Osteopontin

{{Infobox protein family

| Symbol = Osteopontin

| Name = Osteopontin

| image =

| width =

| caption = crystal structure of anti-osteopontin antibody 23c3 in complex with w43a mutated epitope peptide

| Pfam = PF00865

| Pfam_clan =

| InterPro = IPR002038

| SMART =

| PROSITE = PDOC00689

| MEROPS =

| SCOP =

| TCDB =

| OPM family =

| OPM protein =

| CAZy =

| CDD =

}}

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),{{cite web | title = Entrez Gene: SPP1 secreted phosphoprotein 1 | url = https://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=retrieve&dopt=default&list_uids=6696&rn=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.

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

OPN is a highly negatively charged, heavily phosphorylated extracellular matrix protein that lacks an extensive secondary structure as an intrinsically disordered protein. 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.{{cite journal | vauthors = Rangaswami H, Bulbule A, Kundu GC | title = Osteopontin: role in cell signaling and cancer progression | journal = Trends in Cell Biology | volume = 16 | issue = 2 | pages = 79–87 | date = February 2006 | pmid = 16406521 | doi = 10.1016/j.tcb.2005.12.005 }} The OPN gene is composed of 7 exons, 6 of which containing coding sequence.{{cite journal | vauthors = Young MF, Kerr JM, Termine JD, Wewer UM, Wang MG, McBride OW, Fisher LW | title = cDNA cloning, mRNA distribution and heterogeneity, chromosomal location, and RFLP analysis of human osteopontin (OPN) | journal = Genomics | volume = 7 | issue = 4 | pages = 491–502 | date = August 1990 | pmid = 1974876 | doi = 10.1016/0888-7543(90)90191-V | url = https://zenodo.org/record/1258571 }}{{cite journal | vauthors = Kiefer MC, Bauer DM, Barr PJ | title = The cDNA and derived amino acid sequence for human osteopontin | journal = Nucleic Acids Research | volume = 17 | issue = 8 | pages = 3306 | date = April 1989 | pmid = 2726470 | pmc = 317745 | doi = 10.1093/nar/17.8.3306 }} The first two exons contain the 5' untranslated region (5' UTR).{{cite journal | vauthors = Crosby AH, Edwards SJ, Murray JC, Dixon MJ | title = Genomic organization of the human osteopontin gene: exclusion of the locus from a causative role in the pathogenesis of dentinogenesis imperfecta type II | journal = Genomics | volume = 27 | issue = 1 | pages = 155–160 | date = May 1995 | pmid = 7665163 | doi = 10.1006/geno.1995.1018 }} Exons 2, 3, 4, 5, 6, and 7 code for 17, 13, 27, 14, 108 and 134 amino acids, respectively. All intron-exon boundaries are of the phase 0 type, thus alternative exon splicing maintains the reading frame of the OPN gene.

Image:OPN2.jpg

SPP1 structure corresponds to an osteopontin antibody

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.{{cite journal | vauthors = Laffón A, García-Vicuña R, Humbría A, Postigo AA, Corbí AL, de Landázuri MO, Sánchez-Madrid F | title = Upregulated expression and function of VLA-4 fibronectin receptors on human activated T cells in rheumatoid arthritis | journal = The Journal of Clinical Investigation | volume = 88 | issue = 2 | pages = 546–552 | date = August 1991 | pmid = 1830891 | pmc = 295383 | doi = 10.1172/JCI115338 }}{{cite journal | vauthors = Seiffge D | title = Protective effects of monoclonal antibody to VLA-4 on leukocyte adhesion and course of disease in adjuvant arthritis in rats | journal = The Journal of Rheumatology | volume = 23 | issue = 12 | pages = 2086–91 | date = December 1996 | pmid = 8970045 }} These integrin receptors are present on a number of immune cells such as mast cells,{{cite journal | vauthors = Reinholt FP, Hultenby K, Oldberg A, Heinegård D | title = Osteopontin--a possible anchor of osteoclasts to bone | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 87 | issue = 12 | pages = 4473–5 | date = June 1990 | pmid = 1693772 | pmc = 54137 | doi = 10.1073/pnas.87.12.4473 | doi-access = free | bibcode = 1990PNAS...87.4473R }} neutrophils,{{cite journal | vauthors = Banerjee A, Apte UM, Smith R, Ramaiah SK | title = Higher neutrophil infiltration mediated by osteopontin is a likely contributing factor to the increased susceptibility of females to alcoholic liver disease | journal = The Journal of Pathology | volume = 208 | issue = 4 | pages = 473–485 | date = March 2006 | pmid = 16440289 | doi = 10.1002/path.1917 | s2cid = 45879742 | doi-access = free }} and T cells. It is also expressed by monocytes and macrophages.{{cite journal | vauthors = Sodek J, Batista Da Silva AP, Zohar R | title = Osteopontin and mucosal protection | journal = Journal of Dental Research | volume = 85 | issue = 5 | pages = 404–415 | date = May 2006 | pmid = 16632752 | doi = 10.1177/154405910608500503 | s2cid = 25898774 }}{{Dead link|date=April 2020 |bot=InternetArchiveBot |fix-attempted=yes }} Upon binding these receptors, cells use several signal transduction pathways to elicit immune responses in these cells. OPN-R can be further cleaved by Carboxypeptidase B (CPB) by removal of C-terminal arginine and become OPN-L. 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.{{cite journal | vauthors = Zohar R, Suzuki N, Suzuki K, Arora P, Glogauer M, McCulloch CA, Sodek J | title = Intracellular osteopontin is an integral component of the CD44-ERM complex involved in cell migration | journal = Journal of Cellular Physiology | volume = 184 | issue = 1 | pages = 118–130 | date = July 2000 | pmid = 10825241 | doi = 10.1002/(SICI)1097-4652(200007)184:1<118::AID-JCP13>3.0.CO;2-Y | s2cid = 11548419 }}{{cite journal | vauthors = Suzuki K, Zhu B, Rittling SR, Denhardt DT, Goldberg HA, McCulloch CA, Sodek J | title = Colocalization of intracellular osteopontin with CD44 is associated with migration, cell fusion, and resorption in osteoclasts | journal = Journal of Bone and Mineral Research | volume = 17 | issue = 8 | pages = 1486–97 | date = August 2002 | pmid = 12162503 | doi = 10.1359/jbmr.2002.17.8.1486 | s2cid = 21307088 | doi-access = }}{{cite journal | vauthors = Zhu B, Suzuki K, Goldberg HA, Rittling SR, Denhardt DT, McCulloch CA, Sodek J | title = Osteopontin modulates CD44-dependent chemotaxis of peritoneal macrophages through G-protein-coupled receptors: evidence of a role for an intracellular form of osteopontin | journal = Journal of Cellular Physiology | volume = 198 | issue = 1 | pages = 155–167 | date = January 2004 | pmid = 14584055 | doi = 10.1002/jcp.10394 | s2cid = 21075107 }}{{cite journal | vauthors = Junaid A, Moon MC, Harding GE, Zahradka P | title = Osteopontin localizes to the nucleus of 293 cells and associates with polo-like kinase-1 | journal = American Journal of Physiology. Cell Physiology | volume = 292 | issue = 2 | pages = C919–C926 | date = February 2007 | pmid = 17005603 | doi = 10.1152/ajpcell.00477.2006 }} Intracellular OPN is generated using an alternative translation start site on the same mRNA species used to generate the extracellular isoform.{{cite journal | vauthors = Shinohara ML, Kim HJ, Kim JH, Garcia VA, Cantor H | title = Alternative translation of osteopontin generates intracellular and secreted isoforms that mediate distinct biological activities in dendritic cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 20 | pages = 7235–9 | date = May 2008 | pmid = 18480255 | pmc = 2438233 | doi = 10.1073/pnas.0802301105 | doi-access = free | bibcode = 2008PNAS..105.7235S }} 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.{{cite journal | vauthors = He B, Mirza M, Weber GF | title = An osteopontin splice variant induces anchorage independence in human breast cancer cells | journal = Oncogene | volume = 25 | issue = 15 | pages = 2192–2202 | date = April 2006 | pmid = 16288209 | doi = 10.1038/sj.onc.1209248 | s2cid = 6632395 | doi-access = }}{{cite journal | vauthors = Mirza M, Shaughnessy E, Hurley JK, Vanpatten KA, Pestano GA, He B, Weber GF | title = Osteopontin-c is a selective marker of breast cancer | journal = International Journal of Cancer | volume = 122 | issue = 4 | pages = 889–897 | date = February 2008 | pmid = 17960616 | doi = 10.1002/ijc.23204 | s2cid = 22146646 | doi-access = free }} 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. 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.

