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Gene Review

Spp1  -  secreted phosphoprotein 1

Mus musculus

Synonyms: 2AR, 2ar, 44kDa bone phosphoprotein, AA960535, AI790405, ...
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Disease relevance of Spp1


High impact information on Spp1


Chemical compound and disease context of Spp1


Biological context of Spp1


Anatomical context of Spp1


Associations of Spp1 with chemical compounds

  • Runx2 expression was unaffected in the coronal suture; in contrast, expression of the downstream ossification marker Spp1 was delayed [17].
  • These results indicate that this 24-bp sequence containing two 9-bp motifs binds to the vitamin D receptor and mediates the vitamin D3 enhancement of murine Spp-1 gene expression [18].
  • Here we report that OPN induced alpha(v)beta(3) integrin-mediated phosphorylation and activation of nuclear factor-inducing kinase (NIK) and enhanced the interaction between phosphorylated NIK and IKKalpha/beta in B16F10 cells [19].
  • Osteopontin (OPN) is a sialic acid-rich phosphoprotein secreted by a wide variety of cancers [20].
  • PTHrP stimulation repressed mRNA expression of BSP and OCN in CMs and blocked CM-mediated mineralization, in vitro [21].
  • Although both forms of OPN mediated robust integrin-mediated adhesion of mouse ras-transformed fibroblasts, the less phosphorylated FbOPN mediated binding of MDA-MD-435 human tumor cells almost 6-fold more than the heavy phosphorylated ObOPN [22].

Physical interactions of Spp1


Enzymatic interactions of Spp1


Co-localisations of Spp1

  • Strong osteopontin expression was found co-localizing with calcification in DCC-susceptible strain C3H/HeNCrlBr, which exhibited low osteopontin plasma concentrations otherwise [30].

Regulatory relationships of Spp1


Other interactions of Spp1

  • Moreover, these mice died significantly earlier (4.4 +/- 0.2 wk) than MGP(-/-) OPN(+/+) counterparts (6.6 +/- 1.0 wk) [16].
  • Here we show that a Runx2 site in the OPN promoter is required for activation of the promoter in mammary epithelial cells [31].
  • The level of active MMP-9 in the OPN-induced tumor was higher compared with control [19].
  • Osteopontin regulation by inorganic phosphate is ERK1/2-, protein kinase C-, and proteasome-dependent [33].
  • Osteopontin gene regulation by oscillatory fluid flow via intracellular calcium mobilization and activation of mitogen-activated protein kinase in MC3T3-E1 osteoblasts [34].
  • OPN is a critical intrinsic regulator of cartilage degradation via its effects on MMP-13 expression and proteoglycan loss [35].

Analytical, diagnostic and therapeutic context of Spp1

  • 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 [15].
  • Downregulated expression of OPN during tumour development was confirmed by RT-PCR and RNA blot analysis [32].
  • Consistent with its postulated role in biomineralization, BSP as measured by Western blotting was only present in mineralizing subclones [36].
  • Expression levels of osteoblast maturation genes, type I collagen, osteopontin, bone sialoprotein, and osteocalcin in response to TSA were measured by quantitative PCR [37].
  • Northern hybridization analysis revealed more mRNA for collagen type I (2-fold) and 50% more for OC at 14 days and 21 days, whereas OPN and Cbfa1 mRNA expression remained unaffected by the medium perfusion [38].


