Osteopontin, a Coordinator of Host Defense System: a Cytokine or an Extracellular Adhesive Protein?

Uede, Toshimitsu; Katagiri, Yohko U.; Iizuka, Junko; Murakami, Masaaki

doi:10.1111/j.1348-0421.1997.tb01906.x

Cited by 81 publications

(61 citation statements)

References 52 publications

(13 reference statements)

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“…For example, the role of osteopontin in inflammation and immune function have been reviewed by Weber and Cantor (78), Uede et al (109), and Giachelli and Steitz (45), in mineralized tissues by Denhardt and Noda (70), and in vascular tissue by Ramos (110). A functional role for osteopontin in tumor progression and malignancy has been claimed by several researchers.…”

Section: The Role Of Osteopontin In Cancermentioning

confidence: 99%

The Role of Osteopontin in Tumor Progression and Metastasis in Breast Cancer

Rodrigues

Teixeira

Schmitt

et al. 2007

Cancer Epidemiology, Biomarkers &Amp; Prevention

206

144

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The use of cancer biomarkers to anticipate the outlines of disease has been an emerging issue, especially as cancer treatment has made such positive steps in the last few years. Progress in the development of consistent malignancy markers is imminent because advances in genomics and bioinformatics have allowed the examination of immense amounts of data. Osteopontin is a phosphorylated glycoprotein secreted by activated macrophages, leukocytes, and activated T lymphocytes, and is present in extracellular fluids, at sites of inflammation, and in the extracellular matrix of mineralized tissues. Several physiologic roles have been attributed to osteopontin, i.e., in inflammation and immune function, in mineralized tissues, in vascular tissue, and in kidney. Osteopontin interacts with a variety of cell surface receptors, including several integrins and CD44. Binding of osteopontin to these cell surface receptors stimulates cell adhesion, migration, and specific signaling functions. Overexpression of osteopontin has been found in a variety of cancers, including breast cancer, lung cancer, colorectal cancer, stomach cancer, ovarian cancer, and melanoma. Moreover, osteopontin is present in elevated levels in the blood and plasma of some patients with metastatic cancers. Therefore, suppression of the action of osteopontin may confer significant therapeutic activity, and several strategies for bringing about this suppression have been identified. This review looks at the recent advances in understanding the possible mechanisms by which osteopontin may contribute functionally to malignancy, particularly in breast cancer. Furthermore, the measurement of osteopontin in the blood or tumors of patients with cancer, as a way of providing valuable prognostic information, will be discussed based on emerging clinical data. (Cancer Epidemiol Biomarkers Prev 2007;16(6):1087 -97)

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Section: The Role Of Osteopontin In Cancermentioning

confidence: 99%

The Role of Osteopontin in Tumor Progression and Metastasis in Breast Cancer

Rodrigues

Teixeira

Schmitt

et al. 2007

Cancer Epidemiology, Biomarkers &Amp; Prevention

206

144

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“…OPN has been shown to be multifunctional, with activities in cell migration, cell survival, inhibition of calcification, regulation of immune cell function, and control of tumor cell phenotype (1)(2)(3)(4). Targeting of the gene encoding OPN, spp1, has revealed that while OPN is not necessary for normal embryonic development, fertility, and health under pathogen-free conditions (5,6), loss of the protein has significant consequences in several models of injury/disease as diverse as renal injury, viral and bacterial infection, bone remodeling, and tumor growth (7)(8)(9)(10)(11)(12).…”

Section: Osteopontin (Opn)mentioning

confidence: 99%

Osteopontin, a Novel Substrate for Matrix Metalloproteinase-3 (Stromelysin-1) and Matrix Metalloproteinase-7 (Matrilysin)

Agnihotri¹,

Crawford²,

Haro³

et al. 2001

Journal of Biological Chemistry

359

295

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Osteopontin (OPN) is a secreted phosphoprotein shown to function in wound healing, inflammation, and tumor progression. Expression of OPN is often co-localized with members of the matrix metalloproteinase (MMP) family. We report that OPN is a novel substrate for two MMPs, MMP-3 (stromelysin-1) and MMP-7 (matrilysin). Three cleavage sites were identified for MMP-3 in human OPN, and two of those sites were also cleaved by MMP-7. These include hydrolysis of the human Gly Osteopontin (OPN)1 is an arginine-glycine-aspartic acid (RGD)-containing glycoprotein that interacts with integrins and CD44 as major receptors. OPN has been shown to be multifunctional, with activities in cell migration, cell survival, inhibition of calcification, regulation of immune cell function, and control of tumor cell phenotype (1-4). Targeting of the gene encoding OPN, spp1, has revealed that while OPN is not necessary for normal embryonic development, fertility, and health under pathogen-free conditions (5, 6), loss of the protein has significant consequences in several models of injury/disease as diverse as renal injury, viral and bacterial infection, bone remodeling, and tumor growth (7-12). The fact that no other proteins seem to share a redundant activity with OPN under these conditions suggests that OPN has a unique functional role during tissue injury and stress. Interestingly, several members of the matrix metalloproteinase (MMP) family are also induced during injury/disease processes in patterns overlapping that of OPN (13). In particular, we have found that during squamous cell carcinoma progression, OPN and MMP-3 expression correspond both in a temporal and cell-specific fashion (9, 14). We have also identified overlapping expression patterns of OPN and MMP-3 in the stroma during skin incisional wound healing (5) and OPN and MMP-7 during involution of the postpartum uterus (15).OPN is known to be a substrate for proteolytic cleavage by the proteases thrombin (16, 17) and enterokinase (18). Thrombin cleavage of OPN (Arg 168 -Ser 169 in humans, Arg 153 -Ser 154 in rats) is of interest, since hydrolysis of this peptide bond reveals a binding site for the integrins ␣ 9 ␤ 1 (19) and ␣ 4 ␤ 1 (20), SV-VYGLR, not present in the full-length molecule (16). In addition, functional properties of thrombin-cleaved OPN differ from the intact protein (21-24), demonstrating that proteolytic cleavage is one mechanism of regulating the bioactivity of OPN.In the present study, we have identified and characterized novel cleavage sites in OPN for two members of the MMP family, MMP-3 and MMP-7. Furthermore, we show that lower molecular weight forms of OPN corresponding to predicted MMP cleavage fragments are present in cell lines in vitro and in tissues in vivo. Biological assays demonstrate that the MMPcleaved OPN has increased activity in promoting both cell adhesion and migration compared with full-length OPN. In addition, using inhibitory reagents, we have determined that the same receptors that interact with OPN also mediate interaction of MMP-c...