Tissue distribution

File:Journal.pmed.0020314.g001 Osteopontin.png

Osteopontin is expressed in a variety of tissue types including cardiac fibroblasts,{{cite journal | vauthors = Ashizawa N, Graf K, Do YS, Nunohiro T, Giachelli CM, Meehan WP, Tuan TL, Hsueh WA | display-authors = 6 | title = Osteopontin is produced by rat cardiac fibroblasts and mediates A(II)-induced DNA synthesis and collagen gel contraction | journal = The Journal of Clinical Investigation | volume = 98 | issue = 10 | pages = 2218–27 | date = November 1996 | pmid = 8941637 | pmc = 507670 | doi = 10.1172/JCI119031 }} preosteoblasts, osteoblasts, osteocytes, odontoblasts, some bone marrow cells, hypertrophic chondrocytes, dendritic cells, macrophages,{{cite journal | vauthors = Murry CE, Giachelli CM, Schwartz SM, Vracko R | title = Macrophages express osteopontin during repair of myocardial necrosis | journal = The American Journal of Pathology | volume = 145 | issue = 6 | pages = 1450–62 | date = December 1994 | pmid = 7992848 | pmc = 1887495 }} smooth muscle,{{cite journal | vauthors = Ikeda T, Shirasawa T, Esaki Y, Yoshiki S, Hirokawa K | title = Osteopontin mRNA is expressed by smooth muscle-derived foam cells in human atherosclerotic lesions of the aorta | journal = The Journal of Clinical Investigation | volume = 92 | issue = 6 | pages = 2814–20 | date = December 1993 | pmid = 8254036 | pmc = 288482 | doi = 10.1172/JCI116901 }} skeletal muscle myoblasts,{{cite journal | vauthors = Uaesoontrachoon K, Yoo HJ, Tudor EM, Pike RN, Mackie EJ, Pagel CN | title = Osteopontin and skeletal muscle myoblasts: association with muscle regeneration and regulation of myoblast function in vitro | journal = The International Journal of Biochemistry & Cell Biology | volume = 40 | issue = 10 | pages = 2303–14 | date = April 2008 | pmid = 18490187 | doi = 10.1016/j.biocel.2008.03.020 }} 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 expression 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).{{cite journal | vauthors = Merry K, Dodds R, Littlewood A, Gowen M | title = Expression of osteopontin mRNA by osteoclasts and osteoblasts in modelling adult human bone | journal = Journal of Cell Science | volume = 104 | issue = 4 | pages = 1013–20 | date = April 1993 | pmid = 8314886 | doi = 10.1242/jcs.104.4.1013 }} Runx2 (aka Cbfa1) and osterix (Osx) transcription factors are required for the expression of OPN{{cite journal | vauthors = Nakashima K, Zhou X, Kunkel G, Zhang Z, Deng JM, Behringer RR, de Crombrugghe B | title = The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation | journal = Cell | volume = 108 | issue = 1 | pages = 17–29 | date = January 2002 | pmid = 11792318 | doi = 10.1016/S0092-8674(01)00622-5 | s2cid = 14030684 | doi-access = free }} Runx2 and Osx bind promoters of osteoblast-specific genes such as Col1α1, Bsp, and Opn and upregulate transcription.{{cite journal | vauthors = Ducy P, Zhang R, Geoffroy V, Ridall AL, Karsenty G | title = Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation | journal = Cell | volume = 89 | issue = 5 | pages = 747–754 | date = May 1997 | pmid = 9182762 | doi = 10.1016/S0092-8674(00)80257-3 | s2cid = 16979723 | doi-access = free }}

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.{{cite journal | vauthors = Yucha C, Guthrie D | title = Renal homeostasis of calcium | journal = Nephrology Nursing Journal | volume = 30 | issue = 6 | pages = 755–764 | date = December 2003 | pmid = 14730782 }} This is due to the presence of a high-specificity vitamin D response element (VDRE) in the OPN gene promoter.{{cite journal | vauthors = Prince CW, Butler WT | title = 1,25-Dihydroxyvitamin D3 regulates the biosynthesis of osteopontin, a bone-derived cell attachment protein, in clonal osteoblast-like osteosarcoma cells | journal = Collagen and Related Research | volume = 7 | issue = 4 | pages = 305–313 | date = September 1987 | pmid = 3478171 | doi = 10.1016/s0174-173x(87)80036-5 }}{{cite journal | vauthors = Oldberg A, Jirskog-Hed B, Axelsson S, Heinegård D | title = Regulation of bone sialoprotein mRNA by steroid hormones | journal = The Journal of Cell Biology | volume = 109 | issue = 6 Pt 1 | pages = 3183–6 | date = December 1989 | pmid = 2592421 | pmc = 2115918 | doi = 10.1083/jcb.109.6.3183 }}{{cite journal | vauthors = Chang PL, Prince CW | title = 1 alpha,25-dihydroxyvitamin D3 stimulates synthesis and secretion of nonphosphorylated osteopontin (secreted phosphoprotein 1) in mouse JB6 epidermal cells | journal = Cancer Research | volume = 51 | issue = 8 | pages = 2144–50 | date = April 1991 | pmid = 2009532 }}

Osteopontin (OPN) expression is modulated by Schistosoma mansoni egg antigen.{{cite journal | vauthors = Pereira TA, Vaz de Melo Trindade G, Trindade Santos E, Pereira FE, Souza MM | title = Praziquantel pharmacotherapy reduces systemic osteopontin levels and liver collagen content in murine schistosomiasis mansoni | journal = International Journal for Parasitology | volume = 51 | issue = 6 | pages = 437–440 | date = May 2021 | pmid = 33493521 | doi = 10.1016/j.ijpara.2020.11.002 | s2cid = 231711719 }}

