Osteopontin

Osteopontin

Secreted phosphoprotein 1
Rendering based on PDB .
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols  ; BNSP; BSPI; ETA-1; OPN
External IDs ChEMBL: GeneCards:
RNA expression pattern
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search
Osteopontin
Identifiers
Symbol Osteopontin
Pfam PF00865
InterPro IPR002038
PROSITE PDOC00689
Not to be confused with Osteocalcin, Osteonectin or Osteoprotegerin (OPG).

Osteopontin (OPN), also known as bone sialoprotein I (BSP-1 or BNSP), early T-lymphocyte activation (ETA-1), secreted phosphoprotein 1 (SPP1), 2ar and Rickettsia resistance (Ric),[1] is a protein that in humans is encoded by the SPP1 gene (secreted phosphoprotein 1). The murine ortholog is Spp1. Osteopontin is a SIBLING (glycoprotein) that was first identified in 1986 in osteoblasts.

The prefix osteo- indicates that the protein is expressed in bone. Synonyms for this protein include sialoprotein I and 44K BPP (bone phosphoprotein).

The gene has 7 exons, spans 5 kilobases in length and in humans it is located on the long arm of chromosome 4 region 22 (4q1322.1). The protein is composed of ~300 amino acids residues and has ~30 carbohydrate residues attached including 10 sialic acid residues, which are attached to the protein during post-translational modification in the Golgi apparatus. The protein is rich in acidic residues: 30-36% are either aspartic or glutamic acid.

Contents

  • Structure 1
    • General structure 1.1
    • Isoforms 1.2
  • Biosynthesis 2
    • Regulation 2.1
  • Biological function 3
    • Role in biomineralization 3.1
    • Role in bone remodeling 3.2
    • Role in immune functions 3.3
      • Role in Heart 3.3.1
      • Chemotaxis 3.3.2
      • Cell activation 3.3.3
      • Apoptosis 3.3.4
  • Potential clinical application 4
    • Role in autoimmune diseases 4.1
    • Role in cancers and inflammatory diseases 4.2
    • Role in colitis 4.3
    • Role in allergy and asthma 4.4
    • Role in muscle disease and injury 4.5
  • References 5
  • Additional images 6
  • Further reading 7
  • External links 8

Structure

General structure

OPN is a highly negatively charged, extracellular matrix protein that lacks an extensive secondary structure.[2] It is composed of about 300 amino acids (297 in mouse; 314 in human) and is expressed as a 33-kDa nascent protein; there are also functionally important cleavage sites. OPN can go through posttranslational modifications, which increase its apparent molecular weight to about 44 kDa.[3] The OPN gene is composed of 7 exons, 6 of which containing coding sequence.[4][5] The first two exons contain the 5' untranslated region (5' UTR).[6] Exons 2, 3, 4, 5, 6, and 7 code for 17, 13, 27, 14, 108 and 134 amino acids, respectively.[6] All intron-exon boundaries are of the phase 0 type, thus alternative exon splicing maintains the reading frame of the OPN gene.

Figure 1. Proteolytic cleavage sites for full length osteopontin (OPN-FL). Thrombin exposes the cleaved epitope SVVYGLR (OPN-R), and then CPB removes the c-terminal arginine from OPN-R. The cleaved epitope has a non-RGD domain, which binds to integrin receptors (α4β1, α9β1, and α9β4). Next to the cleaved epitope, there is a RGD domain that interacts with other integrin receptors (αvβ1,3,5, and α5β1).

Isoforms

Full-length OPN (OPN-FL) can be modified by thrombin cleavage, which exposes a cryptic sequence, SVVYGLR on the cleaved form of the protein known as OPN-R (Fig. 1). This thrombin-cleaved OPN (OPN-R) exposes an epitope for integrin receptors of α4β1, α9β1, and α9β4.[7][8] These integrin receptors are present on a number of immune cells such as mast cells,[9] neutrophils,[10] and T cells. It is also expressed by monocytes and macrophages.[11] Upon binding these receptors, cells use several signal transduction pathways to elicit immune responses in these cells (See Section 3 for more detail). OPN-R can be further cleaved by Carboxypeptidase B (CPB) by removal of C-terminal arginine and become OPN-L (Fig. 2). The function of OPN-L is largely unknown.

It appears an intracellular variant of OPN (iOPN) is involved in a number of cellular processes including migration, fusion and motility.[12][13][14][15] Intracellular OPN is generated using an alternative translation start site on the same mRNA species used to generate the extracellular isoform.[16] This alternative translation start site is downstream of the N-terminal endoplasmic reticulum-targeting signal sequence, thus allowing cytoplasmic translation of OPN.

Various human cancers, including breast cancer, have been observed to express splice variants of OPN.[17][18] The cancer-specific splice variants are osteopontin-a, osteopontin-b, and osteopontin-c. Exon 5 is lacking from osteopontin-b, whereas osteopontin-c lacks exon 4.[17] Osteopontin-c has been suggested to facilitate the anchorage-independent phenotype of some human breast cancer cells due to its inability to associate with the extracellular matrix.[17]

Biosynthesis

Osteopontin seen in a lung tissue sample from a patient with ideopathic pulmonary fibrosis.

