• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of amjpatholAmerican Journal of Pathology For AuthorsAmerican Journal of Pathology SubscribeAmerican Journal of Pathology SearchAmerican Journal of Pathology Current IssueAmerican Journal of Pathology About the JournalAmerican Journal of Pathology
Am J Pathol. Feb 1998; 152(2): 353–358.
PMCID: PMC1857977

Evidence for a role of osteopontin in macrophage infiltration in response to pathological stimuli in vivo.


Previous studies have suggested that osteopontin, an arginine-glycine-aspartate-containing secreted protein, might be important in macrophage accumulation during interstitial nephritis and wound healing. The current study investigated the role of osteopontin in intradermal macrophage infiltration using immunohistochemistry and neutralizing antibodies. Purified osteopontin induced macrophage accumulation after injection in rat dermis and facilitated adhesion and migration of cultured macrophage-like cells in vitro. Intradermal injection of N-formyl-met-leu-phe (FMLP), a potent macrophage chemotactic peptide, induced a macrophage-rich infiltrate at the site of injection. Most of these macrophages expressed high levels of osteopontin as shown by immunochemical analysis. To determine whether osteopontin expressed by macrophages was required for their infiltration, we treated rats with either anti-osteopontin neutralizing antibody (OP199) or nonimmune antibody. We found that FMLP-induced macrophage accumulation was largely inhibited (>60%) by anti-osteopontin antibody treatment compared with rats receiving nonimmune antibody. These data support the hypothesis that osteopontin may be a critical mediator of inflammation in specific disease and injury states, potentially by promoting macrophage adhesion and migration.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.3M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Giachelli CM, Pichler R, Lombardi D, Denhardt DT, Alpers CE, Schwartz SM, Johnson RJ. Osteopontin expression in angiotensin II-induced tubulointerstitial nephritis. Kidney Int. 1994 Feb;45(2):515–524. [PubMed]
  • Pichler R, Giachelli CM, Lombardi D, Pippin J, Gordon K, Alpers CE, Schwartz SM, Johnson RJ. Tubulointerstitial disease in glomerulonephritis. Potential role of osteopontin (uropontin). Am J Pathol. 1994 May;144(5):915–926. [PMC free article] [PubMed]
  • Diamond JR, Kees-Folts D, Ricardo SD, Pruznak A, Eufemio M. Early and persistent up-regulated expression of renal cortical osteopontin in experimental hydronephrosis. Am J Pathol. 1995 Jun;146(6):1455–1466. [PMC free article] [PubMed]
  • Giachelli CM, Bae N, Almeida M, Denhardt DT, Alpers CE, Schwartz SM. Osteopontin is elevated during neointima formation in rat arteries and is a novel component of human atherosclerotic plaques. J Clin Invest. 1993 Oct;92(4):1686–1696. [PMC free article] [PubMed]
  • O'Brien ER, Garvin MR, Stewart DK, Hinohara T, Simpson JB, Schwartz SM, Giachelli CM. Osteopontin is synthesized by macrophage, smooth muscle, and endothelial cells in primary and restenotic human coronary atherosclerotic plaques. Arterioscler Thromb. 1994 Oct;14(10):1648–1656. [PubMed]
  • Hirota S, Imakita M, Kohri K, Ito A, Morii E, Adachi S, Kim HM, Kitamura Y, Yutani C, Nomura S. Expression of osteopontin messenger RNA by macrophages in atherosclerotic plaques. A possible association with calcification. Am J Pathol. 1993 Oct;143(4):1003–1008. [PMC free article] [PubMed]
