Q J Med 2002; 95: 3-13
© 2002 Association of Physicians
Review |
Osteopontin—a molecule for all seasons
From the Baylor College of Medicine, Houston, Texas, USA, 1 Phagocyte Laboratory, Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK, 2 Renal Division, Department of Medicine, Chiang Mai University, Chiang Mai, Thailand, and 3 Department of Veterans Affairs, Medical Centre and Medical College of Wisconsin, Milwaukee, Wisconsin, USA
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Introduction |
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 Top Introduction OPN structureRegulation of OPN expressionOPN and pathological...OPN and inflammationOPN and cell survivalOther biological functions of...ConclusionReferences |
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Osteopontin (OPN) is a multifunctional protein, and although highly expressed in bone, it is also expressed by various cell types including macrophages, endothelial cells, smooth muscle cells and epithelial cells.1,2 OPN is involved in diverse biological processes and the aim of this review is to give a broad outline of some important aspects of the biology of OPN. Although this review is written primarily from a renal perspective, it is hoped that the reader will appreciate that OPN is involved in both physiological and pathological processes in multiple organs and tissues including biomineralization, inflammation, leukocyte recruitment and cell survival.
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OPN structure |
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TopIntroductionOPN structureRegulation of OPN expressionOPN and pathological...OPN and inflammationOPN and cell survivalOther biological functions of...ConclusionReferences |
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OPN is a negatively-charged acidic hydrophilic protein of approximately 300 amino acid residues, and is secreted into all body fluids. The OPN cDNA from various mammalian species exhibits a high degree of sequence homology. There is evidence of alternative splicing, although the functional significance of this is unclear at present. The molecule undergoes considerable post-translational modification, and is phosphorylated and glycosylated. OPN has an arginine-glycine-aspartic acid (RGD) cell binding sequence, a calcium binding site and two heparin binding domains.
Cells may bind OPN via multiple integrin receptors including the vitronectin receptor (
vß3) as well as various ß1 and ß5 integrins. Integrin binding may be RGD-dependent or -independent (e.g. via the motif SVVYGLR). OPN does not bind the standard form of CD44 (hyaluronic acid receptor) but does bind various isoforms of CD44. These CD44 isoforms bind OPN via multiple sites. OPN may be cleaved by thrombin, resulting in the exposure of additional cryptic binding sites as well as the production of functional chemotactic fragments.3
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Regulation of OPN expression |
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TopIntroductionOPN structureRegulation of OPN expressionOPN and pathological...OPN and inflammationOPN and cell survivalOther biological functions of...ConclusionReferences |
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The regulation of OPN expression is incompletely understood at present and may differ between various cell types. Studies indicate that the OPN promoter contains various motifs including a purine-rich sequence, an ets-like sequence, glucocorticoid and vitamin D response elements and interferon-inducible elements.4–6 Pro-inflammatory cytokines stimulate OPN gene transcription and expression. For example, activation of macrophages with lipopolysaccharide (LPS) and nitric oxide (NO) induces OPN gene expression and protein secretion.7 Classical mediators of acute inflammation such as tumour necrosis factor
(TNF) and interleukin-1ß (IL-1ß) strongly induce OPN expression4,5,8 while other mediators that can induce OPN upregulation include angiotensin II, transforming growth factor ß(TGFß), hyperglycaemia and hypoxia.9–14 |
OPN and pathological mineralization |
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TopIntroductionOPN structureRegulation of OPN expressionOPN and pathological...OPN and inflammationOPN and cell survivalOther biological functions of...ConclusionReferences |
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OPN is intimately involved in the regulation of both physiological and pathological mineralization. In normal bone tissue, OPN is expressed by both osteoclasts and osteoblasts which are the cells responsible for bone remodelling. During normal bone mineralization, osteoclast-derived OPN inhibits the formation of hydroxyapatite.15,16 Despite the fact that OPN knockout mice exhibit a normal bone structure,17 there is evidence indicating that OPN is involved in bone resorption. For example, OPN knockout mice are markedly protected from bone loss following ovariectomy.18 In addition, bone resorption mediated by parathyroid hormone is also OPN-dependent.19
Prominent OPN expression is found in regions of dystrophic calcification such as that associated with degenerative and atheromatous vascular disease.20–24 Experiments using an in vitro model of smooth muscle cell calcification indicate that OPN exerts an inhibitory effect upon this process,25 thereby suggesting that the upregulation of OPN evident in areas of dystrophic calcification represents an attempt to either prevent or limit vascular calcification.
