DELAYED EXPRESSION OF OSTEOPONTIN AFTER FOCAL STROKE IN THE RAT

Focal brain ischemia induces inflammation, extracellular matrix remode ling, gliosis, and neovascularization. Osteopontin (OPN) is a secreted glycoprotein that has been implicated in vascular injury by promoting cell adhesion, migration, and chemotaxis. To investigate the possible involvement of OPN in brain matrix remodeling after focal stroke, we examined the expression of OPN in ischemic cortex after permanent or t emporary occlusion of the middle cerebral artery (MCAO) of the rat. OP N mRNA and protein levels in nonischemic cortex were not detected cons istently, although significant induction of OPN was observed in the is chemic cortex. OPN mRNA increased 3.5-fold at 12 hr and reached peak l evels 5 d (49.5-fold; p < 0.001) after permanent MCAO. The profile of OPN mRNA induction after transient MCAO (160 min) with reperfusion was essentially the same as that of permanent MCAO. In situ hybridization and immunohistochemical studies demonstrated strong induction of OPN in the ischemic cortex, which was localized primarily in a subset of E D-1-positive macrophages that accumulated in the ischemic zone. Moreov er, OPN immunoreactivity was detected in the matrix of ischemic brain, suggesting a functional role of the newly deposited matrix protein in cell-matrix interactions and remodeling. Indeed, using a modified Boy den chamber, we demonstrated a dose-dependent chemotactic activity of OPN in C6 astroglia cells and normal human astrocytes. Taken together, these data suggest that the upregulation of OPN after focal brain isc hemia may play a role in cellular (glia, macrophage) migration/activat ion and matrix remodeling that provides for new matrix-cell interactio n.