Schistosoma mansoni egg antigens directly stimulate the expression of the profibrogenic molecule osteopontin (OPN), and systemic OPN levels strongly correlate with disease severity, suggesting its use as a potential morbidity biomarker. Investigation into the impact of Praziquantel use on systemic OPN levels and on liver collagen deposition in chronic murine schistosomiasis revealed that Praziquantel treatment significantly reduced systemic OPN levels and liver collagen deposition, indicating that OPN could be a reliable tool for monitoring PZQ efficacy and fibrosis regression.{{cite journal |vauthors=Gill HS, LeJambre LF |title=Preface — Novel approaches to the control of helminth parasites of livestock. Proceedings of an international conference. Armidale, New South Wales, 18-21 April 1995 |journal=Int J Parasitol |volume=26 |issue=8–9 |pages=797–8 |date=1996 |pmid=8923128 |doi=10.1016/S0020-7519(96)80042-7}}

Extracellular inorganic phosphate (ePi) has also been identified as a modulator of OPN expression.{{cite journal | vauthors = Fatherazi S, Matsa-Dunn D, Foster BL, Rutherford RB, Somerman MJ, Presland RB | title = Phosphate regulates osteopontin gene transcription | journal = Journal of Dental Research | volume = 88 | issue = 1 | pages = 39–44 | date = January 2009 | pmid = 19131315 | pmc = 3128439 | doi = 10.1177/0022034508328072 }}

Stimulation of OPN expression also occurs upon exposure of cells to pro-inflammatory cytokines,{{cite journal | vauthors = Guo H, Cai CQ, Schroeder RA, Kuo PC | title = Osteopontin is a negative feedback regulator of nitric oxide synthesis in murine macrophages | journal = Journal of Immunology | volume = 166 | issue = 2 | pages = 1079–86 | date = January 2001 | pmid = 11145688 | doi = 10.4049/jimmunol.166.2.1079 | doi-access = free }} 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),{{cite journal | vauthors = Ricardo SD, Franzoni DF, Roesener CD, Crisman JM, Diamond JR | title = Angiotensinogen and AT(1) antisense inhibition of osteopontin translation in rat proximal tubular cells | journal = American Journal of Physiology. Renal Physiology | volume = 278 | issue = 5 | pages = F708–F716 | date = May 2000 | pmid = 10807582 | doi = 10.1152/ajprenal.2000.278.5.F708 }}{{cite journal | vauthors = Noda M, Rodan GA | title = Transcriptional regulation of osteopontin production in rat osteoblast-like cells by parathyroid hormone | journal = The Journal of Cell Biology | volume = 108 | issue = 2 | pages = 713–8 | date = February 1989 | pmid = 2465299 | pmc = 2115413 | doi = 10.1083/jcb.108.2.713 }} although a detailed mechanistic understanding of these regulatory pathways are not yet known. Hyperglycemia and hypoxia are also known to increase OPN expression.{{cite journal | vauthors = Hullinger TG, Pan Q, Viswanathan HL, Somerman MJ | title = TGFbeta and BMP-2 activation of the OPN promoter: roles of smad- and hox-binding elements | journal = Experimental Cell Research | volume = 262 | issue = 1 | pages = 69–74 | date = January 2001 | pmid = 11120606 | doi = 10.1006/excr.2000.5074 }}{{cite journal | vauthors = Sodhi CP, Phadke SA, Batlle D, Sahai A | title = Hypoxia and high glucose cause exaggerated mesangial cell growth and collagen synthesis: role of osteopontin | journal = American Journal of Physiology. Renal Physiology | volume = 280 | issue = 4 | pages = F667–F674 | date = April 2001 | pmid = 11249858 | doi = 10.1152/ajprenal.2001.280.4.F667 | s2cid = 26145407 }}

Function

= 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.{{cite journal | vauthors = Denhardt DT, Noda M, O'Regan AW, Pavlin D, Berman JS | title = Osteopontin as a means to cope with environmental insults: regulation of inflammation, tissue remodeling, and cell survival | journal = The Journal of Clinical Investigation | volume = 107 | issue = 9 | pages = 1055–61 | date = May 2001 | pmid = 11342566 | pmc = 209291 | doi = 10.1172/JCI12980 }}{{cite journal | vauthors = Standal T, Borset M, Sundan A | title = Role of osteopontin in adhesion, migration, cell survival and bone remodeling | journal = Experimental Oncology | volume = 26 | issue = 3 | pages = 179–184 | date = September 2004 | pmid = 15494684 }} OPN prevents non-programmed cell death in inflammatory colitis.{{cite journal | vauthors = Da Silva AP, Pollett A, Rittling SR, Denhardt DT, Sodek J, Zohar R | title = 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 | journal = Journal of Cellular Physiology | volume = 208 | issue = 3 | pages = 629–639 | date = September 2006 | pmid = 16741956 | doi = 10.1002/jcp.20701 | s2cid = 33704508 }}