OPN is also an important facet of the urinary tract's defence against the formation of renal stones, the majority of which are comprised of calcium oxalate. As a consequence of the essential homeostatic conservation of water, normal urine is supersaturated with respect to crystalline components, and this empirically suggests the existence of physiological mechanisms that actively inhibit urinary crystallization of calcium salts. Various inhibitory macromolecules including urinary OPN have now been isolated and identified from both normal urine and kidney stones, e.g. nephrocalcin, crystal matrix protein, bikunin and Tamm-Horsfall protein.26–30
OPN is synthesized within the kidney and secreted into the urine by epithelial cells, including the loop of Henle, distal convoluted tubule and papillary epithelium.31,32 OPN can inhibit the nucleation, growth and aggregation of calcium oxalate crystals in vitro26,33 and directly inhibits the binding of calcium oxalate crystals to cultured renal epithelial cells.34 In addition, OPN directs calcium oxalate crystallization to the calcium oxalate dihydrate phase, which is significantly less adherent to renal tubular epithelial cells than the calcium oxalate monohydrate phase.35,36
Are the inhibitory properties of OPN regarding calcium oxalate crystal formation and adhesion to tubular epithelial cells important in vivo? Experiments involving hyperoxaluric rats that develop renal calcium oxalate deposition do suggest an important in vivo role, since the upregulation of OPN mRNA and protein expression specifically colocalized with areas of renal calcium oxalate deposition.37,38 However, definitive data regarding the protective role of OPN were lacking until recently. We have used OPN knockout mice to test the hypothesis that OPN is required for the effective prevention of renal calcium oxalate deposition in vivo. Previous studies have indicated that non-manipulated OPN knockout mice exhibit normal kidney architecture and renal function.39–41 We induced comparable hyperoxaluria in OPN knockout and control OPN wild-type mice by the administration of 1% ethylene glycol, an oxalate precursor, in the drinking water for 4 weeks. Hyperoxaluric OPN knockout mice developed significant intratubular deposition of calcium oxalate whilst OPN wild-type mice were completely unaffected (Figure 1
).42 Crystal inclusions were comprised exclusively of calcium oxalate monohydrate, and typically affected the distal nephron and collecting duct, sites where the concentration of oxalate would be predicted to be highest. Interestingly, the absence of calcium oxalate deposition in hyperoxaluric OPN wild-type mice was associated with significant upregulation of renal OPN expression by immunocytochemistry, thereby lending further support for a renoprotective role for OPN (Figure 2). The fact that OPN knockout mice do not spontaneously develop renal calcium oxalate deposition indicates that other urinary inhibitors can adequately compensate for the absence of OPN. However, these studies do indicate that urinary OPN is essential in adverse conditions predisposing to calcium oxalate deposition. OPN-mediated protection is likely to result from effects at various sites along the pathway of crystal formation, growth and retention, as indicated schematically in Figure 3. Currently, the exact molecular mechanism whereby OPN exerts its various inhibitory effects is unclear, although it is known that phosphorylation of the OPN molecule is critically important.43,44
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We believe that these research findings will be of relevance to clinic patients with renal stone disease. Recent data indicates that defective inhibition of urinary crystallization is present in the majority of stone-forming patients and may well be of critical importance in determining individual susceptibility to stone formation.45 It is therefore noteworthy that OPN is present in normal urine at levels that can effectively inhibit crystallization.46,47 However, clinical studies to date are inconclusive regarding the relationship between OPN and renal stone disease. Some investigators have found reduced concentrations of OPN in urine from stone formers compared to normal individuals,48 while others have not.49 One study has described a single base mutation in the OPN gene which has a significantly higher incidence in patients with recurrent stone formation or familial nephrolithiasis.50 Therefore, while these results suggest that OPN may play an important role in protecting the kidney from stone formation, a cause and effect relationship in humans has not been established. However, this may not be of critical importance, since the future determination of the exact molecular mechanism of action of OPN may allow the development of novel water-soluble drugs that will significantly increase the capacity of urine to inhibit pathological crystal formation and deposition. Such a therapeutic strategy may clearly be of great benefit to patients with recurrent renal stone disease.
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OPN and inflammation |
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TopIntroductionOPN structureRegulation of OPN expressionOPN and pathological...OPN and inflammationOPN and cell survivalOther biological functions of...ConclusionReferences |
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OPN plays an important role during both acute and chronic inflammation where it may be expressed by resident epithelial, endothelial and smooth muscle cells as well as infiltrating macrophages and T cells. OPN may exert both pro-inflammatory and anti-inflammatory actions, with the net effect of OPN depending upon the nature of the biological scenario.
