318 humans (Giachelli et al. 1993). In mice, OPN levels are greatly elevated in the spontaneously mineralizing arteries of MGP-/- mice and we have recently shown that OPN is major inducible inhibitor of arterial medial calcification in this system (Steitz et al. 2002). Vascular calcification is now recognized as a marker of atherosclerotic plaque burden as well as a major contributor to loss of arterial compliance and increased pulse pressure seen with age, diabetes, and renal insufficiency. These findings suggest that OPN may be an important inhibitor of arterial mineral deposition under conditions of injury and disease, and that strategies to replenish OPN might be useful to prevent or treat ectopic calcification, including vascular calcification. Conclusions OPN is emerging as a key regulator of immune cell biology. Most of the evidence indicates that OPN is transiently expressed in leukocytes during acute inflammation. How- ever, persistence of OPN expression by immune cells S.A. Lund et al. exacerbates chronic inflammatory diseases. Clinically, this is manifested by increased OPN plasma levels in Crohn’s disease (Agnholt et al. 2007), cancer (El-Tanani et al. 2006), atherosclerosis, and autoimmune diseases including lupus (Kariuki et al. 2009), multiple sclerosis (Comabella et al. 2005), and rheumatoid arthritis (Sennels et al. 2008). Mechanistically, OPN appears to regulate innate immune cells (macrophages and DCs) and adaptive immune cells (T cells) at multiple levels (see Fig. 2). Recent data point to a role for OPN in the regulation of cross-talk between DCs and T cells and their subsequent polarization in Th1 and more recently in Th17 cells. In vitro and in vivo studies show that both the thrombin and MMP proteolytically cleaved OPN fragments possess higher activity than the full-length form. In addition, at least the thrombin cleaved fragment also gains a new cell interacting domain (SVVYGLR). Antibodies specifically reacting toward the SVVYGLR (human and primate) or the SLAYGLR (murine) sequences have been shown effective in ameliorating rheumatoid arthritis symptoms in non- human primates and mice (Yamamoto et al. 2003, 2007). Accumulation migration survival IL-12 Th1 polarization activation IL-10 migration proliferation survival IL-17 Th17 polarization EAE autoimmunity INFγ Th1 polarization ? C-terminal OPN macrophages OPN fragments N-terminal OPN SVVYGLR Rheumatoid Arthritis Angiogenesis INFα Th1 polarization activation IL-12 TNFα Th1 polarization OPN iOPN T-Cells DCs migration Fig. 2 OPN regulation of immune and inflammatory cells. OPN is secreted and modulates the function of macrophages, DCs and T Cells. OPN may induce macrophage accumulation by promoting migration and survival. Further, OPN induces IL-12 and inhibits IL-10 in macrophages, thus, propagating a Th1 response. In DCs OPN appears to modulate their function as an extracellular soluble cytokine and also as an intracellular molecule (iOPN). Both OPN forms appear to induce Th1 polarization. Extracellular OPN appears to induce expression of IL-12 and TNF-α, and iOPN appears to regulate the production of INF-α. In T cells OPN induces migration, proliferation, survival, and IL-17 secretion. These two latter functions have been correlated with Th17 responses and autoimmunity. Further, OPN appears to induce IFN-γ secretion by T cells thus propagating a Th1 response. Finally, the N-terminal OPN fragment (containing the activated adhesive domain SVVYGLR) may be important in the propagation of rheumatoid arthritis