• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of jcinvestThe Journal of Clinical InvestigationCurrent IssueArchiveSubscriptionAbout the Journal
J Clin Invest. Apr 1, 1998; 101(7): 1468–1478.
PMCID: PMC508725

Altered wound healing in mice lacking a functional osteopontin gene (spp1).

Abstract

Osteopontin (OPN) is an arginine-glycine-aspartate (RGD)- containing glycoprotein encoded by the gene secreted phosphoprotein 1 (spp1). spp1 is expressed during embryogenesis, wound healing, and tumorigenesis; however, its in vivo functions are not well understood. Therefore, OPN null mutant mice were generated by targeted mutagenesis in embryonic stem cells. In OPN mutant mice, embryogenesis occurred normally, and mice were fertile. Since OPN shares receptors with vitronectin (VN), we tested for compensation by creating mice lacking both OPN and VN. The double mutants were also viable, suggesting that other RGD-containing ligands replace the embryonic loss of both proteins. We tested the healing of OPN mutants after skin incisions, where spp1 was upregulated as early as 6 h after wounding. Although the tensile properties of the wounds were unchanged, ultrastructural analysis showed a significantly decreased level of debridement, greater disorganization of matrix, and an alteration of collagen fibrillogenesis leading to small diameter collagen fibrils in the OPN mutant mice. These data indicate a role for OPN in tissue remodeling in vivo, and suggest physiological functions during matrix reorganization after injury.