  • 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 Invest. 1993 Dec;92(6):2814–2820. [PMC free article] [PubMed]
  • Murry CE, Giachelli CM, Schwartz SM, Vracko R. Macrophages express osteopontin during repair of myocardial necrosis. Am J Pathol. 1994 Dec;145(6):1450–1462. [PMC free article] [PubMed]
  • O'Brien KD, Kuusisto J, Reichenbach DD, Ferguson M, Giachelli C, Alpers CE, Otto CM. Osteopontin is expressed in human aortic valvular lesions. Circulation. 1995 Oct 15;92(8):2163–2168. [PubMed]
  • Srivatsa SS, Harrity PJ, Maercklein PB, Kleppe L, Veinot J, Edwards WD, Johnson CM, Fitzpatrick LA. Increased cellular expression of matrix proteins that regulate mineralization is associated with calcification of native human and porcine xenograft bioprosthetic heart valves. J Clin Invest. 1997 Mar 1;99(5):996–1009. [PMC free article] [PubMed]
  • Mohler ER, 3rd, Adam LP, McClelland P, Graham L, Hathaway DR. Detection of osteopontin in calcified human aortic valves. Arterioscler Thromb Vasc Biol. 1997 Mar;17(3):547–552. [PubMed]
  • Brown LF, Papadopoulos-Sergiou A, Berse B, Manseau EJ, Tognazzi K, Perruzzi CA, Dvorak HF, Senger DR. Osteopontin expression and distribution in human carcinomas. Am J Pathol. 1994 Sep;145(3):610–623. [PMC free article] [PubMed]
  • Liaw L, Lindner V, Schwartz SM, Chambers AF, Giachelli CM. Osteopontin and beta 3 integrin are coordinately expressed in regenerating endothelium in vivo and stimulate Arg-Gly-Asp-dependent endothelial migration in vitro. Circ Res. 1995 Oct;77(4):665–672. [PubMed]
  • Liaw L, Almeida M, Hart CE, Schwartz SM, Giachelli CM. Osteopontin promotes vascular cell adhesion and spreading and is chemotactic for smooth muscle cells in vitro. Circ Res. 1994 Feb;74(2):214–224. [PubMed]
  • Liaw L, Lombardi DM, Almeida MM, Schwartz SM, deBlois D, Giachelli CM. Neutralizing antibodies directed against osteopontin inhibit rat carotid neointimal thickening after endothelial denudation. Arterioscler Thromb Vasc Biol. 1997 Jan;17(1):188–193. [PubMed]
  • Wang X, Louden C, Ohlstein EH, Stadel JM, Gu JL, Yue TL. Osteopontin expression in platelet-derived growth factor-stimulated vascular smooth muscle cells and carotid artery after balloon angioplasty. Arterioscler Thromb Vasc Biol. 1996 Nov;16(11):1365–1372. [PubMed]
  • 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 Immunol. 1993;13(3-4):225–246. [PubMed]
  • Ashizawa N, Graf K, Do YS, Nunohiro T, Giachelli CM, Meehan WP, Tuan TL, Hsueh WA. Osteopontin is produced by rat cardiac fibroblasts and mediates A(II)-induced DNA synthesis and collagen gel contraction. J Clin Invest. 1996 Nov 15;98(10):2218–2227. [PMC free article] [PubMed]
  • Hwang SM, Lopez CA, Heck DE, Gardner CR, Laskin DL, Laskin JD, Denhardt DT. Osteopontin inhibits induction of nitric oxide synthase gene expression by inflammatory mediators in mouse kidney epithelial cells. J Biol Chem. 1994 Jan 7;269(1):711–715. [PubMed]
  • Hunter GK, Kyle CL, Goldberg HA. Modulation of crystal formation by bone phosphoproteins: structural specificity of the osteopontin-mediated inhibition of hydroxyapatite formation. Biochem J. 1994 Jun 15;300(Pt 3):723–728. [PMC free article] [PubMed]
  • Ross FP, Chappel J, Alvarez JI, Sander D, Butler WT, Farach-Carson MC, Mintz KA, Robey PG, Teitelbaum SL, Cheresh DA. Interactions between the bone matrix proteins osteopontin and bone sialoprotein and the osteoclast integrin alpha v beta 3 potentiate bone resorption. J Biol Chem. 1993 May 5;268(13):9901–9907. [PubMed]