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“…OPN contains an arginine-glycine-aspartate (RGD) cell binding domain (3,4,9) and interacts with integrin and CD44 receptors. Therefore, to study the receptor-mediated effects of OPN, cells were pretreated with GRGDS-pentapeptide (100 nM).…”

Section: Opn Inhibits Il-1␤-stimulated Increases In Mmp Activity-mentioning

confidence: 99%

“…Using spontaneously hypertensive and aorticbanded rats, we have shown increased expression of OPN coincident with heart failure (8). OPN interacts with specific integrins, namely ␣ v ␤ 1 , ␣ v ␤ 3 , ␣ v ␤ 5 , and also with CD44 receptors and affects many cellular processes including cell attachment, spreading, and migration (3,4,9). Recently, we have documented an increased expression of OPN in remote and infarct regions of left ventricle following myocardial infarction (MI).…”

mentioning

confidence: 99%

Osteopontin Inhibits Interleukin-1β-stimulated Increases in Matrix Metalloproteinase Activity in Adult Rat Cardiac Fibroblasts

Xie

Singh

Siwik

et al. 2003

Journal of Biological Chemistry

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We have shown that osteopontin (OPN), an extracellular matrix protein, plays an important role in post myocardial infarction (MI) remodeling by promoting collagen synthesis and accumulation. Interleukin-1␤ (IL-1␤), increased in the heart following MI, increases matrix metalloproteinase (MMP) activity in cardiac fibroblasts in vitro. Here, we show that OPN alone has no effect on MMP activity or expression. However, it reduces IL-1␤-stimulated increases in MMP activity and expression in adult rat cardiac fibroblasts. Pretreatment with bovine serum albumin had no effect on MMP activity or protein content, whereas GRGDS (glycinearginine-glycine-aspartic acid-serine)-pentapeptide (which interrupts binding of RGD-containing proteins to cell surface integrins) and monoclonal antibody m7E3 (a rat ␤ 3 integrins antagonist) inhibited the effects of OPN. Inhibition of PKC using chelerythrine inhibited the activities of both MMP-2 and MMP-9. Stimulation of cells using IL-1␤ increased phosphorylation and translocation of PKC to membrane fractions, which was inhibited by OPN. OPN inhibited IL-1␤-stimulated increases in translocation of PKC-from cytosolic to membrane fractions. Furthermore, the levels of phospho-PKC-were lower in the cytosolic fractions of OPN knock-out mice hearts as compared with wild type 6 days post-MI. Inhibition of PKC-using PKCpseudosubstrate inhibited IL-1␤-stimulated increases in MMP-2 and MMP-9 activities. These observations suggest that OPN, acting via ␤ 3 integrins, inhibits IL-1␤-stimulated increases in MMP-2 and MMP-9 activity, at least in part, via the involvement of PKC-. Thus, OPN may play a key role in collagen deposition during myocardial remodeling following MI by modulating cytokine-stimulated MMP activity.The dynamic synthesis and breakdown of extracellular matrix (ECM) 1 proteins may play an important role in myocardial remodeling (1, 2). Osteopontin (OPN) is a glycosylated and phosphorylated ECM protein (3, 4). Although first isolated from mineralized matrix, OPN has since been shown to be synthesized by cardiac fibroblasts, endothelial cells, and myocytes (3, 5-7). Using spontaneously hypertensive and aorticbanded rats, we have shown increased expression of OPN coincident with heart failure (8). OPN interacts with specific integrins, namely, and also with CD44 receptors and affects many cellular processes including cell attachment, spreading, and migration (3, 4, 9). Recently, we have documented an increased expression of OPN in remote and infarct regions of left ventricle following myocardial infarction (MI). Furthermore, using OPN knock-out mice and MI as a model of myocardial remodeling, we demonstrated that a lack of OPN results in greater left ventricle dilation and reduced collagen synthesis and accumulation 1 month post-MI, suggesting a role for OPN in ECM reorganization in the heart during myocardial remodeling (10). A critical role for OPN in the generation of interstitial fibrosis was observed in the skin incision model of wound healing and in the kidney following obstructive...

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Osteopontin, a Coordinator of Host Defense System: a Cytokine or an Extracellular Adhesive Protein?

Cited by 81 publications

References 52 publications

The Role of Osteopontin in Tumor Progression and Metastasis in Breast Cancer

The Role of Osteopontin in Tumor Progression and Metastasis in Breast Cancer

Osteopontin, a Novel Substrate for Matrix Metalloproteinase-3 (Stromelysin-1) and Matrix Metalloproteinase-7 (Matrilysin)

Osteopontin Inhibits Interleukin-1β-stimulated Increases in Matrix Metalloproteinase Activity in Adult Rat Cardiac Fibroblasts

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