Leucocyte recruitment and function
OPN is involved in the recruitment and retention of macrophages and T cells to inflamed sites. Dermal injection of purified OPN induces an inflammatory macrophage infiltrate, while macrophage recruitment in response to N-formyl-met-leu-phe, a potent macrophage chemotactic peptide, is significantly attenuated by administration of neutralizing anti-OPN antibodies.51 OPN may not only be expressed by T cells but also induces T-cell chemotaxis and costimulates T-cell proliferation.3 In addition, OPN fragments generated by thrombin cleavage, and which are likely to be present at sites of inflammation, are more effective supporters of T-cell adhesion than is the native molecule.3 Furthermore, the administration of neutralizing anti-OPN antibodies to rats with glomerulonephritis significantly inhibited T-cell accumulation, T-cell activation and the delayed type hypersensitivity response.52
OPN expression correlates with macrophage infiltration in various animal models of acute and chronic renal injury such as glomerulonephritis, hypertensive glomerulosclerosis and cyclosporine nephropathy,53–55 with similar findings being reported in human crescentic glomerulonephritis.56 In addition, upregulation of OPN expression precedes the macrophage infiltrate present in injured kidneys.57 An important functional role for OPN in renal disease is supported by studies involving the administration of function blocking anti-OPN antibodies in rat models of acute glomerulonephritis. The administration of neutralizing anti-OPN antibody markedly reduced glomerular and tubulointerstitial macrophage infiltration and T-cell accumulation, as well as various histological and functional parameters of renal injury.52,53 Similarly, the administration of intravenous OPN antisense oligodeoxynucleotide to rats with glomerulonephritis resulted in decreased OPN expression by tubular epithelial cells and diminished interstitial macrophage accumulation.58 Studies involving OPN knockout mice have produced somewhat conflicting results, since the absence of OPN resulted in diminished macrophage infiltration following ureteric obstruction but had no effect upon macrophage infiltration in a model of glomerulonephritis.40,59
OPN expression is pronounced in granulomatous lesions, whether secondary to infections such as tuberculosis or conditions such as sarcoidosis or silicosis.60 OPN knockout mice are more susceptible to infection with mycobacteria.61 Similarly, OPN expression in humans also contributes to resistance to mycobacterial infection and disease.62 It is now established that OPN is critically involved in the initiation of cell-mediated immune responses, and stimulates Th1 cytokine expression and inhibits Th2 cytokine expression.63,64 OPN knockout mice exhibit a defective Th1 response to infection with either Herpes simplex virus or Listeria monocytogenes; this defective response is associated with diminished macrophage production of interleukin-12 (IL-12) and interferon-
and increased production of interleukin-10 (IL-10).65 Furthermore, recombinant OPN directly modulates macrophage production of these cytokines in vitro, with exogenous OPN stimulating macrophage IL-12 production and inhibiting IL-10 production.65 An additional level of complexity is that the differential effect of OPN upon macrophage cytokine production is mediated by ligation of different cell surface receptors by OPN, since stimulation of IL-12 and inhibition of IL-10 result from ß3 integrin and CD44 ligation, respectively.65
OPN modulates activation of T cells as well as cytokine production,66,67 while gene expression profiling studies indicate that OPN is selectively upregulated in Th1 cells.68 Lastly, the elevation in serum OPN levels evident in models of autoimmune disease coupled with the fact that OPN may induce polyclonal activation of B cells and associated immunoglobulin production implicates OPN in the pathogenesis of autoimmunity.67,69–71
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OPN and cell survival |
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TopIntroductionOPN structureRegulation of OPN expressionOPN and pathological...OPN and inflammationOPN and cell survivalOther biological functions of...ConclusionReferences |
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OPN is a cell survival factor and may protect cells from undergoing apoptosis. For example, treatment of serum-starved NRK52E renal epithelial cells with neutralizing anti-OPN antibody markedly enhances the level of apoptosis.40 Furthermore, despite diminished macrophage infiltration and interstitial fibrosis, the obstructed kidneys of OPN knockout mice exhibit increased levels of tubular cell apoptosis compared to wild-type mice, suggesting that OPN is capable of providing survival signals to tubular epithelial cells in vivo.40 The binding of OPN to the
vß3 integrin of endothelial cells activates the pro-survival transcription factor NF
B and protects endothelial cells from undergoing apoptosis.72 There are also reports of OPN exerting pro-survival effects in other cell types, including vascular smooth muscle cells and haemopoietic cells.73,74.
OPN and the regulation of inducible nitric oxide synthase
Recent data indicate that other actions of OPN may also exert important protective effects in tissues. OPN inhibits the expression of inducible nitric oxide synthase (iNOS) in both macrophages and primary renal tubular epithelial cells.75,76 Since iNOS-derived nitric oxide (NO) is a well-documented mediator of tissue injury, the OPN-mediated inhibition of iNOS would be predicted to exert beneficial effects upon surrounding tissues. Indeed, OPN knockout mice fare poorly following renal ischaemia-reperfusion injury, a model documented to involve NO.39 The absence of OPN is associated with significantly worse renal dysfunction, increased tubular expression of iNOS and nitrotyrosine residues and more severe histological injury.39 Interestingly, since the capacity of cultured human tubular epithelial cells to upregulate OPN expression diminishes with increasing age of the kidney from which they were derived, one can speculate that this may be involved in the increased susceptibility of aged kidneys to ischaemia-reperfusion injury.77