  1. Angiotensin II-accelerated atherosclerosis and aneurysm formation is attenuated in osteopontin-deficient mice. Bruemmer, D., Collins, A.R., Noh, G., Wang, W., Territo, M., Arias-Magallona, S., Fishbein, M.C., Blaschke, F., Kintscher, U., Graf, K., Law, R.E., Hsueh, W.A. J. Clin. Invest. (2003) [Pubmed]
  2. Override of the osteoclast defect in osteopontin-deficient mice by metastatic tumor growth in the bone. Natasha, T., Kuhn, M., Kelly, O., Rittling, S.R. Am. J. Pathol. (2006) [Pubmed]
  3. Extensive induction of important mediators of fibrosis and dystrophic calcification in desmin-deficient cardiomyopathy. Mavroidis, M., Capetanaki, Y. Am. J. Pathol. (2002) [Pubmed]
  4. Osteopontin regulates hindlimb-unloading-induced lymphoid organ atrophy and weight loss by modulating corticosteroid production. Wang, K.X., Shi, Y., Denhardt, D.T. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  5. Osteopontin mediates obesity-induced adipose tissue macrophage infiltration and insulin resistance in mice. Nomiyama, T., Perez-Tilve, D., Ogawa, D., Gizard, F., Zhao, Y., Heywood, E.B., Jones, K.L., Kawamori, R., Cassis, L.A., Tschöp, M.H., Bruemmer, D. J. Clin. Invest. (2007) [Pubmed]
  6. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Komori, T., Yagi, H., Nomura, S., Yamaguchi, A., Sasaki, K., Deguchi, K., Shimizu, Y., Bronson, R.T., Gao, Y.H., Inada, M., Sato, M., Okamoto, R., Kitamura, Y., Yoshiki, S., Kishimoto, T. Cell (1997) [Pubmed]
  7. The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Chabas, D., Baranzini, S.E., Mitchell, D., Bernard, C.C., Rittling, S.R., Denhardt, D.T., Sobel, R.A., Lock, C., Karpuj, M., Pedotti, R., Heller, R., Oksenberg, J.R., Steinman, L. Science (2001) [Pubmed]
  8. Eta-1 (osteopontin): an early component of type-1 (cell-mediated) immunity. Ashkar, S., Weber, G.F., Panoutsakopoulou, V., Sanchirico, M.E., Jansson, M., Zawaideh, S., Rittling, S.R., Denhardt, D.T., Glimcher, M.J., Cantor, H. Science (2000) [Pubmed]
  9. Identification of a ras-activated enhancer in the mouse osteopontin promoter and its interaction with a putative ETS-related transcription factor whose activity correlates with the metastatic potential of the cell. Guo, X., Zhang, Y.P., Mitchell, D.A., Denhardt, D.T., Chambers, A.F. Mol. Cell. Biol. (1995) [Pubmed]
  10. Osteopontin, a key component of the hematopoietic stem cell niche and regulator of primitive hematopoietic progenitor cells. Nilsson, S.K., Johnston, H.M., Whitty, G.A., Williams, B., Webb, R.J., Denhardt, D.T., Bertoncello, I., Bendall, L.J., Simmons, P.J., Haylock, D.N. Blood (2005) [Pubmed]
  11. Osteopontin, a transformation-associated cell adhesion phosphoprotein, is induced by 12-O-tetradecanoylphorbol 13-acetate in mouse epidermis. Craig, A.M., Smith, J.H., Denhardt, D.T. J. Biol. Chem. (1989) [Pubmed]
  12. Altered bleomycin-induced lung fibrosis in osteopontin-deficient mice. Berman, J.S., Serlin, D., Li, X., Whitley, G., Hayes, J., Rishikof, D.C., Ricupero, D.A., Liaw, L., Goetschkes, M., O'Regan, A.W. Am. J. Physiol. Lung Cell Mol. Physiol. (2004) [Pubmed]
  13. A gain-of-function mutation of Fgfr2c demonstrates the roles of this receptor variant in osteogenesis. Eswarakumar, V.P., Horowitz, M.C., Locklin, R., Morriss-Kay, G.M., Lonai, P. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  14. Secreted phosphoprotein 1 (osteopontin) is expressed by stromal macrophages in cyclic and pregnant endometrium of mice, but is induced by estrogen in luminal epithelium during conceptus attachment for implantation. White, F.J., Burghardt, R.C., Hu, J., Joyce, M.M., Spencer, T.E., Johnson, G.A. Reproduction (2006) [Pubmed]
  15. Altered wound healing in mice lacking a functional osteopontin gene (spp1). Liaw, L., Birk, D.E., Ballas, C.B., Whitsitt, J.S., Davidson, J.M., Hogan, B.L. J. Clin. Invest. (1998) [Pubmed]
  16. Inactivation of the osteopontin gene enhances vascular calcification of matrix Gla protein-deficient mice: evidence for osteopontin as an inducible inhibitor of vascular calcification in vivo. Speer, M.Y., McKee, M.D., Guldberg, R.E., Liaw, L., Yang, H.Y., Tung, E., Karsenty, G., Giachelli, C.M. J. Exp. Med. (2002) [Pubmed]
  17. Alx4 and Msx2 play phenotypically similar and additive roles in skull vault differentiation. Antonopoulou, I., Mavrogiannis, L.A., Wilkie, A.O., Morriss-Kay, G.M. J. Anat. (2004) [Pubmed]
  18. Identification of a DNA sequence responsible for binding of the 1,25-dihydroxyvitamin D3 receptor and 1,25-dihydroxyvitamin D3 enhancement of mouse secreted phosphoprotein 1 (SPP-1 or osteopontin) gene expression. Noda, M., Vogel, R.L., Craig, A.M., Prahl, J., DeLuca, H.F., Denhardt, D.T. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  19. Nuclear factor-inducing kinase plays a crucial role in osteopontin-induced MAPK/IkappaBalpha kinase-dependent nuclear factor kappaB-mediated promatrix metalloproteinase-9 activation. Rangaswami, H., Bulbule, A., Kundu, G.C. J. Biol. Chem. (2004) [Pubmed]
