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10 Recent Advances in Angiogenesis and Antiangiogenesis, 2009, 10-19 The Role of Osteopontin in Angiogenesis Daria Leali 1 and Antonella Naldini 2 Domenico Ribatti (Ed.) All rights reserved - © 2009 Bentham Science Publishers Ltd. CHAPTER 2 1 Unit of General Pathology and Immunology, Department of Biomedical Sciences and Biotechnology, University of Brescia, Brescia, Italy; 2 Unit of Neuroimmunophysiology, Department of Physiology, University of Siena, Siena, Italy Address correspondence: Prof. Antonella Naldini, Department of Physiology, University of Siena, Via Aldo Moro 2, 53100 SIENA, ITALY. Tel.: +39-0577-234212. Fax: +39-0577-234219. E-mail: Naldini@Unisi.it 1. INTRODUCTION Abstract: Osteopontin (OPN) is a phosphorylated acidic (Arg-Gly-Asp) RGD-containing glycoprotein, which exists both as an immobilized extracellular matrix component and as a soluble molecule. The biological functions of OPN are extensively regulated on the posttranscriptional and post-translational levels and many of the signaling pathways mediated by secreted OPN are activated by ligation of the integrin and CD44 families of receptors. Such a multifaceted glycoprotein, that is expressed by numerous different cells and tissues, is expected to exert pleiotropic functions. Indeed, OPN is implicated in tumor metastases, tissue remodeling, inflammation, and cell-mediated immunity. Recently, substantial evidence suggests that OPN positively regulates angiogenesis. However, the mechanisms that define the role of this molecule in angiogenesis are incompletely understood. The following review will discuss the biochemical and biological properties of OPN in the context of its role in the modulation of angiogenesis. Osteopontin (OPN) is an arginine-glycine-aspartate (RGD)-containing acidic member of the small integrinbinding ligand N-linked glycoprotein (SIBLING) family of proteins [1]. OPN was originally isolated as a protein secreted by transformed mammalian cells [2]. Due to independent isolation from different sources, and with recognition of its diverse biological roles, OPN has also been known as “bone sialoprotein I (BSP-1)”, “secreted phosphoprotein 1 (Spp1)”, “2ar”, “uropontin” and “early T-lymphocyte activation (ETA-1) factor” [3-7]. As immobilized extracellular matrix (ECM) molecule and soluble cytokine, OPN is implicated in tumor metastases, tissue remodeling, inflammation, and cell-mediated immunity [8,9] and exerts its biological activity by interacting with integrin receptors and several CD44 variants expressed on target cells [9]. Nevertheless, an intracellular form of OPN has also been described [10]. Such a multifaceted glycoprotein, that is expressed by numerous different cells and tissues (see below), is expected to exert pleiotropic functions. Indeed, OPN acts as a pro-inflammatory cytokine that plays important roles in monocytes/macrophage functions [9]. Experiments performed on OPN null mice implicate OPN in T helper (Th)1 cell-mediated immunity during infection, autoimmune demyelinating disease, rheumatoid arthritis, wound healing, and bone resorption [11-13]. On the other hand, OPN exerts cell-adhesive and chemotactic activity for endothelial cells that are protected from apoptosis via v3 integrin-induced NF-B activation [14]. Also, OPN upregulation occurs in endothelial cells treated with interleukin (IL-1), interferon (IFN)-, glucocorticoids, or vascular endothelial growth factor (VEGF) [14,15] during angiogenesis in vitro, and during endothelium regeneration in balloon-injured artery [9]. The latter reports suggest that OPN may play an important role in angiogenesis. Angiogenesis is a complex process, where several cell types and mediators interact to establish a specific microenvironment suitable for the formation of new capillaries from pre-existing vessels [16]. Such biological processes occur in several physiological conditions, such as embryo development and wound healing, as well as in pathological conditions, including tumors and diabetic retinopathy. Inflammatory cells, such as T lymphocytes, neutrophils and monocytes, fully participate in the angiogenic process by secreting cytokines, that could control endothelial cell proliferation, their survival and apoptosis, as well as their migration and activation [17]. On the other hand, recent studies on cytokines released by T lymphocytes support the hypothesis that Th cells may control angiogenesis by switching to different phenotypes, which promote or antagonize the angiogenic process [18]. Thus, angiogenesis is the result of a net balance between the activities exerted by positive and negative regulators. Cytokines released by monocytes have been extensively studied in that context. Indeed, monocytes/macrophages produce direct and indirect inducers of angiogenesis, including