NO is an important facet of macrophage cytotoxicity and is involved in macrophage killing of tumour cells78 and glomerular mesangial cells in vitro.79 Recently, we have investigated the mechanism underlying the induction of apoptosis in MDCK renal tubular epithelial cells during coculture with macrophages activated with lipopolysaccharide and interferon-. Interestingly, MDCK cell death is also dependent upon macrophage generation of NO, since macrophage-mediated MDCK cell apoptosis is significantly blocked by the iNOS inhibitor L-NAME. In addition, activated macrophages from iNOS wild-type mice induce a 3.5-fold higher level of MDCK cell apoptosis compared to activated macrophages from iNOS knockout mice (unpublished data, Figure 4). Since inflammatory macrophages are implicated in the induction of tubular epithelial cell death in vivo,80 it can be appreciated that OPN-mediated inhibition of iNOS may protect resident renal cells from macrophage cytotoxicity during renal inflammation. Interestingly, NO induces OPN production by macrophages,7 thereby providing a negative feedback loop predicted to limit NO-mediated tissue injury. This raises the possibility that the absence of OPN-mediated iNOS inhibition may be at least partly responsible for the increased level of tubular epithelial cell death evident in the obstructed kidneys of OPN knockout mice.40
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Other biological functions of OPN |
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TopIntroductionOPN structureRegulation of OPN expressionOPN and pathological...OPN and inflammationOPN and cell survivalOther biological functions of...ConclusionReferences |
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OPN is important in tissue repair. OPN knockout mice exhibit defective repair of incisional skin wounds with abnormal collagen fibrillogenesis,81 although the mechanism underlying this defect is unclear at present. OPN is also associated with cellular regeneration. For example, OPN expression was localized to PCNA-positive regenerating tubules in a rat model of acute renal failure induced by the administration of the nephrotoxic drug gentamicin.82 In addition, OPN is involved in the proliferation of vascular smooth muscle cells and glomerular mesangial cells induced by hypoxia.83,84
OPN expression is also associated with tissue scarring and fibrosis, with OPN upregulation evident in models of renal disease exhibiting extensive fibrotic changes such as progressive glomerulonephritis and the remnant kidney model.85,86 The correlation of OPN with tissue fibrosis is most likely to be secondary to the concomitant macrophage infiltrate and associated production of TGFß.40 However, recent data suggest that OPN may play a more direct role in the development of tissue fibrosis, since OPN is chemotactic for fibroblasts, potentiates growth factor mediated fibroblast proliferation and modulates fibroblast secretion of metalloproteinases.87–89
OPN is important in tumour cell biology. Indeed, OPN was originally isolated from epithelial and fibroblastic cells that had undergone malignant transformation.90 Treatment of neoplastic cell lines with OPN antisense oligodeoxynucleotide results in diminished malignant potential in vitro and in vivo.91 In a study of patients with breast carcinoma, increased expression of OPN by tumour tissue was associated with a significantly reduced disease-free survival and overall survival.92 It may well be significant that the binding of OPN to cells may stimulate metalloproteinase production and thereby facilitate cell migration through extracellular matrix,93,94 although it should be noted that the opposite effect may occur in some cell types.95
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Conclusion |
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TopIntroductionOPN structureRegulation of OPN expressionOPN and pathological...OPN and inflammationOPN and cell survivalOther biological functions of...ConclusionReferences |
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OPN is an impressively multifunctional molecule (Figure 5
). Although non-manipulated OPN knockout mice exhibit a normal phenotype, they exhibit markedly abnormal responses to a variety of injurious stimuli, revealing much about the biological role of OPN in vivo. Further work is required to determine the full role of OPN in human disease. However, it is envisaged that the elucidation of the molecular mechanisms underlying the myriad actions of OPN will allow the development of novel therapeutic agents designed to modulate the action of OPN for patient benefit in a broad range of diseases, including renal stone disease, inflammation and cancer.
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Acknowledgments |
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JH was a Wellcome Trust Advanced Fellow and is now in receipt of a Wellcome Trust Senior Research Fellowship in Clinical Science. RJJ is supported by NIH grants DK-43422, DK-47659 and DK-52121. JAW was primarily supported through a Research Career Development Grant from the Department of Veterans Affairs (RCD9305) and received additional support from the Medical College of Wisconsin.
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Notes |
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Address correspondence to Dr J. Hughes, Phagocyte Laboratory, MRC Centre for Inflammation Research, University of Edinburgh Medical School, Teviot Place, Edinburgh, UK. e-mail: jeremy.hughes{at}ed.ac.uk
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References |
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TopIntroductionOPN structureRegulation of OPN expressionOPN and pathological...OPN and inflammationOPN and cell survivalOther biological functions of...ConclusionReferences |
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1. O'Brien ER, Garvin MR, Stewart DK, Hinohara T, Simpson JB, Schwartz SM, et al. Osteopontin is synthesized by macrophage, smooth muscle, and endothelial cells in primary and restenotic human coronary atherosclerotic plaques. Arterioscler Thromb1994; 14:1648–56.
2. Malyankar UM, Almeida M, Johnson RJ, Pichler RH, Giachelli CM. Osteopontin regulation in cultured rat renal epithelial cells. Kidney Int1997; 51:1766–73.[ISI][Medline]
3.
O'Regan AW, Chupp GL, Lowry JA, Goetschkes M, Mulligan N, Berman JS. Osteopontin is associated with T cells in sarcoid granulomas and has T cell adhesive and cytokine-like properties in vitro. J Immunol1999; 162:1024–31.
4. Denhardt DT, Guo X. Osteopontin: a protein with diverse functions. FASEB J1993; 7:1475–82.[Abstract]
5. Patarca R, Saavedra RA, Cantor H. Molecular and cellular basis of genetic resistance to bacterial infection: the role of the early T-lymphocyte activation-1/osteopontin gene. Crit Rev Immunol1993; 13:225–46.[ISI][Medline]
6. Koszewski NJ, Reinhardt TA, Horst RL. Vitamin D receptor interactions with the murine osteopontin response element. J Steroid Biochem Mol Biol1996; 59:377–88.[ISI][Medline]
7.
Guo H, Cai CQ, Schroeder RA, Kuo PC. Osteopontin is a negative feedback regulator of nitric oxide synthesis in murine macrophages. J Immunol2001; 166:1079–86.
8.
Yu XQ, Fan JM, Nikolic-Paterson DJ, Yang N, Mu W, Pichler R, et al. IL-1 up-regulates osteopontin expression in experimental crescentic glomerulonephritis in the rat. Am J Pathol1999; 154:833–41.
9.