= Biomineralization =

OPN belongs to a family of secreted acidic proteins (SIBLINGs, Small Integrin Binding LIgand N-Glycosylated proteins) whose members have an abundance of negatively charged amino acids such as Asp and Glu.{{cite journal | vauthors = Fisher LW, Fedarko NS | title = Six genes expressed in bones and teeth encode the current members of the SIBLING family of proteins | journal = Connective Tissue Research | volume = 44 | issue = Suppl 1 | pages = 33–40 | year = 2003 | pmid = 12952171 | doi = 10.1080/03008200390152061 | s2cid = 29910722 }} OPN also has a large number of consensus sequence sites for post-translational phosphorylation of Ser residues to form phosphoserine, providing additional negative charge.{{cite journal | vauthors = Christensen B, Nielsen MS, Haselmann KF, Petersen TE, Sørensen ES | title = 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 | journal = The Biochemical Journal | volume = 390 | issue = Pt 1 | pages = 285–292 | date = August 2005 | pmid = 15869464 | pmc = 1184582 | doi = 10.1042/BJ20050341 }} 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 aspartate-rich motif), with the latter sequence having multiple phosphorylation sites.{{cite journal | vauthors = David V, Martin A, Hedge AM, Drezner MK, Rowe PS | title = ASARM peptides: PHEX-dependent and -independent regulation of serum phosphate | journal = American Journal of Physiology. Renal Physiology | volume = 300 | issue = 3 | pages = F783–F791 | date = March 2011 | pmid = 21177780 | pmc = 3064126 | doi = 10.1152/ajprenal.00304.2010 }}{{cite journal | vauthors = Martin A, David V, Laurence JS, Schwarz PM, Lafer EM, Hedge AM, Rowe PS | title = Degradation of MEPE, DMP1, and release of SIBLING ASARM-peptides (minhibins): ASARM-peptide(s) are directly responsible for defective mineralization in HYP | journal = Endocrinology | volume = 149 | issue = 4 | pages = 1757–72 | date = April 2008 | pmid = 18162525 | pmc = 2276704 | doi = 10.1210/en.2007-1205 }}{{cite journal | vauthors = Addison WN, Nakano Y, Loisel T, Crine P, McKee MD | title = MEPE-ASARM peptides control extracellular matrix mineralization by binding to hydroxyapatite: an inhibition regulated by PHEX cleavage of ASARM | journal = Journal of Bone and Mineral Research | volume = 23 | issue = 10 | pages = 1638–49 | date = October 2008 | pmid = 18597632 | doi = 10.1359/jbmr.080601 | s2cid = 7709872 | doi-access = free }}{{cite journal | vauthors = Addison WN, Masica DL, Gray JJ, McKee MD | title = Phosphorylation-dependent inhibition of mineralization by osteopontin ASARM peptides is regulated by PHEX cleavage | journal = Journal of Bone and Mineral Research | volume = 25 | issue = 4 | pages = 695–705 | date = April 2010 | pmid = 19775205 | doi = 10.1359/jbmr.090832 | s2cid = 25689595 }} This overall negative charge of OPN, along with its specific acidic motifs and the fact that OPN is an intrinsically disordered protein{{cite journal | vauthors = Kurzbach D, Platzer G, Schwarz TC, Henen MA, Konrat R, Hinderberger D | title = Cooperative unfolding of compact conformations of the intrinsically disordered protein osteopontin | journal = Biochemistry | volume = 52 | issue = 31 | pages = 5167–75 | date = August 2013 | pmid = 23848319 | pmc = 3737600 | doi = 10.1021/bi400502c }}{{cite journal | vauthors = Kalmar L, Homola D, Varga G, Tompa P | title = Structural disorder in proteins brings order to crystal growth in biomineralization | journal = Bone | volume = 51 | issue = 3 | pages = 528–534 | date = September 2012 | pmid = 22634174 | doi = 10.1016/j.bone.2012.05.009 }} allowing for open and flexible structures, permit OPN to bind strongly to calcium atoms available at crystal surfaces in various biominerals.{{cite journal | vauthors = Azzopardi PV, O'Young J, Lajoie G, Karttunen M, Goldberg HA, Hunter GK | title = Roles of electrostatics and conformation in protein-crystal interactions | journal = PLOS ONE | volume = 5 | issue = 2 | pages = e9330 | date = February 2010 | pmid = 20174473 | pmc = 2824833 | doi = 10.1371/journal.pone.0009330 | doi-access = free | bibcode = 2010PLoSO...5.9330A }}{{cite journal | vauthors = Hunter GK, O'Young J, Grohe B, Karttunen M, Goldberg HA | title = The flexible polyelectrolyte hypothesis of protein-biomineral interaction | journal = Langmuir | volume = 26 | issue = 24 | pages = 18639–46 | date = December 2010 | pmid = 20527831 | doi = 10.1021/la100401r }} Such binding of OPN to various types of calcium-based biominerals ‒ such as calcium-phosphate mineral in bones and teeth,{{cite journal | vauthors = McKee MD, Nanci A | title = Postembedding colloidal-gold immunocytochemistry of noncollagenous extracellular matrix proteins in mineralized tissues | journal = Microscopy Research and Technique | volume = 31 | issue = 1 | pages = 44–62 | date = May 1995 | pmid = 7626799 | doi = 10.1002/jemt.1070310105 | s2cid = 5767310 }} calcium-carbonate mineral in inner ear otoconia{{cite journal | vauthors = Takemura T, Sakagami M, Nakase T, Kubo T, Kitamura Y, Nomura S | title = Localization of osteopontin in the otoconial organs of adult rats | journal = Hearing Research | volume = 79 | issue = 1–2 | pages = 99–104 | date = September 1994 | pmid = 7806488 | doi = 10.1016/0378-5955(94)90131-7 | s2cid = 4765287 }} and avian eggshells,{{cite journal | vauthors = Hincke MT, Nys Y, Gautron J, Mann K, Rodriguez-Navarro AB, McKee MD | title = The eggshell: structure, composition and mineralization | journal = Frontiers in Bioscience | volume = 17 | issue = 4 | pages = 1266–80 | date = January 2012 | pmid = 22201802 | doi = 10.2741/3985 | doi-access = free }} and calcium-oxalate mineral in kidney stones{{cite journal | vauthors = McKee MD, Nanci A, Khan SR | title = Ultrastructural immunodetection of osteopontin and osteocalcin as major matrix components of renal calculi | journal = Journal of Bone and Mineral Research | volume = 10 | issue = 12 | pages = 1913–29 | date = December 1995 | pmid = 8619372 | doi = 10.1002/jbmr.5650101211 | s2cid = 37508279 }}{{cite journal | vauthors = O'Young J, Chirico S, Al Tarhuni N, Grohe B, Karttunen M, Goldberg HA, Hunter GK | title = Phosphorylation of osteopontin peptides mediates adsorption to and incorporation into calcium oxalate crystals | journal = Cells Tissues Organs | volume = 189 | issue = 1–4 | pages = 51–55 | year = 2009 | pmid = 18728346 | doi = 10.1159/000151724 | s2cid = 5534110 }}{{cite journal | vauthors = Chien YC, Masica DL, Gray JJ, Nguyen S, Vali H, McKee MD | title = Modulation of calcium oxalate dihydrate growth by selective crystal-face binding of phosphorylated osteopontin and polyaspartate peptide showing occlusion by sectoral (compositional) zoning | journal = The Journal of Biological Chemistry | volume = 284 | issue = 35 | pages = 23491–501 | date = August 2009 | pmid = 19581305 | pmc = 2749123 | doi = 10.1074/jbc.M109.021899 | doi-access = free }} — acts as a mineralization inhibitor by stabilizing transient mineral precursor phases and by binding directly to crystal surfaces, all of which regulate crystal growth.{{cite journal | vauthors = Sodek J, Ganss B, McKee MD | title = Osteopontin | journal = Critical Reviews in Oral Biology and Medicine | volume = 11 | issue = 3 | pages = 279–303 | year = 2000 | pmid = 11021631 | doi = 10.1177/10454411000110030101 | doi-access = free }}{{cite journal | vauthors = Reznikov N, Hoac B, Buss DJ, Addison WN, Barros NM, McKee MD | title = Biological stenciling of mineralization in the skeleton: Local enzymatic removal of inhibitors in the extracellular matrix | journal = Bone | volume = 138 | pages = 115447 | date = September 2020 | pmid = 32454257 | doi = 10.1016/j.bone.2020.115447 | s2cid = 218909350 }}{{cite journal | vauthors = McKee MD, Buss DJ, Reznikov N | title = Mineral tessellation in bone and the stenciling principle for extracellular matrix mineralization | journal = Journal of Structural Biology | volume = 214 | issue = 1 | pages = 107823 | date = March 2022 | pmid = 34915130 | doi = 10.1016/j.jsb.2021.107823 | s2cid = 245187449 }}