Osteopontin is biosynthesized by a variety of tissue types including fibroblasts[19] preosteoblasts, osteoblasts, osteocytes, odontoblasts, some bone marrow cells, hypertrophic chondrocytes, dendritic cells, macrophages,[20] smooth muscle,[21] skeletal muscle myoblasts,[22] endothelial cells, and extraosseous (non-bone) cells in the inner ear, brain, kidney, deciduum, and placenta. Synthesis of osteopontin is stimulated by calcitriol (1,25-dihydroxy-vitamin D3).

Regulation

Regulation of the osteopontin gene is incompletely understood. Different cell types may differ in their regulatory mechanisms of the OPN gene. OPN expression in bone predominantly occurs by osteoblasts and osteocyctes (bone-forming cells) as well as osteoclasts (bone-resorbing cells).[23] Runx2 (aka Cbfa1) and osterix (Osx) transcription factors are required for the expression of OPN [24] Runx2 and Osx bind promoters of osteoblast-specific genes such as Col1α1, Bsp, and Opn and upregulate transcription.[25]

Hypocalcemia and hypophosphatemia (instances that stimulate kidney proximal tubule cells to produce calcitriol (1α,25-dihydroxyvitamin D3)) lead to increases in OPN transcription, translation and secretion.[26] This is due to the presence of a high-specificity vitamin D response element (VDRE) in the OPN gene promoter.[27][28][29]

Extracellular inorganic phosphate (ePi) has also been identified as a modulator of OPN expression.[30]

Stimulation of OPN expression also occurs upon exposure of cells to pro-inflammatory cytokines,[31] classical mediators of acute inflammation (e.g. tumour necrosis factor α [TNFα], infterleukin-1β [IL-1β]), angiotensin II, transforming growth factor β (TGFβ) and parathyroid hormone (PTH),[32][33] although a detailed mechanistic understanding of these regulatory pathways are not yet known. Hyperglycemia and hypoxia are also known to increase OPN expression.[32][34][35]

Biological function

Role in biomineralization

OPN belongs to a family of secreted acidic proteins whose members have an abundance of negatively charged amino acids such as Asp and Glu.[36] OPN also has a large number of consensus sequence sites for post-translational phosphorylation of Ser residues to form phosphoserine, providing additional negative charge.[37] Contiguous stretches of high negative charge in OPN have been identified and named the polyAsp motif (poly-aspartic acid) and the ASARM motif (acidic serine- and asparate-rich motif), with the latter sequence having multiple phosphorylation sites.[38][39][40][41] This overall negative charge of OPN, along with its specific acidic motifs and the fact that OPN is an intrinsically disordered protein[42][43] allowing for open and flexible structures, permit OPN to bind strongly to calcium atoms available at crystal surfaces in various biominerals.[41][44][45] Such binding of OPN to various types of calcium-based biominerals ‒ such as calcium-phosphate mineral in bones and teeth,[46] calcium-carbonate mineral in inner ear otoconia[47] and avian eggshells,[48] and calcium-oxalate mineral in kidney stones[49][50][51] – acts as a mineralization inhibitor to regulate crystal growth.[52]

OPN is a substrate protein for a number of enzymes whose actions may modulate the mineralization-inhibiting function of OPN, a prominent one being PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome), which can extensively degrade OPN and whose inactivating gene mutations lead to altered processing of OPN and osteomalacia (soft hypomineralized bones) in X-linked hypophosphatemia (XLH).[53]

Along with its role in the regulation of normal mineralization within the extracellular matrices of bones and teeth,[54] OPN is also upregulated at sites of pathologic, ectopic calcification[55][56] – such as for example, in urolithiasis and vascular calcification ‒ presumably at least in part to inhibit debilitating mineralization in these soft tissues.

Role in bone remodeling

Osteopontin has been implicated as an important factor in hydroxyapatite, Ca10(PO4)6(OH)2. Loss of this mineral may lead to osteoporosis, as the bone is depleted for calcium if this is not supplied in the diet.

OPN serves to initiate the process by which osteoclasts develop their ruffled borders to begin bone resorption. It is also found in urine, where it inhibits kidney stone formation.

Role in immune functions

As discussed, OPN binds to several integrin receptors including α4β1, α9β1, and α9β4 expressed by leukocytes. These receptors have been well-established to function in cell adhesion, migration, and survival in these cells. Therefore, recent research efforts have focused on the role of OPN in mediating such responses.

Osteopontin (OPN) is expressed in a range of immune cells, including macrophages, neutrophils, dendritic cells, and T and B cells, with varying kinetics. OPN is reported to act as an immune modulator in a variety of manners.[2] Firstly, it has chemotactic properties, which promote cell recruitment to inflammatory sites. It also functions as an adhesion protein, involved in cell attachment and wound healing. In addition, OPN mediates cell activation and cytokine production, as well as promoting cell survival by regulating apoptosis.[2] The following examples are found.[2]

Role in Heart

OPN expression increases under a variety of conditions of the heart, and is associated with increased myocyte apoptosis and myocardial dysfunction.[58]

Chemotaxis

OPN plays an important role in neutrophil recruitment in alcoholic liver disease.[10][59] OPN is important for the migration of neutrophil in vitro.[60] In addition, OPN recruits inflammatory cells to arthritis joints in the collagen-induced arthritis model of rheumatoid arthritis.[61][62] A recent in vitro study in 2008 has found that OPN plays a role in mast cell migration.[63] Here OPN knock-out mast cells were cultured and they observed a decreased level of chemotaxis in these cells compared to wildtype mast cells. OPN was also found to act as a macrophage chemotactic factor.[64] In this study, researchers looked at the accumulation of macrophages in the brain of rhesus monkeys and found that OPN prevented macrophages from leaving the accumulation site, indicating an increased level of chemotaxis.

