Guest Editor

Department Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, Calif

This article has been cited by other articles:

				J.-Y. C. Hsu, L. Y. W. Bourguignon, C. M. Adams, K. Peyrollier, H. Zhang, T. Fandel, C. L. Cun, Z. Werb, and L. J. Noble-Haeusslein Matrix Metalloproteinase-9 Facilitates Glial Scar Formation in the Injured Spinal Cord J. Neurosci., December 10, 2008; 28(50): 13467 - 13477. [Abstract] [Full Text] [PDF]

				G. Chidlow, J. P. M. Wood, J. Manavis, N. N. Osborne, and R. J. Casson Expression of Osteopontin in the Rat Retina: Effects of Excitotoxic and Ischemic Injuries Invest. Ophthalmol. Vis. Sci., February 1, 2008; 49(2): 762 - 771. [Abstract] [Full Text] [PDF]

				L. R. Rodrigues, J. A. Teixeira, F. L. Schmitt, M. Paulsson, and H. Lindmark-Mansson The Role of Osteopontin in Tumor Progression and Metastasis in Breast Cancer Cancer Epidemiol. Biomarkers Prev., June 1, 2007; 16(6): 1087 - 1097. [Abstract] [Full Text] [PDF]

				M. Hashimoto, D. Sun, S. R. Rittling, D. T. Denhardt, and W. Young Osteopontin-Deficient Mice Exhibit Less Inflammation, Greater Tissue Damage, and Impaired Locomotor Recovery from Spinal Cord Injury Compared with Wild-Type Controls J. Neurosci., March 28, 2007; 27(13): 3603 - 3611. [Abstract] [Full Text] [PDF]

				G. J. del Zoppo, R. Milner, T. Mabuchi, S. Hung, X. Wang, G. I. Berg, and J. A. Koziol Microglial Activation and Matrix Protease Generation During Focal Cerebral Ischemia Stroke, February 1, 2007; 38(2): 646 - 651. [Abstract] [Full Text] [PDF]

				N. Shimamura, G. Matchett, H. Yatsushige, J. W. Calvert, H. Ohkuma, and J. Zhang Inhibition of Integrin {alpha}v{beta}3 Ameliorates Focal Cerebral Ischemic Damage in the Rat Middle Cerebral Artery Occlusion Model Stroke, July 1, 2006; 37(7): 1902 - 1909. [Abstract] [Full Text] [PDF]

				M. Schroeter, P. Zickler, D. T. Denhardt, H.-P. Hartung, and S. Jander Increased thalamic neurodegeneration following ischaemic cortical stroke in osteopontin-deficient mice Brain, June 1, 2006; 129(6): 1426 - 1437. [Abstract] [Full Text] [PDF]

				M. W.M. Schellings, Y. M. Pinto, and S. Heymans Matricellular proteins in the heart: possible role during stress and remodeling Cardiovasc Res, October 1, 2004; 64(1): 24 - 31. [Abstract] [Full Text] [PDF]

				Y. Shimazu, A. Nanci, and T. Aoba Immunodetection of Osteopontin at Sites of Resorption in the Pulp of Rat Molars J. Histochem. Cytochem., July 1, 2002; 50(7): 911 - 922. [Abstract] [Full Text] [PDF]

				J. K. Relton, K. E. Sloan, E. M. Frew, E. T. Whalley, S. P. Adams, R. R. Lobb, and M. A. Yenari Inhibition of {{alpha}}4 Integrin Protects Against Transient Focal Cerebral Ischemia in Normotensive and Hypertensive Rats Editorial Comment Stroke, January 1, 2001; 32(1): 199 - 205. [Abstract] [Full Text] [PDF]

				T. Mabuchi, K. Kitagawa, T. Ohtsuki, K. Kuwabara, Y. Yagita, T. Yanagihara, M. Hori, M. Matsumoto, D.-I. Chang, and G. J. del Zoppo Contribution of Microglia/Macrophages to Expansion of Infarction and Response of Oligodendrocytes After Focal Cerebral Ischemia in Rats Editorial Comment Stroke, July 1, 2000; 31(7): 1735 - 1743. [Abstract] [Full Text] [PDF]

				J. Sodek, B. Ganss, and M.D. McKee Osteopontin Critical Reviews in Oral Biology & Medicine, January 1, 2000; 11(3): 279 - 303. [Abstract] [Full Text] [PDF]

				K. J. Bayless and G. E. Davis Identification of Dual alpha 4beta 1 Integrin Binding Sites within a 38 Amino Acid Domain in the N-terminal Thrombin Fragment of Human Osteopontin J. Biol. Chem., April 13, 2001; 276(16): 13483 - 13489. [Abstract] [Full Text] [PDF]