The role of osteopontin in inflammatory processes A more recent study by Mori et al. explored the use of local OPN knockdown at the site of wound healing by delivering antisense oligodeoxynucleotides from a drug delivery polymer gel. Consistent with the finding in OPN- mice, in OPN knockdown wounds the diameter of collagen fibrils was also smaller than in control wounds. Further, OPN knockdown hindered the migration of inflammatory cells to the wound site and resulted in accelerated healing and a reduction in granulation tissue formation and scarring (Mori et al. 2008). Whether the infiltrated macrophages in OPN knockdown wounds also had a less pro-inflammatory and more pro-healing pheno- type was not established, however, this may be behind the observed accelerated healing. The reduced size of the collagen fibers that was observed in the OPN-null and OPN knockdown wounds may be related to the finding that OPN has been shown to bind directly to collagen type I (Chen et al. 1992), and to interact with collagen types II, III, IV, and V (Bulter et al. 1995). Further, it has recently been shown that OPN is necessary for TGF-β1-induced myofibroblast differentiation and OPN-null fibroblasts exhibited less spreading, less resistance to detachment, and a reduction in collagen gel contraction (Lenga et al. 2008). These studies indicate a role for OPN in promoting proper collagen organization and regulating ECM and myofibroblast interactions. Vascular disease To date, several studies have investigated the role of OPN in the progression of atherosclerosis. In hyperlipidemic apoE- deficient mice, Matsui et al, showed that osteopontin deficiency significantly reduces atherosclerotic lesion size in female ApoE-/-OPN-/- mice compared to ApoE-/-OPN+/+ mice after 36 weeks on a normal chow diet (Matsui et al. 2003). Similarly, studies in ApoE/LDLreceptor/OPN triple knockout mice showed that OPN deficiency resulted in decreased atherosclerotic lesion size and an increase in the number of apoptotic cells in lesions (Strom et al. 2004). Bone marrow transplantation studies in an angiotensin II- accelerated model of atherosclerosis indicated that leukocyte derived OPN contributes to OPN mediated development of atherosclerosis (Bruemmer et al. 2003). These studies suggest that OPN promotes macrophage accumulation and retention in the atherosclerotic lesions, thus contributing to the chronicity of the disease. OPN also modulates other vascular cells associated with vascular disease. In human atherosclerotic lesions, OPN is expressed in smooth muscle cells (SMC), angiogenic endo- thelial cells, and macrophages and it is re-expressed in SMCs associated with human restenotic lesions (Giachelli et al. 1993; Panda et al. 1997). Consistently, animal models have confirmed the role of OPN in promoting SMC migration and 317 proliferation (Liaw et al. 1994; Isoda et al. 2002). All these data indicate that during injury, OPN enhances the prolifer- ation, migration, and accumulation of smooth muscle and endothelial cells involved in repair and remodeling processes of the vasculature. Cancer OPN is highly expressed in transformed cells and is found in a variety of cancers (Wai and Kuo 2008). OPN overexpression can confer metastatic phenotype to non- metastatic, benign transformed cells, and increased OPN expression correlates with tumor progression, poor progno- sis and increased invasiveness. In metastatic models, OPN has been shown to induce matrix proteases MMP2 and uPA in an integrin-dependent manner (Mi et al. 2006). Further, OPN has been shown to bind and activate MMP3. Thus, the ability of OPN to stimulate migration and matrix break- down could contribute to invasiveness and to the metastatic potential of tumors cells. OPN may also promote tumori- genesis and metastasis by inhibiting apoptosis of tumor cells (Zhao et al. 2008), and by stimulating neovasculariza- tion (Wai and Kuo 2004). Finally, OPN is widely expressed by macrophages, which infiltrate tumor tissue (Brown et al. 1994; Chambers et al. 1996). Macrophage-derived OPN functions as a chemoattractant and was associated with reduced tumor burden while tumor-derived OPN appeared to inhibit macrophage function and enhance tumor growth (Crawford et al. 1998). It is possible that tumor cell-derived OPN may enhance cancer cell survival by downregulating iNOS expression and NO production in macrophages. OPN is currently being studied as a potential biomarker for cancer and there is interest in targeting OPN as a therapeutic treatment for cancer. Biomineralization OPN is one of the most abundant non-collagenous proteins in bone. Because of its abundance in bone, OPN has been studied as a regulator of biomineralization. OPN is a potent inhibitor of mineralization, prevents ectopic calcification, and is an inducible inhibitor of vascular calcification (Steitz et al. 2002). OPN binds hydroxyapatite and calcium ions thereby physically inhibiting crystal formation and growth in vivo. Studies in OPN-null mice have shown that OPN-/- bones are hypermineralized, with increased mineral content and crystal size (Boskey et al. 2002). OPN also plays a role in osteoclast differentiation and osteoblast recruitment and function (Rittling et al. 1998). OPN functions in osteoclast migration to sites of resorption and is crucial for normal resorption and bone turnover (Chellaiah et al. 2003). OPN appears also to be an important regulator of vascular calcification and is associated with mineralized deposits in