Cell activation

Activated T cells are promoted by IL-12 to differentiate towards the Th1 type, producing cytokines including IL-12 and IFNγ. OPN inhibits production of the Th2 cytokine IL-10, which leads to enhanced Th1 response. OPN influences cell-mediated immunity and has Th1 cytokine functions. It enhances B cell immunoglobulin production and proliferation.[2] Recent studies in 2008 suggest that OPN also induces mast cell degranulation.[63] The researchers here observed that IgE-mediated anaphylaxis was significantly reduced in OPN knock-out mice compared to wild-type mice. The role of OPN in activation of macrophages has also been implicated in a cancer study, when researchers discovered that OPN-producing tumors were able to induce macrophage activation compared to OPN-deficient tumors.[65]

Fig 2. Known immunologic functions of OPN. OPN binds to several integrin receptors including α4β1, α9β1, and α9β4 expressed by leukocytes and are known to induce cell adhesion, migration, and survival in immune cells including neutrophils, macrophages, T cells, mast cells, and osteoclasts.

Apoptosis

OPN is an important anti-apoptotic factor in many circumstances. OPN blocks the activation-induced cell death of macrophages and T cells as well as fibroblasts and endothelial cells exposed to harmful stimuli.[66][67] OPN prevents non-programmed cell death in inflammatory colitis.[68]

Potential clinical application

The fact that OPN interacts with multiple cell surface receptors that are ubiquitously expressed makes it an active player in many physiological and pathological processes including wound healing, bone turnover, tumorigenesis, inflammation, ischemia, and immune responses1. Therefore, manipulation of plasma (or local) OPN levels may be useful in the treatment of autoimmune diseases, cancer metastasis, bone (and tooth) mineralization diseases, osteoporosis, and some forms of stress.[2]

Role in autoimmune diseases

OPN has been implicated in pathogenesis of rheumatoid arthritis. For instance, researchers found that OPN-R, the thrombin-cleaved form of OPN, was elevated in the rheumatoid arthritis joint. However, the role of OPN in rheumatoid arthritis is still unclear. One group found that OPN knock-out mice were protected against arthritis.[69] while others were not able to reproduce this observation.[70] OPN has been found to play a role in other autoimmune diseases including autoimmune hepatitis, allergic airway disease, and multiple sclerosis.[71]

Role in cancers and inflammatory diseases

It has been shown that OPN drives IL-17 production;[72] OPN is overexpressed in a variety of cancers, including lung cancer, breast cancer, colorectal cancer, stomach cancer, ovarian cancer, papillary thyroid carcinoma, melanoma and pleural mesothelioma; OPN contributes both glomerulonephritis and tubulointerstitial nephritis; and OPN is found in atheromatous plaques within arteries. Thus, manipulation of plasma OPN levels may be useful in the treatment of autoimmune diseases, cancer metastasis, osteoporosis and some forms of stress.[2]

Research has implicated osteopontin in excessive scar-forming and a gel has been developed to inhibit its effect.[73]

Role in colitis

Opn is up-regulated in inflammatory bowel disease (IBD).[74] Opn expression is highly up-regulated in intestinal immune and non-immune cells and in the plasma of patients with Crohn’s disease (CD) and Ulcerative colitis (UC), as well as in the colon and plasma of mice with experimental colitis.[74][75][76] Increased plasma Opn levels are related to the severity of CD inflammation, and certain Opn gene (Spp1) haplotypes are modifiers of CD susceptibility. Opn has also a proinflammatory role in TNBS- and dextran sulfate sodium (DSS)-induced colitis, which are mouse models for IBD. Opn was found highly expressed by a specific dendritic cell (DC) subset derived from murine mesenteric lymph nodes (MLNs)and is highly proinflammatory for colitis.[77] Dendritic cells are important for the development of intestinal inflammation in humans with IBD and in mice with experimental colitis. Opn expression by this inflammatory MLN DC subset is crucial for their pathogenic action during colitis.[77]

Role in allergy and asthma

Osteopontin has recently been associated with allergic inflammation and asthma. Expression of Opn is significantly increased in lung epithelial and subepithelial cells of asthmatic patients in comparison to healthy subjects.[78] Opn expression is also upregulated in lungs of mice with allergic airway inflammation.[78] The secreted form of Opn (Opn-s) plays a proinflammatory role during allergen sensitization (OVA/Alum), as neutralization of Opn-s during that phase results in significantly milder allergic airway inflammation.[78] In contrast, neutralization of Opn-s during antigenic challenge exacerbates allergic airway disease.[78] These effects of Opn-s are mainly mediated by the regulation of Th2-suppressing plasmacytoid dendritic cells (DCs) during primary sensitization and Th2-promoting conventional DCs during secondary antigenic challenge.[78] OPN deficiency was also reported to protect against remodeling and bronchial hyperresponsiveness (BHR), again using a chronic allergen-challenge model of airway remodeling.[79] Furthermore, it was recently demonstrated that OPN expression is upregulated in human asthma, is associated with remodeling changes and its subepithelial expression correlates to disease severity.[80] OPN has also been reported to be increased in the sputum supernatant of smoking asthmatics,[81] as well as the BALF and bronchial tissue of smoking controls and asthmatics.[82]