Full Text

The Full Text of this article is available as a PDF (3.4M).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Franzén A, Heinegård D. Isolation and characterization of two sialoproteins present only in bone calcified matrix. Biochem J. 1985 Dec 15;232(3):715–724. [PMC free article] [PubMed]
  • Oldberg A, Franzén A, Heinegård D. Cloning and sequence analysis of rat bone sialoprotein (osteopontin) cDNA reveals an Arg-Gly-Asp cell-binding sequence. Proc Natl Acad Sci U S A. 1986 Dec;83(23):8819–8823. [PMC free article] [PubMed]
  • Senger DR, Wirth DF, Hynes RO. Transformation-specific secreted phosophoproteins. Nature. 1980 Aug 7;286(5773):619–621. [PubMed]
  • Smith JH, Denhardt DT. Molecular cloning of a tumor promoter-inducible mRNA found in JB6 mouse epidermal cells: induction is stable at high, but not at low, cell densities. J Cell Biochem. 1987 May;34(1):13–22. [PubMed]
  • Patarca R, Freeman GJ, Singh RP, Wei FY, Durfee T, Blattner F, Regnier DC, Kozak CA, Mock BA, Morse HC, 3rd, et al. Structural and functional studies of the early T lymphocyte activation 1 (Eta-1) gene. Definition of a novel T cell-dependent response associated with genetic resistance to bacterial infection. J Exp Med. 1989 Jul 1;170(1):145–161. [PMC free article] [PubMed]
  • Weber GF, Cantor H. The immunology of Eta-1/osteopontin. Cytokine Growth Factor Rev. 1996 Oct;7(3):241–248. [PubMed]
  • Denhardt DT, Lopez CA, Rollo EE, Hwang SM, An XR, Walther SE. Osteopontin-induced modifications of cellular functions. Ann N Y Acad Sci. 1995 Apr 21;760:127–142. [PubMed]
  • Thayer JM, Giachelli CM, Mirkes PE, Schwartz SM. Expression of osteopontin in the head process late in gastrulation in the rat. J Exp Zool. 1995 Jun 15;272(3):240–244. [PubMed]
  • Fan CM, Tessier-Lavigne M. Patterning of mammalian somites by surface ectoderm and notochord: evidence for sclerotome induction by a hedgehog homolog. Cell. 1994 Dec 30;79(7):1175–1186. [PubMed]
  • Nomura S, Wills AJ, Edwards DR, Heath JK, Hogan BL. Developmental expression of 2ar (osteopontin) and SPARC (osteonectin) RNA as revealed by in situ hybridization. J Cell Biol. 1988 Feb;106(2):441–450. [PMC free article] [PubMed]
  • Zheng X, Saunders TL, Camper SA, Samuelson LC, Ginsburg D. Vitronectin is not essential for normal mammalian development and fertility. Proc Natl Acad Sci U S A. 1995 Dec 19;92(26):12426–12430. [PMC free article] [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]
  • 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]
  • 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]
  • Leibovich SJ, Ross R. The role of the macrophage in wound repair. A study with hydrocortisone and antimacrophage serum. Am J Pathol. 1975 Jan;78(1):71–100. [PMC free article] [PubMed]
  • Portera CA, Love EJ, Memore L, Zhang L, Müller A, Browder W, Williams DL. Effect of macrophage stimulation on collagen biosynthesis in the healing wound. Am Surg. 1997 Feb;63(2):125–131. [PubMed]
  • 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]
  • Tybulewicz VL, Crawford CE, Jackson PK, Bronson RT, Mulligan RC. Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene. Cell. 1991 Jun 28;65(7):1153–1163. [PubMed]
  • Zhao GQ, Deng K, Labosky PA, Liaw L, Hogan BL. The gene encoding bone morphogenetic protein 8B is required for the initiation and maintenance of spermatogenesis in the mouse. Genes Dev. 1996 Jul 1;10(13):1657–1669. [PubMed]
  • Davisson MT. Genetic nomenclature guide. Mouse. Trends Genet. 1995 Mar;:35–38. [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]
  • Zhao GQ, Hogan BL. Evidence that mouse Bmp8a (Op2) and Bmp8b are duplicated genes that play a role in spermatogenesis and placental development. Mech Dev. 1996 Jul;57(2):159–168. [PubMed]
  • Birk DE, Trelstad RL. Extracellular compartments in matrix morphogenesis: collagen fibril, bundle, and lamellar formation by corneal fibroblasts. J Cell Biol. 1984 Dec;99(6):2024–2033. [PMC free article] [PubMed]
  • Craig AM, Denhardt DT. The murine gene encoding secreted phosphoprotein 1 (osteopontin): promoter structure, activity, and induction in vivo by estrogen and progesterone. Gene. 1991 Apr;100:163–171. [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]
  • Rowe LB, Nadeau JH, Turner R, Frankel WN, Letts VA, Eppig JT, Ko MS, Thurston SJ, Birkenmeier EH. Maps from two interspecific backcross DNA panels available as a community genetic mapping resource. Mamm Genome. 1994 May;5(5):253–274. [PubMed]
  • Segre JA, Nemhauser JL, Taylor BA, Nadeau JH, Lander ES. Positional cloning of the nude locus: genetic, physical, and transcription maps of the region and mutations in the mouse and rat. Genomics. 1995 Aug 10;28(3):549–559. [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]
  • Hynes RO. Targeted mutations in cell adhesion genes: what have we learned from them? Dev Biol. 1996 Dec 15;180(2):402–412. [PubMed]
  • 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 Immunol. 1991 Nov 1;147(9):2902–2906. [PubMed]
  • Shepherd VL, Abdolrasulnia R, Garrett M, Cowan HB. Down-regulation of mannose receptor activity in macrophages after treatment with lipopolysaccharide and phorbol esters. J Immunol. 1990 Sep 1;145(5):1530–1536. [PubMed]
  • Noorman F, Braat EA, Barrett-Bergshoeff M, Barbé E, van Leeuwen A, Lindeman J, Rijken DC. Monoclonal antibodies against the human mannose receptor as a specific marker in flow cytometry and immunohistochemistry for macrophages. J Leukoc Biol. 1997 Jan;61(1):63–72. [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]
  • Clore JN, Cohen IK, Diegelmann RF. Quantitation of collagen types I and III during wound healing in rat skin. Proc Soc Exp Biol Med. 1979 Jul;161(3):337–340. [PubMed]
  • Liu X, Wu H, Byrne M, Krane S, Jaenisch R. Type III collagen is crucial for collagen I fibrillogenesis and for normal cardiovascular development. Proc Natl Acad Sci U S A. 1997 Mar 4;94(5):1852–1856. [PMC free article] [PubMed]
  • Birk DE, Mayne R. Localization of collagen types I, III and V during tendon development. Changes in collagen types I and III are correlated with changes in fibril diameter. Eur J Cell Biol. 1997 Apr;72(4):352–361. [PubMed]
  • Birk DE, Nurminskaya MV, Zycband EI. Collagen fibrillogenesis in situ: fibril segments undergo post-depositional modifications resulting in linear and lateral growth during matrix development. Dev Dyn. 1995 Mar;202(3):229–243. [PubMed]
  • Birk DE, Zycband EI, Woodruff S, Winkelmann DA, Trelstad RL. Collagen fibrillogenesis in situ: fibril segments become long fibrils as the developing tendon matures. Dev Dyn. 1997 Mar;208(3):291–298. [PubMed]
  • Iozzo RV. The family of the small leucine-rich proteoglycans: key regulators of matrix assembly and cellular growth. Crit Rev Biochem Mol Biol. 1997;32(2):141–174. [PubMed]
  • Danielson KG, Baribault H, Holmes DF, Graham H, Kadler KE, Iozzo RV. Targeted disruption of decorin leads to abnormal collagen fibril morphology and skin fragility. J Cell Biol. 1997 Feb 10;136(3):729–743. [PMC free article] [PubMed]
  • Okada A, Tomasetto C, Lutz Y, Bellocq JP, Rio MC, Basset P. Expression of matrix metalloproteinases during rat skin wound healing: evidence that membrane type-1 matrix metalloproteinase is a stromal activator of pro-gelatinase A. J Cell Biol. 1997 Apr 7;137(1):67–77. [PMC free article] [PubMed]
  • Chen Y, Bal BS, Gorski JP. Calcium and collagen binding properties of osteopontin, bone sialoprotein, and bone acidic glycoprotein-75 from bone. J Biol Chem. 1992 Dec 5;267(34):24871–24878. [PubMed]
  • Butler WT. Structural and functional domains of osteopontin. Ann N Y Acad Sci. 1995 Apr 21;760:6–11. [PubMed]
  • Mukherjee BB, Nemir M, Beninati S, Cordella-Miele E, Singh K, Chackalaparampil I, Shanmugam V, DeVouge MW, Mukherjee AB. Interaction of osteopontin with fibronectin and other extracellular matrix molecules. Ann N Y Acad Sci. 1995 Apr 21;760:201–212. [PubMed]
  • McKee MD, Zalzal S, Nanci A. Extracellular matrix in tooth cementum and mantle dentin: localization of osteopontin and other noncollagenous proteins, plasma proteins, and glycoconjugates by electron microscopy. Anat Rec. 1996 Jun;245(2):293–312. [PubMed]

Articles from The Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...