SurveyOsteopontin: Role in immune regulation and stress responses
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.
Section snippets
Structure and function of OPN
The functional motifs of the OPN molecule, illustrated in Fig. 1, may provide clues to OPN’s broad biological functions. OPN is a highly negatively charged protein that lacks extensive secondary structure. It is encoded by a single gene in a cluster of “SIBLING” family proteins (Small Integrin Binding Ligand N-linked Glycoprotein, though not all are “N-linked”) located on chromosome 4 in humans [22]. Its promoter is responsive to a number of different transcription factors [6], [23].
OPN and innate immunity
Most infectious agents induce inflammatory responses by activating innate immunity in processes often involving macrophages and neutrophils. These cells are the professional phagocytes that provide the first line of defense of the immune system. Epithelial damage causes release of the cytokines IL-1 and IL-8, which recruit macrophages and neutrophils to the site of injury. Macrophages express toll-like receptors that recognize pathogen-associated molecular patterns (PAMPs) and engulf the
OPN and cell-mediated immunity
Elevated OPN expression is found in various immunological disorders. Up-regulation of OPN is implicated in the formation of granulomas in tuberculosis, sarcoidosis and silicosis, all of which involve cell-mediated immune reactions [4], [80]. Studies of OPN−/− mice revealed that OPN’s main immune-modulatory function is the enhancement of Th1 over Th2 immunity through two general mechanisms: regulation of cytokine production via 1) interaction with the αvβ3 integrin to induce pro-inflammatory
OPN and stress
Depending on the duration, stress can be immuno-enhancing or immuno-suppressive. An acute stress (minutes up to hours) can stimulate the immune system and induce leukocyte redistribution, thereby augmenting immune functions in response to the injury [111]; chronic stress (days and months) suppresses immunity and leads to increased susceptibility to disease. These opposite actions are believed to be mediated by stress-induced glucocorticoid hormones that are produced by the adrenal gland [112].
Conclusions
In the immune system, OPN is expressed by various immune cells at various differentiation stages and activation states; it modulates immune responses at several levels. First, its chemotactic property promotes cell recruitment to sites of inflammation. Second, its function as an adhesion protein facilitates cell attachment and wound healing. Third, OPN mediates cell activation and cytokine production through interaction with cellular signaling pathways, and fourth, it promotes cell survival by
Acknowledgements
This research was supported in part by a Busch Biomedical Research Grant, by the National Multiple Sclerosis Society, by the Rutgers Technology Commercialization Fund, and by a research grant from Mrs. George Harrar. We thank our colleagues Lori Covey, Yacov Ron, Mari Shinohara, Yufang Shi, Guy Werlen, and Ping Xie for useful comments on the manuscript.
Kathryn X. Wang obtained her Bachelor’s degree in plant physiology and biochemistry from Nanjing University, China in 1983, her Master’s degree in forestry from Michigan Technological University in 1989, and her PhD degree in Immunology in 2008 from Rutgers University/UMDNJ-Robert Wood Johnson Medical School. She has worked at Harvard Medical School, Genzyme, Bristol-Myers Squibb and now at Sanofi-Aventis as a research scientist. One of her research interests is in osteopontin’s role in the
References (133)
- et al.
Distinct structural requirements for binding of the integrins alphavbeta6, alphavbeta3, alphavbeta5, alpha5beta1 and alpha9beta1 to osteopontin
Matrix Biol
(2005) - et al.
The regulation and role of osteopontin in malignant transformation and cancer
Cytokine Growth Factor Rev
(2006) - et al.
Osteopontin: role in cell signaling and cancer progression
Trends Cell Biol
(2006) - et al.
Flexible structures of SIBLING proteins, bone sialoprotein, and osteopontin
Biochem Biophys Res Commun
(2001) - et al.
Analysis of the alpha4beta1 integrin-osteopontin interaction
Exp Cell Res
(2000) - et al.
The activation state of alphavbeta3 regulates platelet and lymphocyte adhesion to intact and thrombin-cleaved osteopontin
J Biol Chem
(2000) - et al.
The role of OPN in tumor metastasis
J Surg Res
(2004) - et al.
Cell type-specific post-translational modifications of mouse osteopontin are associated with different adhesive properties
J Biol Chem
(2007) - et al.
Osteopontin posttranslational modifications, possibly phosphorylation, are required for in vitro bone resorption but not osteoclast adhesion
Bone
(2002) - et al.
