Both osteopontin (OPN) and natural killer T (NKT) cells play a role in the development of immunological disorders. We examined a functional link between OPN and NKT cells. Concanavalin A (Con A)-induced hepatitis is a well-characterized murine model of T cell-mediated liver diseases. Here, we show that NKT cells secrete OPN, which augments NKT cell activation and triggers neutrophil infiltration and activation. Thus, OPN- and NKT cell-deficient mice were refractory to Con A-induced hepatitis. In addition, a neutralizing antibody specific for a cryptic epitope of OPN, exposed by thrombin cleavage, ameliorated hepatitis. These findings identify NKT cell-derived OPN as a novel target for the treatment of inflammatory liver diseases.

It has been shown that osteopontin (OPN) plays a pivotal role in the pathogenesis of rheumatoid arthritis (RA). However, the molecular mechanism of OPN action is yet to be elucidated. Splenic monocytes obtained from arthritic mice exhibited a significant capacity for cell migration toward thrombin-cleaved OPN but not toward full-length OPN. Migratory monocytes expressed α9 and α4 integrins. Since cleavage of OPN by thrombin exposes the cryptic epitope recognized by α9 and α4 integrins, we investigated the role of the cryptic epitope SLAYGLR in a murine RA model by using a specific antibody (M5) reacting to SLAYGLR sequence. The M5 antibody could abrogate monocyte migration toward the thrombin-cleaved form of OPN. Importantly, M5 antibody could inhibit the proliferation of synovium, bone erosion, and inflammatory cell infiltration in arthritic joints. Thus, we demonstrated that a cryptic epitope, the SLAYGLR sequence of murine OPN, is critically involved in the pathogenesis of a murine model of RA

Objective-Osteopontin (OPN), a noncollagenous adhesive protein, is implicated in atherosclerosis, in which macrophages within atherosclerotic plaques express OPN. However, it is not known whether the elevated OPN expression is a cause or result of atherosclerosis. Methods and Results-We generated mice that lacked OPN and crossed them with apolipoprotein (apo) E-deficient mice and analyzed these mice with a mixed C57BL/6ϫ129 background after 36 weeks on a normal chow diet. In female mice, OP ϩ/Ϫ E Ϫ/Ϫ and OP Ϫ/Ϫ E Ϫ/Ϫ mice had significantly smaller atherosclerotic and inflammatory lesions compared with OP ϩ/ϩ E Ϫ/Ϫ mice, and that was reflected by smaller area of MOMA-2-positive staining. In male mice, however, there was no significant difference in the atherosclerosis lesion areas among 3 genotypes. In both OP Ϫ/Ϫ E Ϫ/Ϫ and OP ϩ/ϩ E Ϫ/Ϫ mice, typical atherosclerotic lesions were detected, which include necrotic core, foamy cell collections, and cholesterol clefts. However, we found that vascular mineral-deposited areas in 60-week-old male OP Ϫ/Ϫ E Ϫ/Ϫ mice were significantly increased compared with those in OP ϩ/ϩ E Ϫ/Ϫ male mice. Key Words: osteopontin Ⅲ atherosclerosis Ⅲ macrophage Ⅲ calcification Ⅲ lipid metabolism A therosclerosis is characterized as a chronic inflammatory process of the vessel wall. Atherosclerosis is initiated by the infiltration of monocytes and T-lymphocytes into activated endothelium, followed by their migration into the intima and subsequent lipid accumulation within macrophages. In late stages of atherosclerosis, calcification is a common advanced complication. Osteopontin (OPN), a noncollagenous adhesive protein, was first found at sites of dystrophic calcification and is synthesized at high levels by macrophages in calcified aortic valves and atherosclerotic plaques. 1 The expression of OPN protein was detected in not only macrophages but also vascular smooth muscle cells within atherosclerotic lesion. [1][2][3][4][5] In addition, it was shown that vascular smooth muscle cells during the proliferative and migratory phase, but not the quiescent and contractile phase, expressed OPN in a model of balloon catheter injury of rat carotid artery. 2 More importantly, Liaw et al 6 reported that neutralizing antibodies directed against OPN inhibited rat carotid neointimal thickening after endothelial denudation. Taken together, these results suggested that OPN can play a pivotal role in the early stage of atherosclerosis, including proliferation and migration of smooth muscle cells as well as at the late stage of atherosclerosis, characterized by calcified atheromatous plaque formation. Conclusions-TheseTo more directly address the question of whether OPN initiates the development of atherosclerotic lesion and plays a role in calcification, we took advantage of OPN-deficient mice we had recently generated. 7 We crossed them with apolipoprotein (apo) E-deficient mice and made OPN and apoE double-deficient mice. In mice deficient for OPN gene expression, OPN mRNA was not detected in any organs. ...

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