Role in muscle disease and injury

Evidence is accumulating that suggests that osteopontin plays a number of roles in diseases of skeletal muscle, such as Duchenne muscular dystrophy. Osteopontin has been described as a component of the inflammatory environment of dystrophic and injured muscles,[22][83][84][85] and has also been shown to increase scarring of diaphragm muscles of aged dystrophic mice.[86] A recent study has identified osteopontin as a determinant of disease severity in patients with Duchenne muscular dystrophy.[87] This study found that a mutation in the osteopontin gene promoter, known to cause low levels of osteopontin expression, is associated with a decrease in age to loss of ambulation and muscle strength in patients with Duchenne muscular dystrophy.

References

  1. ^ "Entrez Gene: SPP1 secreted phosphoprotein 1". 
  2. ^ a b c d e f g Wang KX, Denhardt DT (2008). "Osteopontin: role in immune regulation and stress responses". Cytokine Growth Factor Rev. 19 (5-6): 333–45.  
  3. ^ Rangaswami H, Bulbule A, Kundu GC (February 2006). "Osteopontin: role in cell signaling and cancer progression". Trends Cell Biol. 16 (2): 79–87.  
  4. ^ Young MF, Kerr JM, Termine JD, Wewer UM, Wang MG, McBride OW, Fisher LW (August 1990). "cDNA cloning, mRNA distribution and heterogeneity, chromosomal location, and RFLP analysis of human osteopontin (OPN)". Genomics. 7 (1): 491–502.  
  5. ^ Kiefer MC, Bauer DM, Barr PJ (April 1989). "The cDNA and derived amino acid sequence for human osteopontin.". Nucleic Acids Res. 17 (1): 3306.  
  6. ^ a b Crosby AH, Edwards SJ, Murray JC, Dixon MJ (May 1995). "Genomic organization of the human osteopontin gene: exclusion of the locus from a causative role in the pathogenesis of dentinogenesis imperfecta type II". Genomics 27 (1): 155–160.  
  7. ^ Laffón A, García-Vicuña R, Humbría A, Postigo AA, Corbí AL, de Landázuri MO, Sánchez-Madrid F (August 1991). "Upregulated expression and function of VLA-4 fibronectin receptors on human activated T cells in rheumatoid arthritis". J. Clin. Invest. 88 (2): 546–52.  
  8. ^ Seiffge D (December 1996). "Protective effects of monoclonal antibody to VLA-4 on leukocyte adhesion and course of disease in adjuvant arthritis in rats". J. Rheumatol. 23 (12): 2086–91.  
  9. ^ a b Reinholt FP, Hultenby K, Oldberg A, Heinegård D (June 1990). "Osteopontin--a possible anchor of osteoclasts to bone". Proc. Natl. Acad. Sci. U.S.A. 87 (12): 4473–5.  
  10. ^ a b Banerjee A, Apte UM, Smith R, Ramaiah SK (March 2006). "Higher neutrophil infiltration mediated by osteopontin is a likely contributing factor to the increased susceptibility of females to alcoholic liver disease". J. Pathol. 208 (4): 473–85.  
  11. ^ Sodek J, Batista Da Silva AP, Zohar R (May 2006). "Osteopontin and mucosal protection". J. Dent. Res. 85 (5): 404–15.  
  12. ^ Zohar R, Suzuki N, Suzuki K, Arora P, Glogauer M, McCulloch CA, Sodek J (July 2000). "Intracellular osteopontin is an integral component of the CD44-ERM complex involved in cell migration". J Cell Physiol 184 (1): 118–130.  
  13. ^ Suzuki K, Zhu B, Rittling SR, Denhardt DT, Goldberg HA, McCulloch CA, Sodek J (August 2002). "Colocalization of intracellular osteopontin with CD44 is associated with migration, cell fusion, and resorption in osteoclasts". J Bone Miner Res 17 (1): 1486–1497.  
  14. ^ Zhu B, Suzuki K, Goldberg HA, Rittling SR, Denhardt DT, McCulloch CA, Sodek J (January 2004). "Osteopontin modulates CD44-dependent chemotaxis of peritoneal macrophages through G-protein-coupled receptors: evidence of a role for an intracellular form of osteopontin". Journal of Cellular Physiology 198 (1): 155–167.  
  15. ^ Junaid A, Moon MC, Harding GE, Zahradka P (February 2007). "Osteopontin localizes to the nucleus of 293 cells and associates with polo-like kinase-1". Am J Physiol Cell Physiol 292 (1): 919–926.  
  16. ^ Shinohara ML, Kim HJ, Kim JH, Garcia VA, Cantor H (May 2008). "Alternative translation of osteopontin generates intracellular and secreted isoforms that mediate distinct biological activities in dendritic cells". Proc Natl Acad Sci USA 105 (1): 7235–7239.  
  17. ^ a b c He B, Mirza M, Weber GF (April 2006). "An osteopontin splice variant induces anchorage independence in human breast cancer cells". Oncogene 25 (1): 2192–2202.  
  18. ^ Mirza M, Shaughnessy E, Hurley JK, Vanpatten KA, Pestano GA, He B, Weber GF (February 2008). "Osteopontin-c is a selective marker of breast cancer". Int J Cancer 122 (1): 889–897.  
  19. ^ Ashizawa N, Graf K, Do YS, Nunohiro T, Giachelli CM, Meehan WP, Tuan TL, Hsueh WA (November 1996). "Osteopontin is produced by rat cardiac fibroblasts and mediates A(II)-induced DNA synthesis and collagen gel contraction". J. Clin. Invest. 98 (10): 2218–27.  
  20. ^ Murry CE, Giachelli CM, Schwartz SM, Vracko R (December 1994). "Macrophages express osteopontin during repair of myocardial necrosis". Am. J. Pathol. 145 (6): 1450–62.  