  • Miyazaki Y, Setoguchi M, Yoshida S, Higuchi Y, Akizuki S, Yamamoto S. The mouse osteopontin gene. Expression in monocytic lineages and complete nucleotide sequence. J Biol Chem. 1990 Aug 25;265(24):14432–14438. [PubMed]
  • McKee MD, Nanci A. Secretion of Osteopontin by macrophages and its accumulation at tissue surfaces during wound healing in mineralized tissues: a potential requirement for macrophage adhesion and phagocytosis. Anat Rec. 1996 Jun;245(2):394–409. [PubMed]
  • Chambers AF, Wilson SM, Kerkvliet N, O'Malley FP, Harris JF, Casson AG. Osteopontin expression in lung cancer. Lung Cancer. 1996 Nov;15(3):311–323. [PubMed]
  • Krause SW, Rehli M, Kreutz M, Schwarzfischer L, Paulauskis JD, Andreesen R. Differential screening identifies genetic markers of monocyte to macrophage maturation. J Leukoc Biol. 1996 Oct;60(4):540–545. [PubMed]
  • Groves MG, Rosenstreich DL, Taylor BA, Osterman JV. Host defenses in experimental scrub typhus: mapping the gene that controls natural resistance in mice. J Immunol. 1980 Sep;125(3):1395–1399. [PubMed]
  • Fet V, Dickinson ME, Hogan BL. Localization of the mouse gene for secreted phosphoprotein 1 (Spp-1) (2ar, osteopontin, bone sialoprotein 1, 44-kDa bone phosphoprotein, tumor-secreted phosphoprotein) to chromosome 5, closely linked to Ric (Rickettsia resistance). Genomics. 1989 Aug;5(2):375–377. [PubMed]
  • Nasu K, Ishida T, Setoguchi M, Higuchi Y, Akizuki S, Yamamoto S. Expression of wild-type and mutated rabbit osteopontin in Escherichia coli, and their effects on adhesion and migration of P388D1 cells. Biochem J. 1995 Apr 1;307(Pt 1):257–265. [PMC free article] [PubMed]
  • Singh RP, Patarca R, Schwartz J, Singh P, Cantor H. Definition of a specific interaction between the early T lymphocyte activation 1 (Eta-1) protein and murine macrophages in vitro and its effect upon macrophages in vivo. J Exp Med. 1990 Jun 1;171(6):1931–1942. [PMC free article] [PubMed]
  • Liaw L, Skinner MP, Raines EW, Ross R, Cheresh DA, Schwartz SM, Giachelli CM. The adhesive and migratory effects of osteopontin are mediated via distinct cell surface integrins. Role of alpha v beta 3 in smooth muscle cell migration to osteopontin in vitro. J Clin Invest. 1995 Feb;95(2):713–724. [PMC free article] [PubMed]
  • Yue TL, McKenna PJ, Ohlstein EH, Farach-Carson MC, Butler WT, Johanson K, McDevitt P, Feuerstein GZ, Stadel JM. Osteopontin-stimulated vascular smooth muscle cell migration is mediated by beta 3 integrin. Exp Cell Res. 1994 Oct;214(2):459–464. [PubMed]
  • Smith LL, Cheung HK, Ling LE, Chen J, Sheppard D, Pytela R, Giachelli CM. Osteopontin N-terminal domain contains a cryptic adhesive sequence recognized by alpha9beta1 integrin. J Biol Chem. 1996 Nov 8;271(45):28485–28491. [PubMed]
  • Bautista DS, Saad Z, Chambers AF, Tonkin KS, O'Malley FP, Singhal H, Tokmakejian S, Bramwell V, Harris JF. Quantification of osteopontin in human plasma with an ELISA: basal levels in pre- and postmenopausal women. Clin Biochem. 1996 Jun;29(3):231–239. [PubMed]
  • Weber GF, Ashkar S, Glimcher MJ, Cantor H. Receptor-ligand interaction between CD44 and osteopontin (Eta-1). Science. 1996 Jan 26;271(5248):509–512. [PubMed]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • Compound
    PubChem Compound links
  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...