OPN is a substrate protein for a number of enzymes whose actions may modulate the mineralization-inhibiting function of OPN. PHEX (phosphate-regulating endopeptidase homolog X-linked) is one such enzyme, which extensively degrades OPN, and whose inactivating gene mutations (in X-linked hypophosphatemia, XLH) lead to altered processing of OPN such that inhibitory OPN cannot be degraded and accumulates in the bone (and tooth) extracellular matrix, contributing locally to the osteomalacia (soft hypomineralized bones, and odontomalacia — soft teeth) characteristic of XLH.{{cite journal | vauthors = McKee MD, Hoac B, Addison WN, Barros NM, Millán JL, Chaussain C | title = Extracellular matrix mineralization in periodontal tissues: Noncollagenous matrix proteins, enzymes, and relationship to hypophosphatasia and X-linked hypophosphatemia | journal = Periodontology 2000 | volume = 63 | issue = 1 | pages = 102–122 | date = October 2013 | pmid = 23931057 | pmc = 3766584 | doi = 10.1111/prd.12029 }}{{cite journal | vauthors = Boukpessi T, Hoac B, Coyac BR, Leger T, Garcia C, Wicart P, Whyte MP, Glorieux FH, Linglart A, Chaussain C, McKee MD | display-authors = 6 | title = Osteopontin and the dento-osseous pathobiology of X-linked hypophosphatemia | journal = Bone | volume = 95 | pages = 151–161 | date = February 2017 | pmid = 27884786 | doi = 10.1016/j.bone.2016.11.019 }} A relationship describing local, physiologic double-negative (inhibiting inhibitors) regulation of mineralization involving OPN has been termed the Stenciling Principle of mineralization, whereby enzyme-substrate pairs imprint mineralization patterns into the extracellular matrix (most notably described for bone) by degrading mineralization inhibitors (e.g. TNAP enzyme degrading pyrophosphate inhibition, and PHEX enzyme degrading osteopontin inhibition). In relation to mineralization diseases, the Stenciling Principle is particularly relevant to the osteomalacia and odontomalacia observed in hypophosphatasia and X-linked hypophosphatemia.

Along with its role in the regulation of normal mineralization within the extracellular matrices of bones and teeth,{{cite journal | vauthors = McKee MD, Addison WN, Kaartinen MT | title = Hierarchies of extracellular matrix and mineral organization in bone of the craniofacial complex and skeleton | journal = Cells Tissues Organs | volume = 181 | issue = 3–4 | pages = 176–188 | year = 2005 | pmid = 16612083 | doi = 10.1159/000091379 | s2cid = 40705942 }} OPN is also upregulated at sites of pathologic, ectopic calcification{{cite journal | vauthors = Steitz SA, Speer MY, McKee MD, Liaw L, Almeida M, Yang H, Giachelli CM | title = Osteopontin inhibits mineral deposition and promotes regression of ectopic calcification | journal = The American Journal of Pathology | volume = 161 | issue = 6 | pages = 2035–46 | date = December 2002 | pmid = 12466120 | pmc = 1850905 | doi = 10.1016/S0002-9440(10)64482-3 }}{{cite journal | vauthors = Giachelli CM | title = Ectopic calcification: gathering hard facts about soft tissue mineralization | journal = The American Journal of Pathology | volume = 154 | issue = 3 | pages = 671–5 | date = March 1999 | pmid = 10079244 | pmc = 1866412 | doi = 10.1016/S0002-9440(10)65313-8 }} — such as for example, in urolithiasis and vascular calcification{{cite journal | vauthors = Kaartinen MT, Murshed M, Karsenty G, McKee MD | title = Osteopontin upregulation and polymerization by transglutaminase 2 in calcified arteries of Matrix Gla protein-deficient mice | journal = The Journal of Histochemistry and Cytochemistry | volume = 55 | issue = 4 | pages = 375–386 | date = April 2007 | pmid = 17189522 | doi = 10.1369/jhc.6A7087.2006 | doi-access = free }} ‒ presumably at least in part to inhibit debilitating mineralization in these soft tissues.

= Bone remodeling =

File:Osteoclast1.jpg

Osteopontin has been implicated as an important factor in bone remodeling.{{cite journal | vauthors = Choi ST, Kim JH, Kang EJ, Lee SW, Park MC, Park YB, Lee SK | title = Osteopontin might be involved in bone remodelling rather than in inflammation in ankylosing spondylitis | journal = Rheumatology | volume = 47 | issue = 12 | pages = 1775–9 | date = December 2008 | pmid = 18854347 | doi = 10.1093/rheumatology/ken385 | doi-access = free }} Specifically, OPN anchors osteoclasts to the surface of bones where it is immobilized by its mineral-binding properties allowing subsequent usage of its RGD motif for osteoclast integrin binding for cell attachment and migration. OPN at bone surfaces is located in a thin organic layer, the so-called lamina limitans.{{cite journal | vauthors = McKee MD, Nanci A | title = Osteopontin: an interfacial extracellular matrix protein in mineralized tissues | journal = Connective Tissue Research | volume = 35 | issue = 1–4 | pages = 197–205 | date = 1996 | pmid = 9084658 | doi = 10.3109/03008209609029192 }} The organic part of bone is about 20% of the dry weight, and counts in, other than osteopontin, collagen type I, osteocalcin, osteonectin, 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 bone 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. OPN contains and RGD integrin-binding motif

= 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. OPN also induces mast cell degranulation. IgE-mediated anaphylaxis is 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 since OPN-producing tumors were able to induce macrophage activation compared to OPN-deficient tumors.{{cite journal | vauthors = Crawford HC, Matrisian LM, Liaw L | title = Distinct roles of osteopontin in host defense activity and tumor survival during squamous cell carcinoma progression in vivo | journal = Cancer Research | volume = 58 | issue = 22 | pages = 5206–15 | date = November 1998 | pmid = 9823334 }}