  20. Ets-1 and runx2 regulate transcription of a metastatic gene, osteopontin, in murine colorectal cancer cells. Wai, P.Y., Mi, Z., Gao, C., Guo, H., Marroquin, C., Kuo, P.C. J. Biol. Chem. (2006) [Pubmed]
  21. Parathyroid hormone-related protein regulates extracellular matrix gene expression in cementoblasts and inhibits cementoblast-mediated mineralization in vitro. Ouyang, H., McCauley, L.K., Berry, J.E., Saygin, N.E., Tokiyasu, Y., Somerman, M.J. J. Bone Miner. Res. (2000) [Pubmed]
  22. Cell type-specific post-translational modifications of mouse osteopontin are associated with different adhesive properties. Christensen, B., Kazanecki, C.C., Petersen, T.E., Rittling, S.R., Denhardt, D.T., Sørensen, E.S. J. Biol. Chem. (2007) [Pubmed]
  23. Alterations in the expression of osteonectin, osteopontin and osteocalcin mRNAs during the development of skeletal tissues in vivo. Nakase, T., Takaoka, K., Hirakawa, K., Hirota, S., Takemura, T., Onoue, H., Takebayashi, K., Kitamura, Y., Nomura, S. Bone and mineral. (1994) [Pubmed]
  24. Highly potent transcriptional activation by 16-ene derivatives of 1,25-dihydroxyvitamin D3. Lack of modulation by 9-cis-retinoic acid of response to 1,25-dihydroxyvitamin D3 or its derivatives. Ferrara, J., McCuaig, K., Hendy, G.N., Uskokovic, M., White, J.H. J. Biol. Chem. (1994) [Pubmed]
  25. Increased proteinase expression during tumor progression of cell lines down-modulated for TIMP levels: a new transformation paradigm? [corrected]. Khokha, R., Waterhouse, P., Lala, P., Zimmer, M., Denhardt, D.T., Khokka, R. J. Cancer Res. Clin. Oncol. (1991) [Pubmed]
  26. Transcriptional regulatory functions of heterogeneous nuclear ribonucleoprotein-U and -A/B in endotoxin-mediated macrophage expression of osteopontin. Gao, C., Guo, H., Mi, Z., Wai, P.Y., Kuo, P.C. J. Immunol. (2005) [Pubmed]
  27. Matrix metalloproteinase-12 (MMP-12) in osteoclasts: new lesson on the involvement of MMPs in bone resorption. Hou, P., Troen, T., Ovejero, M.C., Kirkegaard, T., Andersen, T.L., Byrjalsen, I., Ferreras, M., Sato, T., Shapiro, S.D., Foged, N.T., Delaissé, J.M. Bone (2004) [Pubmed]
  28. Expression and distribution of osteopontin and matrix metalloproteinase (MMP)-3 and -7 in mouse salivary glands. Muramatsu, T., Ohta, K., Asaka, M., Kizaki, H., Shimono, M. European journal of morphology. (2002) [Pubmed]
  29. In vitro phosphorylation of mouse osteopontin expressed in E. coli. Ashkar, S., Teplow, D.B., Glimcher, M.J., Saavedra, R.A. Biochem. Biophys. Res. Commun. (1993) [Pubmed]
  30. A locus on chromosome 7 determines dramatic up-regulation of osteopontin in dystrophic cardiac calcification in mice. Aherrahrou, Z., Axtner, S.B., Kaczmarek, P.M., Jurat, A., Korff, S., Doehring, L.C., Weichenhan, D., Katus, H.A., Ivandic, B.T. Am. J. Pathol. (2004) [Pubmed]
  31. The osteoblast transcription factor Runx2 is expressed in mammary epithelial cells and mediates osteopontin expression. Inman, C.K., Shore, P. J. Biol. Chem. (2003) [Pubmed]
  32. The dioxin/aryl hydrocarbon receptor mediates downregulation of osteopontin gene expression in a mouse model of gastric tumourigenesis. Kuznetsov, N.V., Andersson, P., Gradin, K., Stein, P., Dieckmann, A., Pettersson, S., Hanberg, A., Poellinger, L. Oncogene (2005) [Pubmed]
  33. Osteopontin regulation by inorganic phosphate is ERK1/2-, protein kinase C-, and proteasome-dependent. Beck, G.R., Knecht, N. J. Biol. Chem. (2003) [Pubmed]
  34. Osteopontin gene regulation by oscillatory fluid flow via intracellular calcium mobilization and activation of mitogen-activated protein kinase in MC3T3-E1 osteoblasts. You, J., Reilly, G.C., Zhen, X., Yellowley, C.E., Chen, Q., Donahue, H.J., Jacobs, C.R. J. Biol. Chem. (2001) [Pubmed]
  35. Accelerated development of aging-associated and instability-induced osteoarthritis in osteopontin-deficient mice. Matsui, Y., Iwasaki, N., Kon, S., Takahashi, D., Morimoto, J., Matsui, Y., Denhardt, D.T., Rittling, S., Minami, A., Uede, T. Arthritis Rheum. (2009) [Pubmed]
  36. Isolation and characterization of MC3T3-E1 preosteoblast subclones with distinct in vitro and in vivo differentiation/mineralization potential. Wang, D., Christensen, K., Chawla, K., Xiao, G., Krebsbach, P.H., Franceschi, R.T. J. Bone Miner. Res. (1999) [Pubmed]
  37. Histone deacetylase inhibitors promote osteoblast maturation. Schroeder, T.M., Westendorf, J.J. J. Bone Miner. Res. (2005) [Pubmed]
  38. Medium perfusion enhances osteogenesis by murine osteosarcoma cells in three-dimensional collagen sponges. Mueller, S.M., Mizuno, S., Gerstenfeld, L.C., Glowacki, J. J. Bone Miner. Res. (1999) [Pubmed]
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