Ricardo SD, Franzoni DF, Roesener CD, Crisman JM, Diamond JR. Angiotensinogen and AT(1) antisense inhibition of osteopontin translation in rat proximal tubular cells. Am J Physiol Renal Physiol2000; 278:F708–16.
10. Hullinger TG, Pan Q, Viswanathan HL, Somerman MJ. TGFbeta and BMP-2 activation of the OPN promoter: roles of smad- and hox-binding elements. Exp Cell Res2001; 262:69–74.[ISI][Medline]
11. Diamond JR, Kreisberg R, Evans R, Nguyen TA, Ricardo SD. Regulation of proximal tubular osteopontin in experimental hydronephrosis in the rat. Kidney Int1998; 54:1501–9.[ISI][Medline]
12. Ashizawa N, Graf K, Do YS, Nunohiro T, Giachelli CM, Meehan WP, et al. Osteopontin is produced by rat cardiac fibroblasts and mediates A(II)-induced DNA synthesis and collagen gel contraction. J Clin Invest1996; 98:2218–27.[ISI][Medline]
13.
Takemoto M, Yokote K, Yamazaki M, Ridall AL, Butler WT, Matsumoto T, et al. Enhanced expression of osteopontin by high glucose. Involvement of osteopontin in diabetic macroangiopathy. Ann N Y Acad Sci2000; 902:357–63.
14.
Sodhi CP, Phadke SA, Batlle D, Sahai A. Hypoxia and high glucose cause exaggerated mesangial cell growth and collagen synthesis: role of osteopontin. Am J Physiol Renal Physiol2001; 280:F667–74.
15. Hunter GK, Kyle CL, Goldberg HA. Modulation of crystal formation by bone phosphoproteins: structural specificity of the osteopontin-mediated inhibition of hydroxyapatite formation. Biochem J1994; 300:723–8.
16. Hunter GK, Hauschka PV, Poole AR, Rosenberg LC, Goldberg HA. Nucleation and inhibition of hydroxyapatite formation by mineralized tissue proteins. Biochem J1996; 317:59–64.
17. Rittling SR, Matsumoto HN, McKee MD, Nanci A, An XR, Novick KE, et al. Mice lacking osteopontin show normal development and bone structure but display altered osteoclast formation in vitro. J Bone Miner Res1998; 13:1101–11.[ISI][Medline]
18.
Yoshitake H, Rittling SR, Denhardt DT, Noda M. Osteopontin-deficient mice are resistant to ovariectomy-induced bone resorption. Proc Natl Acad Sci USA1999; 96:8156–60.
19.
Ihara H, Denhardt DT, Furuya K, Yamashita T, Muguruma Y, Tsuji K, et al. Parathyroid hormone-induced bone resorption does not occur in the absence of osteopontin. J Biol Chem2001; 276:13065–71.
20.
O'Brien KD, Kuusisto J, Reichenbach DD, Ferguson M, Giachelli C, Alpers CE, et al. Osteopontin is expressed in human aortic valvular lesions. Circulation1995; 92:2163–8.
21. Srivatsa SS, Harrity PJ, Maercklein PB, Kleppe L, Veinot J, Edwards WD, et al. Increased cellular expression of matrix proteins that regulate mineralization is associated with calcification of native human and porcine xenograft bioprosthetic heart valves. J Clin Invest1997; 99:996–1009.[ISI][Medline]
22. Shanahan CM, Cary NR, Metcalfe JC, Weissberg PL. High expression of genes for calcification-regulating proteins in human atherosclerotic plaques. J Clin Invest1994; 93:2393–402.
23. Hirota S, Imakita M, Kohri K, Ito A, Morii E, Adachi S, et al. Expression of osteopontin messenger RNA by macrophages in atherosclerotic plaques. A possible association with calcification. Am J Pathol1993; 143:1003–8.[Abstract]
24. Ikeda T, Shirasawa T, Esaki Y, Yoshiki S, Hirokawa K. Osteopontin mRNA is expressed by smooth muscle-derived foam cells in human atherosclerotic lesions of the aorta. J Clin Invest1993; 92:2814–20.
25.
Wada T, McKee MD, Steitz S, Giachelli CM. Calcification of vascular smooth muscle cell cultures: inhibition by osteopontin. Circ Res1999; 84:166–78.
26.
Shiraga H, Min W, VanDusen WJ, Clayman MD, Miner D, Terrell CH, et al. Inhibition of calcium oxalate crystal growth in vitro by uropontin: another member of the aspartic acid-rich protein superfamily. Proc Natl Acad Sci USA1992; 89:426–30.
27. Coe FL, Nakagawa Y, Asplin J, Parks JH. Role of nephrocalcin in inhibition of calcium oxalate crystallization and nephrolithiasis. Miner Electrolyte Metab1994; 20:378–84.[ISI][Medline]
28. Stapleton AM, Ryall RL. Crystal matrix protein–getting blood out of a stone. Miner Electrolyte Metab1994; 20:399–409.[ISI][Medline]
29. Atmani F, Khan SR. Role of urinary bikunin in the inhibition of calcium oxalate crystallization. J Am Soc Nephrol1999; 10 (Suppl. 14):S385–8.
30. Hess B. Tamm-Horsfall glycoprotein and calcium nephrolithiasis. Miner Electrolyte Metab1994; 20:393–8.[ISI][Medline]
31.