Image:Biological functions of OPN.jpg

= Chemotaxis =

OPN plays an important role in neutrophil recruitment in alcoholic liver disease.{{cite journal | vauthors = Apte UM, Banerjee A, McRee R, Wellberg E, Ramaiah SK | title = Role of osteopontin in hepatic neutrophil infiltration during alcoholic steatohepatitis | journal = Toxicology and Applied Pharmacology | volume = 207 | issue = 1 | pages = 25–38 | date = August 2005 | pmid = 15885730 | doi = 10.1016/j.taap.2004.12.018 | bibcode = 2005ToxAP.207...25A }} OPN is important for the migration of neutrophil in vitro.{{cite journal | vauthors = Koh A, da Silva AP, Bansal AK, Bansal M, Sun C, Lee H, Glogauer M, Sodek J, Zohar R | display-authors = 6 | title = Role of osteopontin in neutrophil function | journal = Immunology | volume = 122 | issue = 4 | pages = 466–475 | date = December 2007 | pmid = 17680800 | pmc = 2266047 | doi = 10.1111/j.1365-2567.2007.02682.x }} In addition, OPN recruits inflammatory cells to arthritis joints in the collagen-induced arthritis model of rheumatoid arthritis.{{cite journal | vauthors = Ohshima S, Kobayashi H, Yamaguchi N, Nishioka K, Umeshita-Sasai M, Mima T, Nomura S, Kon S, Inobe M, Uede T, Saeki Y | display-authors = 6 | title = 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 | journal = Arthritis and Rheumatism | volume = 46 | issue = 4 | pages = 1094–1101 | date = April 2002 | pmid = 11953989 | doi = 10.1002/art.10143 | doi-access = free }}{{cite journal | vauthors = Sakata M, Tsuruha JI, Masuko-Hongo K, Nakamura H, Matsui T, Sudo A, Nishioka K, Kato T | display-authors = 6 | title = Autoantibodies to osteopontin in patients with osteoarthritis and rheumatoid arthritis | journal = The Journal of Rheumatology | volume = 28 | issue = 7 | pages = 1492–5 | date = July 2001 | pmid = 11469452 }} A recent in vitro study in 2008 has found that OPN plays a role in mast cell migration.{{cite journal | vauthors = Nagasaka A, Matsue H, Matsushima H, Aoki R, Nakamura Y, Kambe N, Kon S, Uede T, Shimada S | display-authors = 6 | title = Osteopontin is produced by mast cells and affects IgE-mediated degranulation and migration of mast cells | journal = European Journal of Immunology | volume = 38 | issue = 2 | pages = 489–499 | date = February 2008 | pmid = 18200503 | doi = 10.1002/eji.200737057 | title-link = degranulation | doi-access = free }} 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.{{cite journal | vauthors = Burdo TH, Wood MR, Fox HS | title = Osteopontin prevents monocyte recirculation and apoptosis | journal = Journal of Leukocyte Biology | volume = 81 | issue = 6 | pages = 1504–11 | date = June 2007 | pmid = 17369493 | pmc = 2490714 | doi = 10.1189/jlb.1106711 }} In rhesus monkey, OPN prevents macrophages from leaving the accumulation site in brains, indicating an increased level of chemotaxis.

= Immune system =

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.

Osteopontin (OPN) is expressed in a range of immune cells, including macrophages, neutrophils, dendritic cells, microglia and T and B cells, with varying kinetics. OPN is reported to act as an immune modulator in a variety of manners.{{cite journal | vauthors = Wang KX, Denhardt DT | title = Osteopontin: role in immune regulation and stress responses | journal = Cytokine & Growth Factor Reviews | volume = 19 | issue = 5–6 | pages = 333–345 | year = 2008 | pmid = 18952487 | doi = 10.1016/j.cytogfr.2008.08.001 | url = http://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.17059 }} 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. The following examples are found.

Clinical significance

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 responses. 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.

= Autoimmune diseases =

OPN has been implicated in pathogenesis of rheumatoid arthritis. OPN-R, the thrombin-cleaved form of OPN, is elevated in rheumatoid arthritis–affected joints. However, the role of OPN in rheumatoid arthritis is still unclear. One group found that OPN knock-out mice were protected against arthritis.{{cite journal | vauthors = Yumoto K, Ishijima M, Rittling SR, Tsuji K, Tsuchiya Y, Kon S, Nifuji A, Uede T, Denhardt DT, Noda M | display-authors = 6 | title = Osteopontin deficiency protects joints against destruction in anti-type II collagen antibody-induced arthritis in mice | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 7 | pages = 4556–61 | date = April 2002 | pmid = 11930008 | pmc = 123686 | doi = 10.1073/pnas.052523599 | doi-access = free | bibcode = 2002PNAS...99.4556Y }} while others were not able to reproduce this observation.{{cite journal | vauthors = Jacobs JP, Pettit AR, Shinohara ML, Jansson M, Cantor H, Gravallese EM, Mathis D, Benoist C | display-authors = 6 | title = Lack of requirement of osteopontin for inflammation, bone erosion, and cartilage damage in the K/BxN model of autoantibody-mediated arthritis | journal = Arthritis and Rheumatism | volume = 50 | issue = 8 | pages = 2685–94 | date = August 2004 | pmid = 15334485 | doi = 10.1002/art.20381 | doi-access = }}

OPN has been found to play a role in other autoimmune diseases including autoimmune hepatitis, allergic airway disease, and multiple sclerosis.{{cite journal | vauthors = 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 | display-authors = 6 | title = The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease | journal = Science | volume = 294 | issue = 5547 | pages = 1731–5 | date = November 2001 | pmid = 11721059 | doi = 10.1126/science.1062960 | s2cid = 86208485 | bibcode = 2001Sci...294.1731C }}

= 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.{{cite journal | vauthors = Xanthou G, Alissafi T, Semitekolou M, Simoes DC, Economidou E, Gaga M, Lambrecht BN, Lloyd CM, Panoutsakopoulou V | display-authors = 6 | title = Osteopontin has a crucial role in allergic airway disease through regulation of dendritic cell subsets | journal = Nature Medicine | volume = 13 | issue = 5 | pages = 570–8 | date = May 2007 | pmid = 17435770 | pmc = 3384679 | doi = 10.1038/nm1580 }} Opn expression is also upregulated in lungs of mice with allergic airway inflammation. 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. In contrast, neutralization of Opn-s during antigenic challenge exacerbates allergic airway disease. 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. OPN deficiency was also reported to protect against remodeling and bronchial hyperresponsiveness (BHR), again using a chronic allergen-challenge model of airway remodeling.{{cite journal | vauthors = Simoes DC, Xanthou G, Petrochilou K, Panoutsakopoulou V, Roussos C, Gratziou C | title = Osteopontin deficiency protects against airway remodeling and hyperresponsiveness in chronic asthma | journal = American Journal of Respiratory and Critical Care Medicine | volume = 179 | issue = 10 | pages = 894–902 | date = May 2009 | pmid = 19234104 | doi = 10.1164/rccm.200807-1081OC }} 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.{{cite journal | vauthors = Samitas K, Zervas E, Vittorakis S, Semitekolou M, Alissafi T, Bossios A, Gogos H, Economidou E, Lötvall J, Xanthou G, Panoutsakopoulou V, Gaga M | display-authors = 6 | title = Osteopontin expression and relation to disease severity in human asthma | journal = The European Respiratory Journal | volume = 37 | issue = 2 | pages = 331–341 | date = February 2011 | pmid = 20562127 | doi = 10.1183/09031936.00017810 | doi-access = free }} OPN has also been reported to be increased in the sputum supernatant of smoking asthmatics,{{cite journal | vauthors = Hillas G, Loukides S, Kostikas K, Simoes D, Petta V, Konstantellou E, Emmanouil P, Papiris S, Koulouris N, Bakakos P | display-authors = 6 | title = Increased levels of osteopontin in sputum supernatant of smoking asthmatics | journal = Cytokine | volume = 61 | issue = 1 | pages = 251–5 | date = January 2013 | pmid = 23098767 | doi = 10.1016/j.cyto.2012.10.002 }} as well as the BALF and bronchial tissue of smoking controls and asthmatics.{{cite journal | vauthors = Samitas K, Zervas E, Xanthou G, Panoutsakopoulou V, Gaga M | title = Osteopontin is increased in the bronchoalveolar lavage fluid and bronchial tissue of smoking asthmatics | journal = Cytokine | volume = 61 | issue = 3 | pages = 713–5 | date = March 2013 | pmid = 23384656 | doi = 10.1016/j.cyto.2012.12.028 }}