Phosphorylation of osteopontin is required for inhibition of vascular smooth muscle cell calcification
J Biol Chem
(2000)
Osteopontin, a key component of the hematopoietic stem cell niche and regulator of primitive hematopoietic progenitor cells
Blood
The osteopontin-CD44 survival signal involves activation of the phosphatidylinositol 3-kinase/Akt signaling pathway
J Biol Chem
TGFbeta and BMP-2 activation of the OPN promoter: roles of smad- and hox-binding elements
Exp Cell Res
S-Nitrosylation of heterogeneous nuclear ribonucleoprotein A/B regulates osteopontin transcription in endotoxin-stimulated murine macrophages
J Biol Chem
Role of osteopontin in hepatic neutrophil infiltration during alcoholic steatohepatitis
Toxicol Appl Pharmacol
Polarization and directed migration of murine neutrophils is dependent on cell surface expression of CD44
Cell Immunol
Osteopontin functionally activates dendritic cells and induces their differentiation toward a Th1-polarizing phenotype
Blood
Successful treatment of collagen-induced arthritis in non-human primates by chimeric anti-osteopontin antibody
Int Immunopharmacol
Molecular and cellular basis of genetic resistance to bacterial infection: the role of the early T-lymphocyte activation-1/osteopontin gene
Crit Rev Immunol
Osteopontin
Crit Rev Oral Biol Med
Osteopontin as a means to cope with environmental insults: regulation of inflammation, tissue remodeling, and cell survival
J Clin Invest
Osteopontin: a key cytokine in cell-mediated and granulomatous inflammation
Int J Exp Pathol
Receptor-ligand interaction between CD44 and osteopontin (Eta-1)
Science
CD44 variants but not CD44 s cooperate with beta1-containing integrins to permit cells to bind to osteopontin independently of arginine–glycine–aspartic acid, thereby stimulating cell motility and chemotaxis
Cancer Res
Osteopontin and mucosal protection
J Dent Res
Plasma osteopontin levels and expression in adipose tissue are increased in obesity
J Clin Endocrinol Metab
Pathophysiological role of osteopontin in hepatic inflammation, toxicity and cancer
Toxicol Sci
Multiple sclerosis: deeper understanding of its pathogenesis reveals new targets for therapy
Annu Rev Neurosci
SLE and infections
Clin Rev Allergy Immunol
Role of osteopontin in amplification and perpetuation of rheumatoid synovitis
J Clin Invest
The roles of cytokines, inflammation and immunity in vascular diseases
J Atheroscler Thromb
Impairment of myocardial angiogenic response in the absence of osteopontin
Microcirculation
A distinctive alveolar macrophage activation state induced by cigarette smoking
Respir Crit Care Med
Expression of osteopontin (Eta-1) in Crohn disease of the terminal ileum
Scand J Gastroenterol
Higher neutrophil infiltration mediated by osteopontin is a likely contributing factor to the increased susceptibility of females to alcoholic liver disease
J Pathol
Osteopontin has a crucial role in allergic airway disease through regulation of dendritic cell subsets
Nat Med
Transcriptional regulation of osteopontin and the metastatic phenotype: evidence for a Ras-activated enhancer in the human OPN promoter
Clin Exp Metastasis
Characterization of anti-osteopontin monoclonal antibodies: binding sensitivity to post-translational modifications
J Cell Biochem
Control of osteopontin signaling and function by post-translational phosphorylation and protein folding
J Cell Biochem
Osteopontin is a ligand for the alpha4beta1 integrin
J Cell Sci
Identification of osteopontin as a novel ligand for the integrin alpha8 beta1 and potential roles for this integrin–ligand interaction in kidney morphogenesis
Mol Biol Cell
Enhanced cell surface CD44 variant (v6, v9) expression by osteopontin in breast cancer epithelial cells facilitates tumor cell migration: novel post-transcriptional, post-translational regulation
Clin Exp Metastasis
Eta-1 (osteopontin): an early component of type-1 (cell-mediated) immunity
Science
Coupling of osteopontin and its cell surface receptor CD44 to the cell survival response elicited by interleukin-3 or granulocyte-macrophage colony-stimulating factor
Mol Cell Biol
An osteopontin splice variant induces anchorage independence in human breast cancer cells
Oncogene
Post-translationally modified residues of native human osteopontin are located in clusters: identification of 36 phosphorylation and five O-glycosylation sites and their biological implications
Biochem J
Comprehensive identification of post-translational modifications of rat bone osteopontin by mass spectrometry
Biochemistry
Phosphorylated osteopontin promotes migration of human choriocarcinoma cells via a p70 S6 kinase-dependent pathway
J Cell Biochem
Importance of phosphorylation for osteopontin regulation of biomineralization
Calcif Tissue Int
Alternative translation of osteopontin generates intracellular and secreted isoforms that mediate distinct biological activities in dendritic cells
Proc Natl Acad Sci USA
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Kathryn X. Wang obtained her Bachelor’s degree in plant physiology and biochemistry from Nanjing University, China in 1983, her Master’s degree in forestry from Michigan Technological University in 1989, and her PhD degree in Immunology in 2008 from Rutgers University/UMDNJ-Robert Wood Johnson Medical School. She has worked at Harvard Medical School, Genzyme, Bristol-Myers Squibb and now at Sanofi-Aventis as a research scientist. One of her research interests is in osteopontin’s role in the regulation of immune cell function and its involvement in stress responses. Recently she has discovered that osteopontin is critical in mediating stress-induced weight loss and lymphoid organ atrophy in mice; she is presently investigating the mechanism underlying how OPN affects stress-induced organ atrophy and immune suppression.
David T. Denhardt earned a degree with High Honors in Chemistry at Swarthmore College (1960) and a PhD in Biophysics at the California Institute of Technology (1965). His early research at Harvard University and subsequently at McGill University was largely focused on bacteriophage ΦX174 and DNA replication in E. coli. In 1980 he accepted the position of Director of the Cancer Research Laboratory at the University of Western Ontario, where he initiated research on tumor promotion and cell proliferation in mammalian cells. Among the novel mouse cDNA clones isolated and characterized during this period were those encoding osteopontin, TIMP-1, MRP/proliferin, carnitine acetyltransferase, and MEP/cathepsin L. Studies on several of these genes continued when he moved to Rutgers University in 1989 to assume the Chair of Biological Sciences. Presently a member of the Department of Cell Biology and Neuroscience, his current research (much of which is collaborative) is focused on identifying functional consequences of OPN expression in cell culture and in the mammalian organism, in part using recently isolated novel anti-(human)OPN monoclonal antibodies to inhibit one or more of those functions.
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Present address: Sanofi-Aventis, Internal Medicine, 1041 Route 202-206, Bridgewater, NJ 08540, USA.