Hudkins KL, Giachelli CM, Cui Y, Couser WG, Johnson RJ, Alpers CE. Osteopontin expression in fetal and mature human kidney. J Am Soc Nephrol1999; 10:444–57.
32. Kleinman JG, Beshensky A, Worcester EM, Brown D. Expression of osteopontin, a urinary inhibitor of stone mineral crystal growth, in rat kidney. Kidney Int1995; 47:1585–96.[ISI][Medline]
33. Worcester EM, Beshensky AM. Osteopontin inhibits nucleation of calcium oxalate crystals. Ann N Y Acad Sci1995; 760:375–7.[ISI][Medline]
34.
Lieske JC, Leonard R, Toback FG. Adhesion of calcium oxalate monohydrate crystals to renal epithelial cells is inhibited by specific anions. Am J Physiol1995; 268:F604–12.
35. Wesson JA, Worcester E. Formation of hydrated calcium oxalates in the presence of poly-L-aspartic acid. Scanning Microsc1996; 10:415–24.[Medline]
36. Wesson JA, Worcester EM, Wiessner JH, Mandel NS, Kleinman JG. Control of calcium oxalate crystal structure and cell adherence by urinary macromolecules. Kidney Int1998; 53:952–7.[ISI][Medline]
37. Gokhale JA, Glenton PA, Khan SR. Localization of Tamm-Horsfall protein and osteopontin in a rat nephrolithiasis model. Nephron1996; 73:456–61.[ISI][Medline]
38. Jiang XJ, Feng T, Chang LS, Kong XT, Wang G, Zhang ZW, et al. Expression of osteopontin mRNA in normal and stone-forming rat kidney. Urol Res1998; 26:389–94.[ISI][Medline]
39. Noiri E, Dickman K, Miller F, Romanov G, Romanov VI, Shaw R, et al. Reduced tolerance to acute renal ischemia in mice with a targeted disruption of the osteopontin gene. Kidney Int1999; 56:74–82.[ISI][Medline]
40. Ophascharoensuk V, Giachelli CM, Gordon K, Hughes J, Pichler R, Brown P, et al. Obstructive uropathy in the mouse: role of osteopontin in interstitial fibrosis and apoptosis. Kidney Int1999; 56:571–80.[ISI][Medline]
41. Rittling SR, Denhardt DT. Osteopontin function in pathology: lessons from osteopontin-deficient mice. Exp Nephrol1999; 7:103–13.[ISI][Medline]
42. Beshensky AM, Wesson JA, Kleinman JG, Liaw L, Steitz S, Giachelli CM, et al. Renoprotective modulation of calcium oxalate crystal structure by osteopontin in vivo. J Am Soc Nephrol2000; 11:558A.
43.
Jono SPC, Giachelli CM. Phosphorylation of osteopontin is required for inhibition of vascular smooth muscle cell calcification. J Biol Chem2000; 275:20197–203.
44. Hoyer JR, Asplin JR, Otvos L. Phosphorylated osteopontin peptides suppress crystallization by inhibiting the growth of calcium oxalate crystals. Kidney Int2001; 60:77–82.[ISI][Medline]
45. Asplin JR, Parks JH, Chen MS, Lieske JC, Toback FG, Pillay SN, et al. Reduced crystallization inhibition by urine from men with nephrolithiasis. Kidney Int1999; 56:1505–16.[ISI][Medline]
46. Min W, Shiraga H, Chalko C, Goldfarb S, Krishna GG, Hoyer JR. Quantitative studies of human urinary excretion of uropontin. Kidney Int1998; 53:189–93.[ISI][Medline]
47. Sorensen S, Justesen SJ, Johnsen AH. Identification of a macromolecular crystal growth inhibitor in human urine as osteopontin. Urol Res1995; 23:327–34.[ISI][Medline]
48. Nishio S, Hatanaka M, Takeda H, Aoki K, Iseda T, Iwata H, et al. Calcium Phosphate Crystal-Associated Proteins: alpha2-HS-Glycoprotein, Prothrombin F1, and Osteopontin. Mol Urol2000; 4:383–90.[ISI][Medline]
49. Hedgepeth RC, Yang L, Resnick MI, Marengo SR. Expression of Proteins That Inhibit Calcium Oxalate Crystallization In Vitro in the Urine of Normal and Stone-Forming Individuals. Am J Kidney Dis2001; 37:104–12.[ISI][Medline]
50. Yamate T, Tsuji H, Amasaki N, Iguchi M, Kurita T, Kohri K. Analysis of osteopontin DNA in patients with urolithiasis. Urol Res2000; 28:159–66.[ISI][Medline]
51. Giachelli CM, Lombardi D, Johnson RJ, Murry CE, Almeida M. Evidence for a role of osteopontin in macrophage infiltration in response to pathological stimuli in vivo. Am J Pathol1998; 152:353–8.[Abstract]
52. Yu XQ, Nikolic-Paterson DJ, Mu W, Giachelli CM, Atkins RC, Johnson RJ, et al. A functional role for osteopontin in experimental crescentic glomerulonephritis in the rat. Proc Assoc Am Physicians1998; 110:50–64.[ISI][Medline]
53. Panzer U, Thaiss F, Zahner G, Barth P, Reszka M, Reinking RR, et al. Monocyte chemoattractant protein-1 and osteopontin differentially regulate monocytes recruitment in experimental glomerulonephritis. Kidney Int2001; 59:1762–9.[ISI][Medline]
54. Hartner A, Porst M, Gauer S, Prols F, Veelken R, Hilgers KF. Glomerular osteopontin expression and macrophage infiltration in glomerulosclerosis of doca-salt rats. Am J Kidney Dis2001; 38:153–64.[ISI][Medline]
55. Pichler RH, Franceschini N, Young BA, Hugo C, Andoh TF, Burdmann EA, et al. Pathogenesis of cyclosporine nephropathy: roles of angiotensin II and osteopontin. J Am Soc Nephrol1995; 6:1186–96.[Abstract]
56. Hudkins KL, Giachelli CM, Eitner F, Couser WG, Johnson RJ, Alpers CE. Osteopontin expression in human crescentic glomerulonephritis. Kidney Int2000; 57:105–16.[ISI][Medline]
57. Pichler R, Giachelli CM, Lombardi D, Pippin J, Gordon K, Alpers CE, et al. Tubulointerstitial disease in glomerulonephritis. Potential role of osteopontin (uropontin). Am J Pathol1994; 144:915–26.[Abstract]
58.