= Colitis =

Opn is up-regulated in inflammatory bowel disease (IBD).{{cite journal | vauthors = Gassler N, Autschbach F, Gauer S, Bohn J, Sido B, Otto HF, Geiger H, Obermüller N | display-authors = 6 | title = Expression of osteopontin (Eta-1) in Crohn disease of the terminal ileum | journal = Scandinavian Journal of Gastroenterology | volume = 37 | issue = 11 | pages = 1286–95 | date = November 2002 | pmid = 12465727 | doi = 10.1080/003655202761020560 | s2cid = 6381267 }} 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.{{cite journal | vauthors = Sato T, Nakai T, Tamura N, Okamoto S, Matsuoka K, Sakuraba A, Fukushima T, Uede T, Hibi T | display-authors = 6 | title = Osteopontin/Eta-1 upregulated in Crohn's disease regulates the Th1 immune response | journal = Gut | volume = 54 | issue = 9 | pages = 1254–62 | date = September 2005 | pmid = 16099792 | pmc = 1774642 | doi = 10.1136/gut.2004.048298 }}{{cite journal | vauthors = Mishima R, Takeshima F, Sawai T, Ohba K, Ohnita K, Isomoto H, Omagari K, Mizuta Y, Ozono Y, Kohno S | display-authors = 6 | title = High plasma osteopontin levels in patients with inflammatory bowel disease | journal = Journal of Clinical Gastroenterology | volume = 41 | issue = 2 | pages = 167–172 | date = February 2007 | pmid = 17245215 | doi = 10.1097/MCG.0b013e31802d6268 | s2cid = 25039321 }} 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.{{cite journal | vauthors = Kourepini E, Aggelakopoulou M, Alissafi T, Paschalidis N, Simoes DC, Panoutsakopoulou V | title = Osteopontin expression by CD103- dendritic cells drives intestinal inflammation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 111 | issue = 9 | pages = E856–E865 | date = March 2014 | pmid = 24550510 | pmc = 3948306 | doi = 10.1073/pnas.1316447111 | doi-access = free | bibcode = 2014PNAS..111E.856K }} 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.

= Cancer =

It has been shown that OPN drives IL-17 production;{{cite journal | vauthors = Steinman L | title = 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 | journal = Nature Medicine | volume = 13 | issue = 2 | pages = 139–145 | date = February 2007 | pmid = 17290272 | doi = 10.1038/nm1551 | s2cid = 10640379 }} 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.

Osteopontin is implicated in PDAC (pancreatic adenocarcinoma) disease progression.{{Cite journal | vauthors = Clay R, Siddiqi SA |date= January 2019 |title=Recent advances in molecular diagnostics and therapeutic targets for pancreatic cancer |journal=Theranostic Approach for Pancreatic Cancer|language=en|pages=325–367|doi=10.1016/B978-0-12-819457-7.00016-5 |isbn=978-0-12-819457-7 |s2cid= 214323538 }} It is expressed as one of three splice variants in PDAC, with osteopontin-a expressed in nearly all PDAC, osteopontin-b expression correlating with survival, and osteopontin-c correlating with metastatic disease . Because PDAC secretes alternatively spliced forms of osteopontin, it shows potential for tumor- and disease stage-specific targeting. Although the exact mechanisms of osteopontin signaling in PDAC are unknown, it binds to CD44 and integrins to trigger processes such as tumor progression and complement inhibition. Osteopontin also drives metastasis by triggering the release of vascular endothelial growth factor (VEGF) and matrix metalloprotease (MMP), which is inhibited by knocking down osteopontin. This process is also stimulated by nicotine, which is the proposed mechanism by which smokers experience elevated PC risk. Osteopontin is being explored as a marker for PC. It was found to perform better than CA19.9 in discerning IPMN [80] and resectable PDAC from pancreatitis . Antiosteopontin antibodies are being developed, including hu1A12, which inhibited metastasis in an in vivo study and also when hybridized with the anti-VEGF antibody bevacizumab . At least one clinical trial is exploring the use of osteopontin as a marker of intratumoral hypoxia. However, this marker remains relatively unexplored.{{Cite journal | vauthors = Clay R, Siddiqi SA |date=2019-01-01|title=Recent advances in molecular diagnostics and therapeutic targets for pancreatic cancer |journal=Theranostic Approach for Pancreatic Cancer|language=en|pages=325–367|doi=10.1016/B978-0-12-819457-7.00016-5 |isbn=978-0-12-819457-7 | s2cid=214323538 }}

Osteopontin is also implicated in excessive scar-formation and a gel has been developed to inhibit its effect.{{cite journal | vauthors = Mori R, Shaw TJ, Martin P | title = Molecular mechanisms linking wound inflammation and fibrosis: knockdown of osteopontin leads to rapid repair and reduced scarring | journal = The Journal of Experimental Medicine | volume = 205 | issue = 1 | pages = 43–51 | date = January 2008 | pmid = 18180311 | pmc = 2234383 | doi = 10.1084/jem.20071412 }}

{{cite news |date=22 January 2008 |title=Gel 'to speed up wound healing' |work=BBC News |url=http://news.bbc.co.uk/2/hi/health/7199897.stm}}

AOM1, an anti-osteopontin monoclonal antibody drug developed by Pfizer, Inc. to inhibit osteopontin, showed promise at preventing progression of large metastatic tumors in mouse models of NSCLC.{{cite journal | vauthors = Shojaei F, Scott N, Kang X, Lappin PB, Fitzgerald AA, Karlicek S, Simmons BH, Wu A, Lee JH, Bergqvist S, Kraynov E | display-authors = 6 | title = Osteopontin induces growth of metastatic tumors in a preclinical model of non-small lung cancer | journal = Journal of Experimental & Clinical Cancer Research | volume = 31 | pages = 26 | date = March 2012 | issue = 1 | pmid = 22444159 | doi = 10.1186/1756-9966-31-26 | pmc = 3325875 | doi-access = free }}{{cite journal | vauthors = Farrokhi V, Chabot JR, Neubert H, Yang Z | title = Assessing the Feasibility of Neutralizing Osteopontin with Various Therapeutic Antibody Modalities | journal = Scientific Reports | volume = 8 | issue = 1 | pages = 7781 | date = May 2018 | pmid = 29773891 | doi = 10.1038/s41598-018-26187-w | pmc = 5958109 | bibcode = 2018NatSR...8.7781F }}

