Osteopontin

Secreted phosphoprotein 1

Rendering based on PDB 3CXD.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
SymbolsSPP1 ; BNSP; BSPI; ETA-1; OPN
External IDsOMIM: 166490 MGI: 98389 HomoloGene: 20156 ChEMBL: 1741309 GeneCards: SPP1 Gene
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez669620750
EnsemblENSG00000118785ENSMUSG00000029304
UniProtP10451P10923
RefSeq (mRNA)NM_000582NM_001204201
RefSeq (protein)NP_000573NP_001191130
Location (UCSC)Chr 4:
88.9 – 88.9 Mb		Chr 5:
104.44 – 104.44 Mb
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, although it is also expressed in other tissues. The suffix -pontin is derived from "pons," the Latin word for bridge, and signifies osteopontin's role as a linking protein. Osteopontin is an extracellular structural protein and therefore an organic component of 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.

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 bone remodeling.[57] Specifically, research suggests it plays a role in anchoring osteoclasts to the mineral matrix of bones.[9] The organic part of bone is about 20% of the dry weight, and counts in, other than osteopontin, collagen type I, osteocalcin, osteonectin, bone sialo protein, and alkaline phosphatase. Collagen type I counts for 90% of the protein mass. The inorganic part of bone is the mineral 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. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 Wang KX, Denhardt DT (2008). "Osteopontin: role in immune regulation and stress responses". Cytokine Growth Factor Rev. 19 (5-6): 333–45. doi:10.1016/j.cytogfr.2008.08.001. PMID 18952487.
  3. ↑ Rangaswami H, Bulbule A, Kundu GC (February 2006). "Osteopontin: role in cell signaling and cancer progression". Trends Cell Biol. 16 (2): 79–87. doi:10.1016/j.tcb.2005.12.005. PMID 16406521.
  4. ↑ Young MF, Kerr JM, Termine JD, Wewer UM, Wang MG, McBride OW et al. (August 1990). "cDNA cloning, mRNA distribution and heterogeneity, chromosomal location, and RFLP analysis of human osteopontin (OPN)". Genomics. 7 (1): 491–502. doi:10.1016/0888-7543(90)90191-V. PMID 1974876.
  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. doi:10.1093/nar/17.8.3306. PMC 317745. PMID 2726470.
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  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. doi:10.1006/excr.2000.5074. PMID 11120606.
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  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. doi:10.1080/03008200390152061. PMID 12952171.
  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. doi:10.1042/BJ20050341. PMC 1184582. PMID 15869464.
  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. doi:10.1152/ajprenal.00304.2010. PMC 3064126. PMID 21177780.
  39. ↑ Martin A, David V, Laurence JS, Schwarz PM, Lafer EM, Hedge AM et al. (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. doi:10.1210/en.2007-1205. PMC 2276704. PMID 18162525.
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Additional images

Further reading

  • Fujisawa R (2002). "[Recent advances in research on bone matrix proteins]". Nippon Rinsho. 60. Suppl 3: 72–8. PMID 11979972.
  • Denhardt DT, Mistretta D, Chambers AF, Krishna S, Porter JF, Raghuram S et al. (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. doi:10.1023/A:1022550721404. PMID 12650610.
  • Yeatman TJ, Chambers AF (2003). "Osteopontin and colon cancer progression". Clin. Exp. Metastasis 20 (1): 85–90. doi:10.1023/A:1022502805474. PMID 12650611.
  • O'Regan A (2004). "The role of osteopontin in lung disease". Cytokine Growth Factor Rev. 14 (6): 479–88. doi:10.1016/S1359-6101(03)00055-8. PMID 14563350.
  • Wai PY, Kuo PC (2004). "The role of Osteopontin in tumor metastasis". J. Surg. Res. 121 (2): 228–41. doi:10.1016/j.jss.2004.03.028. PMID 15501463.
  • 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. doi:10.2332/allergolint.55.355. PMID 17130676.
  • 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. doi:10.1158/1055-9965.EPI-06-1008. PMID 17548669.
  • 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. doi:10.1517/17425225.3.4.519. PMID 17696803.

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