  21. ^ Ikeda T, Shirasawa T, Esaki Y, Yoshiki S, Hirokawa K (December 1993). "Osteopontin mRNA is expressed by smooth muscle-derived foam cells in human atherosclerotic lesions of the aorta". J. Clin. Invest. 92 (6): 2814–20.  
  22. ^ a b Uaesoontrachoon K, Yoo HJ, Tudor EM, Pike RN, Mackie EJ, Pagel CN (April 2008). "Osteopontin and skeletal muscle myoblasts: Association with muscle regeneration and regulation of myoblast function in vitro". Int. J. Biochem. Cell Biol. 40 (10): 2303–14.  
  23. ^ Merry K, Dodds R, Littlewood A, Gowen M (April 1993). "Expression of Osteopontin mRNA by osteoclasts and osteoblasts in modelling adult human bone". J Cell Sci 104 (4): 1013–1020.  
  24. ^ Nakashima K, Zhou X, Kunkel G, Zhang Z, Deng JM, Behringer RR, de Crombrugghe B (January 2002). "The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation". Cell 108 (1): 17–29.  
  25. ^ Ducy P, Zhang R, Geoffroy V, Ridall AL, Karsenty G (May 1997). "Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation". Cell 89 (1): 747–754.  
  26. ^ Yucha C, Guthrie D (December 2003). "Renal homeostasis of calcium". Nephrol Nurs J 30 (1): 755–764.  
  27. ^ Prince CW, Butler WT (September 1987). "1,25-Dihydroxyvitamin D3 regulates the biosyntheis of osteopontin, a bone-derived cell attachment protein, in clonal osteoblast-like osteosarcoma cells". Coll Relat Res 7 (1): 305–313.  
  28. ^ Oldberg A, Jirskog-Hed B, Axelsson S, Heinegård D (December 1989). "Regulation of bone sialoprotein mRNA by steroid hormones". J Cell Biol 109 (1): 3183–3186.  
  29. ^ Chang PL, Prince CW (May 1991). "1 alpha,25-Dihydroxyvitamin D3 enhances 12-O-tetradecanoylphorbol-13-acetate- induced tumorigenic transformation and osteopontin expression in mouse JB6 epidermal cells". Cancer Res 51 (8): 2144–2150.  
  30. ^ Fatherazi S, Matsa-Dunn D, Foster BL, Rutherford RB, Somerman MJ, Presland RB (January 2009). "Phosphate regulates osteopontin gene transcription". J Dent Res 88 (1): 39–44.  
  31. ^ Guo H, Cai CQ, Schroeder RA, Kuo PC (January 2001). "Osteopontin is a negative feedback regulator of nitric oxide synthesis in murine macrophages". J Immunol 166 (1): 1079–1086.  
  32. ^ a b Ricardo SD, Franzoni DF, Roesener CD, Crisman JM, Diamond JR (May 2000). "Angiotensinogen and AT(1) antisense inhibition of osteopontin translation in rat proximal tubular cells". Am J Physiol Renal Physiol 278 (1): 708–716.  
  33. ^ Noda M, Rodan GA (February 1989). "Transcriptional regulation of osteopontin production in rat osteoblast-like cells by parathyroid hormone". J Cell Biol 108 (1): 713–718.  
  34. ^ Hullinger TG, Pan Q, Viswanathan HL, Somerman MJ (January 2001). "TGFbeta and BMP-2 activation of the OPN promoter: roles of smad- and hox-binding elements". Exp Cell Res 262 (1): 69–74.  
  35. ^ Sodhi CP, Phadke SA, Batlle D, Sahai A (April 2001). "Hypoxia and high glucose cause exaggerated mesangial cell growth and collagen synthesis: role of osteopontin". Am J Physiol Renal Physiol 280 (1): 667–674.  
  36. ^ Fisher LW, Fedarko NS (2003). "Six genes expressed in bones and teeth encode the current members of the SIBLING family of proteins". Connect. Tissue Res. 44 Suppl 1: 33–40.  
  37. ^ Christensen B, Nielsen MS, Haselmann KF, Petersen TE, Sørensen ES (August 2005). "Post-translationally modified residues of native human osteopontin are located in clusters: identification of 36 phosphorylation and five O-glycosylation sites and their biological implications". Biochem. J. 390 (Pt 1): 285–92.  
  38. ^ David V, Martin A, Hedge AM, Drezner MK, Rowe PS (March 2011). "ASARM peptides: PHEX-dependent and -independent regulation of serum phosphate". Am. J. Physiol. Renal Physiol. 300 (3): F783–91.  
  39. ^ Martin A, David V, Laurence JS, Schwarz PM, Lafer EM, Hedge AM, Rowe PS (April 2008). "Degradation of MEPE, DMP1, and release of SIBLING ASARM-peptides (minhibins): ASARM-peptide(s) are directly responsible for defective mineralization in HYP". Endocrinology 149 (4): 1757–72.  
  40. ^ Addison WN, Nakano Y, Loisel T, Crine P, McKee MD (October 2008). "MEPE-ASARM peptides control extracellular matrix mineralization by binding to hydroxyapatite: an inhibition regulated by PHEX cleavage of ASARM". J. Bone Miner. Res. 23 (10): 1638–49.  
  41. ^ a b Addison WN, Masica DL, Gray JJ, McKee MD (April 2010). "Phosphorylation-dependent inhibition of mineralization by osteopontin ASARM peptides is regulated by PHEX cleavage". J. Bone Miner. Res. 25 (4): 695–705.  
  42. ^ Kurzbach D, Platzer G, Schwarz TC, Henen MA, Konrat R, Hinderberger D (July 2013). "Cooperative Unfolding of Compact Conformations of the Intrinsically Disordered Protein Osteopontin". Biochemistry 52 (31): 5167–75.  
  43. ^ Kalmar L, Homola D, Varga G, Tompa P (September 2012). "Structural disorder in proteins brings order to crystal growth in biomineralization". Bone 51 (3): 528–34.  
