Osteopontin: Role in immune regulation and stress responses

Abstract

Recent research has led to a better but as yet incomplete understanding of the complex roles osteopontin plays in mammalian physiology. A soluble protein found in all body fluids, it stimulates signal transduction pathways (via integrins and CD44 variants) similar to those stimulated by components of the extracellular matrix. This appears to promote the survival of cells exposed to potentially lethal insults such as ischemia/reperfusion or physical/chemical trauma. OPN is chemotactic for many cell types including macrophages, dendritic cells, and T cells; it enhances B lymphocyte immunoglobulin production and proliferation. In inflammatory situations it stimulates both pro- and anti-inflammatory processes, which on balance can be either beneficial or harmful depending on what other inputs the cell is receiving. OPN influences cell-mediated immunity and has been shown to have Th1-cytokine functions. OPN deficiency is linked to a reduced Th1 immune response in infectious diseases, autoimmunity and delayed type hypersensitivity. OPN’s role in the central nervous system and in stress responses has also emerged as an important aspect related to its cytoprotective and immune functions. Evidence suggests that either OPN or anti-OPN monoclonal antibodies (depending on the circumstances) might be clinically useful in modulating OPN function. Manipulation of plasma OPN levels may be useful in the treatment of autoimmune disease, cancer metastasis, osteoporosis and some forms of stress.

Introduction

Osteopontin (OPN) is an O-glycosylated phosphoprotein that is synthesized in a variety of tissues and cells and secreted into body fluids. It was originally identified as a bone matrix protein and subsequently identified as a cytokine (Eta-1) produced by activated T cells and transformed cell lines [1], [2], [3]. Receptors for OPN include certain integrins [4], [5], [6] and CD44 variants [7], [8], [9]. These receptors mediate cell adhesion, migration and survival in a variety of cell types. OPN’s potential to interact with ubiquitously expressed multiple cell surface receptors makes it an active player in many physiological and pathological processes including wound healing, bone turnover, tumorigenesis, inflammation, ischemia and immune responses.

In the immune system, OPN is expressed by many different cell types, including macrophages, neutrophils, dendritic cells, NK cells, and T and B lymphocytes; it is up-regulated in response to injury and inflammation in every organ examined; for example, cardiac tissue, kidney, lung, bone, brain, the gastrointestinal tract, joints, liver, adipose tissue [10] and most tumors [9]. OPN has been identified as a biomarker for various types of cancers and inflammatory diseases [11], [12]. Excessive or dysregulated OPN expression has been linked to the pathogenesis of both autoimmune disorders such as multiple sclerosis [13], systemic lupus erythematosus [14], rheumatoid arthritis [15], atherosclerosis [16] and other inflammatory diseases including cardiovascular disease [17], chronic obstructive pulmonary disease [18], inflammatory bowel disease [19], liver disease [20] and asthma [21]. Although initially regarded as an RGD-containing adhesive bone matrix protein because of its presence in the extracellular matrix of mineralized tissues, considerable evidence has established that OPN is also a soluble cytokine/hormone capable of stimulating signal transduction pathways in many different cell types. Recently, OPN has emerged as a key stress mediator, for example modulating the response of the immune organs (spleen, thymus) to some forms of stress. The purpose of this review is to summarize recent developments in our understanding of OPN’s role in immune and stress responses.