Okada H, Moriwaki K, Kalluri R, Takenaka T, Imai H, Ban S, et al. Osteopontin expressed by renal tubular epithelium mediates interstitial monocyte infiltration in rats. Am J Physiol Renal Physiol2000; 278:F110–21.
59.
Bonvini JM, Schatzmann U, Beck-Schimme RB, Sun LK, Rittling SR, Denhardt DT, et al. Lack of in vivo function of osteopontin in experimental anti-GBM nephritis. J Am Soc Nephrol2000; 11:1647–55.
60.
Nau GJ, Guilfoile P, Chupp GL, Berman JS, Kim SJ, Kornfeld H, et al. A chemoattractant cytokine associated with granulomas in tuberculosis and silicosis. Proc Natl Acad Sci USA1997; 94:6414–19.
61.
Nau GJ, Liaw L, Chupp GL, Berman JS, Hogan BL, Young RA. Attenuated host resistance against Mycobacterium bovis BCG infection in mice lacking osteopontin. Infect Immun1999; 67:4223–30.
62.
Nau GJ, Chupp GL, Emile JF, Jouanguy E, Berman JS, Casanova JL, et al. Osteopontin expression correlates with clinical outcome in patients with mycobacterial infection. Am J Pathol2000; 157:37–42.
63. O'Regan AW, Nau GJ, Chupp GL, Berman JS. Osteopontin (Eta-1) in cell-mediated immunity: teaching an old dog new tricks. Immunol Today2000; 21:475–8.[ISI][Medline]
64. O'Regan A, Berman JS. Osteopontin: a key cytokine in cell-mediated and granulomatous inflammation. Int J Exp Pathol2000; 81:373–90.[ISI][Medline]
65.
Ashkar S, Weber GF, Panoutsakopoulou V, Sanchirico ME, Jansson M, Zawaideh S, et al. Eta-1 (osteopontin): an early component of type-1 (cell-mediated) immunity. Science2000; 287:860–4.
66. Adler B, Ashkar S, Cantor H, Weber GF. Costimulation by extracellular matrix proteins determines the response to tcr ligation. Cell Immunol2001; 210:30–40.[ISI][Medline]
67.
O'Regan AW, Hayden JM, Berman JS. Osteopontin augments CD3-mediated interferon-gamma and CD40 ligand expression by T cells, which results in IL-12 production from peripheral blood mononuclear cells. J Leukoc Biol2000; 68:495–502.
68.
Nagai S, Hashimoto S, Yamashita T, Toyoda N, Satoh T, Suzuki T, et al. Comprehensive gene expression profile of human activated T(h)1- and T(h)2-polarized cells. Int Immunol2001; 13:367–76.
69. Lampe MA, Patarca R, Iregui MV, Cantor H. Polyclonal B cell activation by the Eta-1 cytokine and the development of systemic autoimmune disease. J Immunol1991; 147:2902–6.[Abstract]
70. Iizuka J, Katagiri Y, Tada N, Murakami M, Ikeda T, Sato M, et al. Introduction of an osteopontin gene confers the increase in B1 cell population and the production of anti-DNA autoantibodies. Lab Invest1998; 78:1523–33.[ISI][Medline]
71. Cantor H. The role of Eta-1/osteopontin in the pathogenesis of immunological disorders. Ann N Y Acad Sci1995; 21:143–50.
72.
Scatena M, Almeida M, Chaisson ML, Fausto N, Nicosia RF, Giachelli CM. NF-kappaB mediates alphavbeta3 integrin-induced endothelial cell survival. J Cell Biol1998; 141:1083–93.
73. Weintraub AS, Schnapp LM, Lin X, Taubman MB. Osteopontin deficiency in rat vascular smooth muscle cells is associated with an inability to adhere to collagen and increased apoptosis. Lab Invest2000; 80:1603–15.[ISI][Medline]
74.
Lin YH, Huang CJ, Chao JR, Chen ST, Lee SF, Yen JJ, et al. 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 Biol2000; 20:2734–42.
75. Rollo EE, Laskin DL, Denhardt DT. Osteopontin inhibits nitric oxide production and cytotoxicity by activated RAW264.7 macrophages. J Leukoc Biol1996; 60:397–404.[Abstract]
76.