  44. ^ Azzopardi PV, O'Young J, Lajoie G, Karttunen M, Goldberg HA, Hunter GK (2010). "Roles of electrostatics and conformation in protein-crystal interactions". PLoS ONE 5 (2): e9330.  
  45. ^ Hunter GK, O'Young J, Grohe B, Karttunen M, Goldberg HA (December 2010). "The flexible polyelectrolyte hypothesis of protein-biomineral interaction". Langmuir 26 (24): 18639–46.  
  46. ^ McKee MD, Nanci A (May 1995). "Postembedding colloidal-gold immunocytochemistry of noncollagenous extracellular matrix proteins in mineralized tissues". Microsc. Res. Tech. 31 (1): 44–62.  
  47. ^ Takemura T, Sakagami M, Nakase T, Kubo T, Kitamura Y, Nomura S (September 1994). "Localization of osteopontin in the otoconial organs of adult rats". Hear. Res. 79 (1-2): 99–104.  
  48. ^ Hincke MT, Nys Y, Gautron J, Mann K, Rodriguez-Navarro AB, McKee MD (2012). "The eggshell: structure, composition and mineralization". Front. Biosci. 17: 1266–80.  
  49. ^ McKee MD, Nanci A, Khan SR (December 1995). "Ultrastructural immunodetection of osteopontin and osteocalcin as major matrix components of renal calculi". J. Bone Miner. Res. 10 (12): 1913–29.  
  50. ^ O'Young J, Chirico S, Al Tarhuni N, Grohe B, Karttunen M, Goldberg HA, Hunter GK (2009). "Phosphorylation of osteopontin peptides mediates adsorption to and incorporation into calcium oxalate crystals". Cells Tissues Organs (Print) 189 (1-4): 51–5.  
  51. ^ Chien YC, Masica DL, Gray JJ, Nguyen S, Vali H, McKee MD (August 2009). "Modulation of calcium oxalate dihydrate growth by selective crystal-face binding of phosphorylated osteopontin and polyaspartate peptide showing occlusion by sectoral (compositional) zoning". J. Biol. Chem. 284 (35): 23491–501.  
  52. ^ Sodek J, Ganss B, McKee MD (2000). "Osteopontin". Crit. Rev. Oral Biol. Med. 11 (3): 279–303.  
  53. ^ Barros NM, Hoac B, Neves RL, Addison WN, Assis DM, Murshed M, Carmona AK, McKee MD (March 2013). "Proteolytic processing of osteopontin by PHEX and accumulation of osteopontin fragments in Hyp mouse bone, the murine model of X-linked hypophosphatemia". J. Bone Miner. Res. 28 (3): 688–99.  
  54. ^ McKee MD, Addison WN, Kaartinen MT (2005). "Hierarchies of extracellular matrix and mineral organization in bone of the craniofacial complex and skeleton". Cells Tissues Organs (Print) 181 (3-4): 176–88.  
  55. ^ Steitz SA, Speer MY, McKee MD, Liaw L, Almeida M, Yang H, Giachelli CM (December 2002). "Osteopontin inhibits mineral deposition and promotes regression of ectopic calcification". Am. J. Pathol. 161 (6): 2035–46.  
  56. ^ Giachelli CM (March 1999). "Ectopic calcification: gathering hard facts about soft tissue mineralization". Am. J. Pathol. 154 (3): 671–5.  
  57. ^ Choi ST, Kim JH, Kang EJ, Lee SW, Park MC, Park YB, Lee SK (December 2008). "Osteopontin might be involved in bone remodelling rather than in inflammation in ankylosing spondylitis". Rheumatology (Oxford) 47 (12): 1775–9.  
  58. ^ Singh M, Dalal S, Singh K (2014). "Osteopontin: At the cross-roads of myocyte survival and myocardial function.". Life Sci.  
  59. ^ Apte UM, Banerjee A, McRee R, Wellberg E, Ramaiah SK (August 2005). "Role of osteopontin in hepatic neutrophil infiltration during alcoholic steatohepatitis". Toxicol. Appl. Pharmacol. 207 (1): 25–38.  
  60. ^ Koh A, da Silva AP, Bansal AK, Bansal M, Sun C, Lee H, Glogauer M, Sodek J, Zohar R (December 2007). "Role of osteopontin in neutrophil function". Immunology 122 (4): 466–75.  
  61. ^ Ohshima S, Kobayashi H, Yamaguchi N, Nishioka K, Umeshita-Sasai M, Mima T, Nomura S, Kon S, Inobe M, Uede T, Saeki Y (April 2002). "Expression of osteopontin at sites of bone erosion in a murine experimental arthritis model of collagen-induced arthritis: possible involvement of osteopontin in bone destruction in arthritis". Arthritis Rheum. 46 (4): 1094–101.  
  62. ^ Sakata M, Tsuruha JI, Masuko-Hongo K, Nakamura H, Matsui T, Sudo A, Nishioka K, Kato T (July 2001). "Autoantibodies to osteopontin in patients with osteoarthritis and rheumatoid arthritis". J. Rheumatol. 28 (7): 1492–5.  
  63. ^ a b Nagasaka A, Matsue H, Matsushima H, Aoki R, Nakamura Y, Kambe N, Kon S, Uede T, Shimada S (February 2008). "Osteopontin is produced by mast cells and affects IgE-mediated  
  64. ^ Burdo TH, Wood MR, Fox HS (June 2007). "Osteopontin prevents monocyte recirculation and apoptosis". J. Leukoc. Biol. 81 (6): 1504–11.  
  65. ^ Crawford HC, Matrisian LM, Liaw L (November 1998). "Distinct roles of osteopontin in host defense activity and tumor survival during squamous cell carcinoma progression in vivo". Cancer Res. 58 (22): 5206–15.  
  66. ^ Denhardt DT, Noda M, O'Regan AW, Pavlin D, Berman JS (May 2001). "Osteopontin as a means to cope with environmental insults: regulation of inflammation, tissue remodeling, and cell survival". J. Clin. Invest. 107 (9): 1055–61.  