The Role of Osteopontin in Angiogenesis Recent Advances in Angiogenesis and Antiangiogenesis, 2009 11 IL-1, tumor-necrosis factor (TNF)-, IL-8 and VEGFs, as well as angiogenic inhibitors, such as angiostatin, inhibitory chemokines, and thrombospondin [17,19,20]. There is mounting evidence for the role of another cytokine, secreted by activated macrophages, in providing a link between inflammation and angiogenesis and that cytokine is OPN. While it is widely accepted the definition of OPN as metastasis gene for tumor progression [21,22], information regarding the role of OPN in angiogenesis is still scant. Here, the biochemical and biological properties of OPN will be reviewed in the context of its role in the modulation of angiogenesis. 2. OPN GENE STRUCTURE AND EXPRESSION Comparative analysis of cDNA isolated from different species (human, mouse, rat, bovine and chicken) revealed a high omology degree in OPN sequence [23]. The human OPN gene occurs at the long arm of chromosome 4 (4q21–4q25). Of the seven exons present, six of them (exons 2–7) contain coding sequences which are about 954 bp and the first exon is untranslated. The 5' upstream sequence of OPN gene contains a number of potential regulatory sequences. Regulatory sequences include a TATA-like sequence found at position –27 to –22 [24], CCAAAT-like sequence scattered throughout the 5' upstream region from –73 to –2190 [24,25], and the vitamin D responsive element at positions –698 to –684 and – 1892 to –1878. An interferon regulatory factor-1 binding sequence, AACTGA, is also identified at positions –1270 to –1264 [26]. In addition, potential binding sites for transcription of OPN gene include AP-1, AP-2, Ets-1, E2A, E2BP, TCF, and Myb which are characterized near the 5' cap site of rat and human OPN promoter (see [27] for a recent review). The biological functions of OPN are extensively regulated on the post-transcriptional and posttranslational levels. Human OPN cDNA analysis suggests the existence of three splicing isoforms (hOPNa, hOPNb e hOPNc) [28]. OPN-b lacks exon 5 and OPN-c lacks exon 4 [29]. The shortest splice variant, OPN-c, is a selective marker of breast cancer and may support breast tumor progression[30]. Furthermore, an intracellular form of OPN (iOPN), is generated as a consequence of translation initiation from a non-AUG site residing 40-nt downstream of the canonical AUG sequence [31]. This mechanism, which does not involve alternative mRNA transcription initiation or splicing, generates a fulllength secreted OPN (sOPN) and a smaller product (iOPN) that lacks the signal peptide from a single fulllength mRNA species. In contrast with secreted OPN isoforms, iOPN presumably interacts with the cytoplasmic domain of CD44, thus partecipating to CD44 signaling [31] (see below). Cell types which express OPN include osteoclasts, osteoblasts, kidney, breast and skin epithelial cells, nerve cells, vascular smooth muscle cells and endothelial cells [23,28,32-34]. In the immune system, OPN is expressed by many different cell types, including macrophages, neutrophils, B- and T lymphocytes, NK cells, Kuppfer cells, mast cells and plasmacytoid dendritic cells [10,35-40]. The induced expression of OPN has been detected in T lymphocytes, epidermal cells, bone cells, macrophages and tumor cells in remodeling processes such as inflammation, ischemia-reperfusion, bone resorption and tumor progression [27,28,33,34,41-44]. Furthermore, a variety of stimuli including phorbol 12-myristate 13-acetate (PMA), 1,25dihydroxyvitamin D, basic fibroblast growth factor (FGF2), platelet derived growth factor (PDGF), TNF- , IL-1, IFN- and lipopolysaccharide (LPS) upregulate OPN expression [9,28,33,34,45]. It has been proposed that distinct cell types differ in their post-translational modifications of OPN (see below), which may underlie cell-type specific differences in the functions of OPN [46]. 3. OPN PROTEIN STRUCTURE The complete amino acid sequences of OPN for human, rat, mouse, pig, cow and chicken [24] have been deduced from their cDNA sequences. OPN protein consists of a single chain of 264-333 amino acid, rich in sialic acid, glutamic acid and serine residues, depending on species (297 in mouse; 314 in human) [24]. Human OPN contains a hydrophobic leader sequence typical of secreted protein [9,47] (Fig. 1). A proteasehypersensitive site separates the NH2-terminal/integrin binding from the COOH-terminal/CD44 binding domains, which carry out distinct signaling functions. The thrombin cleavage motif in this region has a conserved sequence, 168 RSK 170 , present in most species [48]. The NH2-terminal region of OPN contains most of the well-conserved functional domains of the protein, such as an aspartate-rich region and several integrin binding sites. Via the RGD sequence located in the 158 GRGDS 162 motif near the centre of the protein, OPN interacts with a variety of v integrin receptors (including v1, v3, v5, v6), 81 and 51 [9,28,49-51]. Furthermore, the RGD-dependent interaction of OPN with v3 integrin requires phosphorylation of the protein [52]. A cryptic binding site located immediately downstream of the RGD domain ( 162 SVVYGLR 168 in human, SLAYGLR in mouse) is exposed upon thrombin cleavage between the R 168 and S 169 residues and mediates an RGDindipendent interaction of OPN with 91 and 47 integrins [28,51,53]. Earlier reports indicated that
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Page 4 and 5: FOREWORD It has been known for a ve
Page 6 and 7: single proangiogenic protein. Howev
Page 8 and 9: v Vito Pistoia Head, Laboratory of
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Page 16 and 17: The Role of Mesenchymal Stem Cells
Page 22 and 23: Thymus and Angiogenesis Recent Adva
Page 32 and 33: Role of Thymidine Recent Advances i
Page 34 and 35: Role of Stromal Cells Recent Advanc
Page 40 and 41: Tumor Targeting with Transgenic End
Page 44 and 45: Tumor Vascular Disrupting Agents Re
Page 50 and 51: Tumour Vascular Disrupting Agents R
Page 52: Index Recent Advances in Angiogenes

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