Recent Advances in Angiogenesis and ... - Bentham Science

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