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Osteopontin and Mucosal Protection

CIHR Group in Matrix Dynamics, Faculty of Dentistry, University of Toronto, 124 Edward Street, Toronto, ON M5G 1G6, Canada

View larger version (52K): [in a new window]   Figure 1. Expression of OPN in inflamed tissues and by inflammatory cells. (A) Immunohistochemical staining for OPN in the normal and inflamed colon. Photomicrographs of sections of the distal colon of 8-week-old mice subjected to experimental colitis were immunostained for OPN and compared with control tissues. Increased staining intensity for OPN is evident in the epithelium and submucosal tissues of the diseased colon (mag. X200). (B) Immunofluorescent staining for OPN (red) and CD44 (green) in isolated neutrophils and macrophages. OPN in neutrophils is present throughout the cells, while CD44 is localized to the periphery of non-polarized neutrophils and in the trailing uropod (green arrowheads) in polarized cells. The distribution of OPN and CD44 is unchanged in CD44–/– and OPN–/– cells. In macrophages, the OPN is seen to co-localize (yellow arrowheads) with CD44 (green arrowheads) in the cell periphery of migrating cells. OPN–/– and particularly CD44–/– macrophages have reduced cell processes and appear more rounded, the OPN in CD44–/– cells being more centrally distributed.

View larger version (25K): [in a new window]   Figure 2. The locations of 2 integrin-binding sites and 3 CD44 signaling sites are shown (the precise location of the third CD44 signaling motif in the carboxy-terminal thrombin fragment has not been identified). The cryptic SLAYGLR (SLVVGLR in human OPN) integrin-binding site, which is contiguous with the RGD domain, is exposed by thrombin digestion of the adjacent arginine. Thrombin digestion also increases the activity of the RGD. The sites of post-translational modifications are adapted from rat OPN, in which 10–11 phosphorylation sites are modified per molecule. M, methionine; S, serine; L, leucine; D, aspartate; R, arginine; G, glycine; N, asparagine; T, threonine.

View larger version (28K): [in a new window]   Figure 3. Diagram showing possible protective functions of OPN that affect the patency of the epithelium, both directly and indirectly, through the innate immune response to mucosal disease. Noxious agents (bacteria, bacterial products, and antigens) cause epithelial damage, resulting in IL-1 and IL-8 release, which attracts neutrophils and macrophages. This immediate response is controlled by secretion of pro-inflammatory cytokines and the expression of Toll-like receptors (TLRs) and chemokine receptors. OPN expressed by epithelial and immune cells acts as a chemoattractant to macrophages and neutrophils and regulates their phagocytic activity, reactive oxidative burst (ROS) and release of cytokines, and proteolytic enzymes. A protracted innate response will cause further destruction of the epithelial barrier.

View larger version (42K): [in a new window]   Figure 4. A diagram indicating how osteopontin may influence the adaptive immune response in mucosal tissues. Antigen taken by APC/dendritic cells and presented to naïve T-cells/CD4+ results in T-cell proliferation and differentiation into Th1 cells. The Th1 cells release IL-12, IFN-, MIF, OPN, and TNF-, which recruit macrophages for further activation of Th1 cells and promote the further recruitment of neutrophils and natural killer cells (NKT). Th2 release of IL-10 and IL-4 increases B-cell differentiation, attenuates macrophage activation, and, in conjunction with regulatory T-cells, initiates repair by myofibroblasts. Following removal of noxious agents, reduced inflammation will allow deposition of new matrix by myofibroblasts, leading to epithelial regeneration. OPN can modulate the inflammatory reaction and promote repair through its effects on T-cell differentiation and by its ability to influence the survival of epithelial cells, macrophages, and fibroblasts.

View larger version (12K): [in a new window]   Figure 5. A simple depiction of the role of OPN in the repair of submucosal connective tissues. Secreted OPN (sOPN), produced mainly by macrophages and Th1 cells, signals through CD44 and integrin receptors on fibroblasts, which differentiate into myofibroblasts. An intracellular form of iOPN associated with CD44 modulates cytoskeleton-related activities, including migration in macrophages (MØs) and fibroblasts, and both sOPN and iOPN produced by myofibroblasts (MyoFb). During the reparative phases, OPN signals through vß3 and/or CD44 receptors to stimulate proliferation and differentiation of fibroblasts and protect them from apoptosis, thereby promoting matrix deposition and mucosal repair.