  67. ^ Standal T, Borset M, Sundan A (September 2004). "Role of osteopontin in adhesion, migration, cell survival and bone remodeling". Exp. Oncol. 26 (3): 179–84.  
  68. ^ Da Silva AP, Pollett A, Rittling SR, Denhardt DT, Sodek J, Zohar R (September 2006). "Exacerbated tissue destruction in DSS-induced acute colitis of OPN-null mice is associated with downregulation of TNF-alpha expression and non-programmed cell death". J. Cell. Physiol. 208 (3): 629–39.  
  69. ^ Yumoto K, Ishijima M, Rittling SR, Tsuji K, Tsuchiya Y, Kon S, Nifuji A, Uede T, Denhardt DT, Noda M (April 2002). "Osteopontin deficiency protects joints against destruction in anti-type II collagen antibody-induced arthritis in mice". Proc. Natl. Acad. Sci. U.S.A. 99 (7): 4556–61.  
  70. ^ Jacobs JP, Pettit AR, Shinohara ML, Jansson M, Cantor H, Gravallese EM, Mathis D, Benoist C (August 2004). "Lack of requirement of osteopontin for inflammation, bone erosion, and cartilage damage in the K/BxN model of autoantibody-mediated arthritis". Arthritis Rheum. 50 (8): 2685–94.  
  71. ^ Chabas D, Baranzini SE, Mitchell D, Bernard CC, Rittling SR, Denhardt DT, Sobel RA, Lock C, Karpuj M, Pedotti R, Heller R, Oksenberg JR, Steinman L (November 2001). "The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease". Science 294 (5547): 1731–5.  
  72. ^ Steinman L (February 2007). "A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage". Nat. Med. 13 (2): 139–45.  
  73. ^ "'"Gel 'to speed up wound healing. Health. BBC NEWS. 2008-01-22. Retrieved 2009-01-26. 
  74. ^ a b Gassler N, Autschbach F, Gauer S, Bohn J, Sido B, Otto HF, Geiger H, Obermüller N (November 2002). "Expression of osteopontin (Eta-1) in Crohn disease of the terminal ileum". Scand J Gastroenterol 37 (11): 1286–95.  
  75. ^ Sato T, Nakai T, Tamura N, Okamoto S, Matsuoka K, Sakuraba A, Fukushima T, Uede T, Hibi T (September 2005). "Osteopontin/Eta-1 upregulated in Crohn's disease regulates the Th1 immune response". Gut 54 (9): 1254–62.  
  76. ^ Mishima R, Takeshima F, Sawai T, Ohba K, Ohnita K, Isomoto H, Omagari K, Mizuta Y, Ozono Y, Kohno S (February 2007). "High plasma osteopontin levels in patients with inflammatory bowel disease". J Clin Gastroenterol 41 (2): 167–72.  
  77. ^ a b Kourepini E, Aggelakopoulou M, Alissafi T, Paschalidis N, Simoes DC, Panoutsakopoulou V (March 2014). "Osteopontin expression by CD103- dendritic cells drives intestinal inflammation". Proc Natl Acad Sci U S A 111 (9): E856–E865.  
  78. ^ a b c d e Xanthou G, Alissafi T, Semitekolou M, Simoes DC, Economidou E, Gaga M, Lambrecht BN, Lloyd CM, Panoutsakopoulou V (May 2007). "Osteopontin has a crucial role in allergic airway disease through regulation of  
  79. ^ Simoes DC, Xanthou G, Petrochilou K, Panoutsakopoulou V, Roussos C, Gratziou C (May 2009). "Osteopontin  
  80. ^ Samitas K, Zervas E, Vittorakis S, Semitekolou M, Alissafi T, Bossios A, Gogos H, Economidou E, Lötvall J, Xanthou G, Panoutsakopoulou V, Gaga M (2010). "Osteopontin expression and relation to disease severity in human asthma.". Eur. Respir. J. 37 (2): 331–41.  
  81. ^ Hillas G, Loukides S, Kostikas K, Simoes D, Petta V, Konstantellou E, Emmanouil P, Papiris S, Koulouris N, Bakakos P (Jan 2013). "Increased levels of osteopontin in sputum supernatant of smoking asthmatics.". Cytokine. 61 (1): 251–5.  
  82. ^ Samitas K, Zervas E, Xanthou G, Panoutsakopoulou V, Gaga M (Feb 2013). "Osteopontin is increased in the bronchoalveolar lavage fluid and bronchial tissue of smoking asthmatics.". Cytokine 61 (3): 713–5.  
  83. ^ Porter JD, Khanna S, Kaminski HJ, Rao JS, Merriam AP, Richmonds CR, Leahy P, Li J, Guo W, Andrade FH (May 2002). "A chronic inflammatory response dominates the skeletal muscle molecular signature in dystrophin-deficient mdx mice". Hum Mol Genet 11 (3): 263–72.  
  84. ^ Haslett JN, Sanoudou D, Kho AT, Bennett RR, Greenberg SA, Kohane IS, Beggs AH, Kunkel LM (2002). "Gene expression comparison of biopsies from Duchenne muscular dystrophy (DMD) and normal skeletal muscle". Proc Natl Acad Sci U S A 99 (23): 15000–15005.  
  85. ^ Hirata A, Masuda S, Tamura T, Kai K, Ojima K, Fukase A, Motoyoshi K, Kamakura K, Miyagoe-Suzuki Y, Takeda S (2003). "Expression profiling of cytokines and related genes in regenerating skeletal muscle after cardiotoxin injection: a role for osteopontin". Am J Pathol 163 (1): 203–215.  
  86. ^ Vetrone SA, Montecino-Rodriguez E, Kudryashova E, Kramerova I, Hoffman EP, Liu SD, Miceli MC, Spencer MJ (2009). "Osteopontin promotes fibrosis in dystrophic mouse muscle by modulating immune cell subsets and intramuscular TGF-beta". J Clin Invest 119 (6): 1583–1594.  
  87. ^ Pegoraro E, Hoffman EP, Piva L, Gavassini BF, Cagnin S, Ermani M, Bello L, Soraru G, Pacchioni B, Bonifati MD, Lanfranchi G, Angelini C, Kesari A, Lee I, Gordish-Dressman H, Devaney JM, McDonald CM (2011). "SPP1 genotype is a determinant of disease severity in Duchenne muscular dystrophy". Neurology 76 (3): 219–226.  