Hwang SM, Lopez CA, Heck DE, Gardner CR, Laskin DL, Laskin JD, et al. Osteopontin inhibits induction of nitric oxide synthase gene expression by inflammatory mediators in mouse kidney epithelial cells. J Biol Chem1994; 269:711–15.
77. Hwang SM, Wilson PD, Laskin JD, Denhardt DT. Age and development-related changes in osteopontin and nitric oxide synthase mRNA levels in human kidney proximal tubule epithelial cells: contrasting responses to hypoxia and reoxygenation. J Cell Physiol1994; 160:61–8.[ISI][Medline]
78.
Cui S, Reichner JS, Mateo RB, Albina JE. Activated murine macrophages induce apoptosis in tumor cells through nitric oxide-dependent or -independent mechanisms. Cancer Res1994; 54:2462–7.
79.
Duffield JS, Erwig LP, Wei X, Liew FY, Rees AJ, Savill JS. Activated macrophages direct apoptosis and suppress mitosis of mesangial cells. J Immunology2000; 164:2110–19.
80. Tesch GH, Schwarting A, Kinoshita K, Lan HY, Rollins BJ, Kelley VR. Monocyte chemoattractant protein-1 promotes macrophage-mediated tubular injury, but not glomerular injury, in nephrotoxic serum nephritis. J Clin Invest1999; 103:73–80.[ISI][Medline]
81. Liaw L, Birk DE, Ballas CB, Whitsitt JS, Davidson JM, Hogan BL. Altered wound healing in mice lacking a functional osteopontin gene (spp1). J Clin Invest1998; 101:1468–78.[ISI][Medline]
82. Xie Y, Nishi S, Iguchi S, Imai N, Sakatsume M, Saito A, et al. Expression of osteopontin in gentamicin-induced acute tubular necrosis and its recovery process. Kidney Int2001; 59:959–74.[ISI][Medline]
83.
Sodhi CP, Phadke SA, Batlle D, Sahai A. Hypoxia stimulates osteopontin expression and proliferation of cultured vascular smooth muscle cells: potentiation by high glucose. Diabetes2001; 50:1482–90.
84. Sodhi CP, Batlle D, Sahai A. Osteopontin mediates hypoxia-induced proliferation of cultured mesangial cells: role of PKC and p38 MAPK. Kidney Int2000; 58:691–700.[ISI][Medline]
85. Narita I, Nakayama H, Goto S, Takeda T, Sakatsume M, Saito A, et al. Identification of genes specifically expressed in chronic and progressive glomerulosclerosis. Kidney Int Suppl1997; 63:S215–17.[Medline]
86. Yu XQ, Wu LL, Huang XR, Yang N, Gilbert RE, Cooper ME, et al. Osteopontin expression in progressive renal injury in remnant kidney: role of angiotensin II. Kidney Int2000; 58:1469–80.[ISI][Medline]
87. Petrow PK, Hummel KM, Schedel J, Franz JK, Klein CL, Muller-Ladner U, et al. Expression of osteopontin messenger RNA and protein in rheumatoid arthritis: effects of osteopontin on the release of collagenase 1 from articular chondrocytes and synovial fibroblasts. Arthritis Rheum2000; 43:1597–605.[ISI][Medline]
88.
Li GCY, Kelpke SS, Oparil S, Thompson JA. Estrogen attenuates integrin-beta(3)-dependent adventitial fibroblast migration after inhibition of osteopontin production in vascular smooth muscle cells. Circulation2000; 101:2949–55.
89.
Takahashi F, Takahashi K, Okazaki T, Maeda K, Ienaga H, Maeda M, et al. Role of osteopontin in the pathogenesis of bleomycin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol2001; 24:264–71.
90. Senger DR, Asch BB, Smith BD, Perruzi CA, Dvorak HF. A sectreted phosphoprotein marker for neoplastic transformation of both epithelial and fibroblastic cell lines. Nature1983; 302:714–15.[Medline]
91. Gardner HA, Berse B, Senger DR. Specific reduction in osteopontin synthesis by antisense RNA inhibits the tumorigenicity of transformed Rat1 fibroblasts. Oncogene1994; 9:2321–6.[ISI][Medline]
92. Tuck AB, OM FP, Singhal H, Harris JF, Tonkin KS, Kerkvliet N, et al. Osteopontin expression in a group of lymph node negative breast cancer patients. Int J Cancer1998; 79:502–8.[ISI][Medline]
93.
Bendeck MP, Irvin C, Reidy M, Smith L, Mulholland D, Horton M, et al. Smooth muscle cell matrix metalloproteinase production is stimulated via alpha(v)beta(3) integrin. Arterioscler Thromb Vasc Biol2000; 20:467–72.
94. Teti A, Farina AR, Villanova I, Tiberio A, Tacconelli A, Sciortino G, et al. Activation of MMP-2 by human GCT23 giant cell tumour cells induced by osteopontin, bone sialoprotein and GRGDSP peptides is RGD and cell shape change dependent. Int J Cancer1998; 77:82–93.[ISI][Medline]
95.
Nemir M, Bhattacharyya D, Li X, Singh K, Mukherjee AB, Mukherjee BB. Targeted inhibition of osteopontin expression in the mammary gland causes abnormal morphogenesis and lactation deficiency. J Biol Chem2000; 275:969–76.
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