The role of osteopontin in inflammatory processes and Giachelli 1998; Smith et al. 1996) and α4β1 (Bayless and Davis 2001) integrins. Thus, the known adhesive functional domains of OPN are located in the thrombin cleaved N-terminal fragment. Little is known about the role of C-terminal fragments; however, as described above, it has been suggested to contain a CD44 binding domain (Weber et al. 2002; Takafuji et al. 2007). Proteolytic processing may represent a way to locally regulate the function of OPN as the functional properties of cleaved OPN differ from those of the intact molecule. Of particular interest, rather than mediating degradation and inactivating OPN-mediated functions, proteolytic process- ing of OPN can increase the biological activity of the molecule (O’Regan et al. 1999). OPN and MMPs are co- localized during wound healing and tumorigenesis, indicat- ing there may be an in vivo role for proteolyzed forms of OPN (Senger et al. 1994). Few studies suggest that OPN fragments may play a functional role in vivo. Enhanced production of the thrombin cleaved form of OPN is found in the synovial fluid of patients with rheumatoid arthritis (Ohshima et al. 2002) and the cryptic SLAYGLR motif was found to play an essential role in a murine and a primate model of rheumatoid arthritis (Yamamoto et al. 2003, 2007). An antibody against the SLAYGLR sequence inhibited inflammatory cell influx into arthritic joints and attenuated the severity of disease. The human OPN derived peptide SVVYGLR has also been found to induce angiogenesis in vitro and in vivo (Hamada et al. 2003, 2007). Several in vitro studies have demonstrated that the N-terminal fragments generated both by thrombin cleavage and MMP cleavage induced enhanced adhesion when compared to the full length molecule. This appears to be due mostly to increased activity of the RGD site, perhaps an indication of conformational change resulting in higher affinity binding (Senger and Perruzzi 1996; Smith and Giachelli 1998; Agnihotri et al. 2001). The SVVYGLR cryptic domain exposed following thrombin cleavage is also able to induce adhesion and migration through the α4 and α9 integrins (Smith and Giachelli 1998). However, the α9-dependent adhesion and migratory functions are com- pletely lost in the N-terminal MMP generated fragment, as Arg168 seems to be required for α9-dependent binding (Yokosaki et al. 2005; Ito et al. 2009). In contrast, α4- dependent adhesion and migratory functions are only partially lost in the N-terminal MMP generated fragment (Ito et al. 2009). The C-terminal fragment of OPN generated by thrombin and MMP cleavage does not contain any integrin adhesive domains, it does not mediate adhesion when presented in immobilized form to cells and, in contrast, it appears to suppress OPN mediated adhesion and migration in monocyte-derived cells (Gao et al. 2004; Smith et al. 1996; Maeda et al. 2001; Takahashi et al. 1998) 313 Intracellular OPN An intracellular form of OPN (iOPN) has been reported to be expressed in dendritic cells and macrophages (Shinohara et al. 2006, 2008a, b; Zohar et al. 2000). Studies by Shinohara et al. suggest that the intracellular form of OPN is generated due to translation initiation downstream of the usual start site in bone marrow-derived DCs and transfected 293T cells. Utilization of this downstream start site generates the truncated iOPN form that lacks the N- terminal signal sequence and consequently localizes to the cytoplasm, where it may associate with TLR9 and the MyD88 adaptor molecule (Shinohara et al. 2008a). The interaction of iOPN with MyD88 appears to activate the transcription factor IRF7 and to induce expression of IFN-α ultimately leading to Th1 cell-mediated immunity and pro-inflammatory responses (Shinohara et al. 2006). The same group has also suggested that iOPN expression in conventional DCs is permissive for Th17 T cell responses (Shinohara et al. 2008b). Th17 T cells are a subset of T helper cells producing IL-17. They are considered devel- opmentally distinct from Th1 and Th2 cells and are thought to play a key role in autoimmune diseases including the tissue injury associated with these conditions (Steinman 2007). Thus iOPN expression may allow for autoimmune type disease progression. Indeed, OPN accelerates the progression of experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (Chabas et al. 2001; Hur et al. 2007; Jansson et al. 2002; Shinohara et al. 2006, 2008b). Others have found that iOPN may associate with the intracellular domain of CD44 and with the ezrin/ radixin/moesin (ERM) protein ezrin. iOPN in this context may modulate cytoskeletal rearrangements important for macrophage migration and osteoclast fusion (Zhu et al. 2004; Zohar et al. 2000). A summary of the structural features of OPN is shown in Fig. 1. The role of OPN in inflammation OPN regulates the immune system at many different levels. It serves as a chemotactic molecule to promote the migration of inflammatory cells to the wound site and acts as an adhesive protein to retain cells at the site. OPN also functions as a pro- inflammatory cytokine and can modulate the immune response by enhancing expression of Th1 cytokines and matrix degrading enzymes (Weber et al. 2002; Bruemmer et al. 2003). OPN plays a pivotal role in T cell and macrophage responses during cell mediated immune responses against bacterial and viral pathogens (Ashkar et al. 2000). More recently, OPN has also been shown to modulate dendritic cell responses and neutrophil chemotaxis.