Additional images

Further reading

  • Fujisawa R (2002). "[Recent advances in research on bone matrix proteins]". Nippon Rinsho. 60. Suppl 3: 72–8.  
  • Denhardt DT, Mistretta D, Chambers AF, Krishna S, Porter JF, Raghuram S, Rittling SR (2003). "Transcriptional regulation of osteopontin and the metastatic phenotype: evidence for a Ras-activated enhancer in the human OPN promoter". Clin. Exp. Metastasis 20 (1): 77–84.  
  • Yeatman TJ, Chambers AF (2003). "Osteopontin and colon cancer progression". Clin. Exp. Metastasis 20 (1): 85–90.  
  • O'Regan A (2004). "The role of osteopontin in lung disease". Cytokine Growth Factor Rev. 14 (6): 479–88.  
  • Wai PY, Kuo PC (2004). "The role of Osteopontin in tumor metastasis". J. Surg. Res. 121 (2): 228–41.  
  • Konno S, Hizawa N, Nishimura M, Huang SK (2007). "Osteopontin: a potential biomarker for successful bee venom immunotherapy and a potential molecule for inhibiting IgE-mediated allergic responses". Allergology international : official journal of the Japanese Society of Allergology 55 (4): 355–9.  
  • Rodrigues LR, Teixeira JA, Schmitt FL, Paulsson M, Lindmark-Mänsson H (2007). "The role of osteopontin in tumor progression and metastasis in breast cancer". Cancer Epidemiol. Biomarkers Prev. 16 (6): 1087–97.  
  • Ramaiah SK, Rittling S (2007). "Role of osteopontin in regulating hepatic inflammatory responses and toxic liver injury". Expert opinion on drug metabolism & toxicology 3 (4): 519–26.  

External links