Even though Opn promotes metastasis and can be used as a cancer biomarker, latest studies described novel protecting functions of the molecule on innate cell populations during tumor development. Particularly, maintenance of a pool of natural killer (NK) cells with optimal immune function is crucial for host defense against cancerous tumor formation. A study in PNAS describes iOpn is an essential molecular component responsible for maintenance of functional NK cell expansion. Absence of iOPN results in failure to maintain normal NK cellularity and increased cell death following stimulation by cytokine IL-15. OPN-deficient NK cells fail to successfully navigate the contraction phase of the immune response, resulting in impaired expansion of long-lived NK cells and defective responses to tumor cells.{{cite journal |vauthors=Leavenworth JW, Verbinnen B, Wang Q, Shen E, Cantor H |title=Intracellular osteopontin regulates homeostasis and function of natural killer cells |journal=Proc Natl Acad Sci U S A |volume=112 |issue=2 |pages=494–9 |date=January 2015 |pmid=25550515 |pmc=4299239 |doi=10.1073/pnas.1423011112 |doi-access=free |bibcode=2015PNAS..112..494L }}

In addition, plasmacytoid dendritic cells (pDCs) protect from melanoma, and this effect is mediated by type I IFNs.{{cite journal |vauthors=Drobits B, Holcmann M, Amberg N, Swiecki M, Grundtner R, Hammer M, Colonna M, Sibilia M |title=Imiquimod clears tumors in mice independent of adaptive immunity by converting pDCs into tumor-killing effector cells |journal=J Clin Invest |volume=122 |issue=2 |pages=575–85 |date=February 2012 |pmid=22251703 |pmc=3266798 |doi=10.1172/JCI61034 }} A study in JCB showed that a specific fragment (SLAYGLR) of the Opn protein can render pDCs more “fit” to protect from melanoma development. This was achieved by activation of a novel α4 integrin/IFN-β axis which is MyD88-independent and operates via a PI3K/mTOR/IRF3 pathway.{{cite journal |vauthors=Simoes DC, Paschalidis N, Kourepini E, Panoutsakopoulou V |title=An integrin axis induces IFN-β production in plasmacytoid dendritic cells |journal=J Cell Biol |volume=221 |issue=9 |pages=e202102055 |date=September 2022 |pmid=35878016 |doi=10.1083/jcb.202102055 |pmc=9354318 }}

= Heart failure =

Osteopontin is minimally expressed under normal conditions, but accumulates quickly as heart function declines.{{cite journal | vauthors = Singh M, Dalal S, Singh K | title = Osteopontin: At the cross-roads of myocyte survival and myocardial function | journal = Life Sciences | volume = 118 | issue = 1 | pages = 1–6 | date = November 2014 | pmid = 25265596 | pmc = 4254317 | doi = 10.1016/j.lfs.2014.09.014 }}{{cite journal | vauthors = Singh M, Foster CR, Dalal S, Singh K | title = Osteopontin: role in extracellular matrix deposition and myocardial remodeling post-MI | journal = Journal of Molecular and Cellular Cardiology | volume = 48 | issue = 3 | pages = 538–543 | date = March 2010 | pmid = 19573532 | doi = 10.1016/j.yjmcc.2009.06.015 | pmc = 2823840 }} Specifically, it plays a central role in the remodeling response to myocardial infarction, and is dramatically upregulated in hypertrophic (HCM) and dilated cardiomyopathy (DCM). Once abundant, it stimulates a wide range of physiological changes in the myocardium, including angiogenesis, local production of cytokines, differentiation of myofibroblasts, increased deposition of extracellular matrix, and hypertrophy of cardiomyocytes. Taken together, these processes remodel the structure of the heart, in effect reducing its ability to function normally, and increasing risk for heart failure.{{cite journal | vauthors = Shirakawa K, Sano M | title = Osteopontin in Cardiovascular Diseases | journal = Biomolecules | volume = 11 | issue = 7 | pages = 1047 | date = July 2021 | pmid = 34356671 | doi = 10.3390/biom11071047 | pmc = 8301767 | doi-access = free }}{{cite journal | vauthors = Graf K, Do YS, Ashizawa N, Meehan WP, Giachelli CM, Marboe CC, Fleck E, Hsueh WA | display-authors = 6 | title = Myocardial osteopontin expression is associated with left ventricular hypertrophy | journal = Circulation | volume = 96 | issue = 9 | pages = 3063–71 | date = November 1997 | pmid = 9386176 | doi = 10.1161/01.CIR.96.9.3063 }}

= Parkinson's disease =

OPN plays a role in oxidative and nitrosative stress, apoptosis, mitochondrial dysfunction, and excitotoxicity, which are also involved in the pathogenesis of Parkinson's disease. PD patients serum and cerebrospinal fluid (CSF) concentrations of OPN were studied, it shows that OPN levels in the body fluid is elevated in PD patients.{{cite journal | vauthors = Maetzler W, Berg D, Schalamberidze N, Melms A, Schott K, Mueller JC, Liaw L, Gasser T, Nitsch C | display-authors = 6 | title = Osteopontin is elevated in Parkinson's disease and its absence leads to reduced neurodegeneration in the MPTP model | journal = Neurobiology of Disease | volume = 25 | issue = 3 | pages = 473–482 | date = March 2007 | pmid = 17188882 | doi = 10.1016/j.nbd.2006.10.020 | s2cid = 30275400 }}

= 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,{{cite journal | vauthors = Porter JD, Khanna S, Kaminski HJ, Rao JS, Merriam AP, Richmonds CR, Leahy P, Li J, Guo W, Andrade FH | display-authors = 6 | title = A chronic inflammatory response dominates the skeletal muscle molecular signature in dystrophin-deficient mdx mice | journal = Human Molecular Genetics | volume = 11 | issue = 3 | pages = 263–272 | date = February 2002 | pmid = 11823445 | doi = 10.1093/hmg/11.3.263 | doi-access = free }}{{cite journal | vauthors = Haslett JN, Sanoudou D, Kho AT, Bennett RR, Greenberg SA, Kohane IS, Beggs AH, Kunkel LM | display-authors = 6 | title = Gene expression comparison of biopsies from Duchenne muscular dystrophy (DMD) and normal skeletal muscle | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 23 | pages = 15000–5 | date = November 2002 | pmid = 12415109 | pmc = 137534 | doi = 10.1073/pnas.192571199 | doi-access = free | bibcode = 2002PNAS...9915000H }}{{cite journal | vauthors = Hirata A, Masuda S, Tamura T, Kai K, Ojima K, Fukase A, Motoyoshi K, Kamakura K, Miyagoe-Suzuki Y, Takeda S | display-authors = 6 | title = Expression profiling of cytokines and related genes in regenerating skeletal muscle after cardiotoxin injection: a role for osteopontin | journal = The American Journal of Pathology | volume = 163 | issue = 1 | pages = 203–215 | date = July 2003 | pmid = 12819025 | pmc = 1868192 | doi = 10.1016/S0002-9440(10)63644-9 }} and has also been shown to increase scarring of diaphragm muscles of aged dystrophic mice.{{cite journal | vauthors = Vetrone SA, Montecino-Rodriguez E, Kudryashova E, Kramerova I, Hoffman EP, Liu SD, Miceli MC, Spencer MJ | display-authors = 6 | title = Osteopontin promotes fibrosis in dystrophic mouse muscle by modulating immune cell subsets and intramuscular TGF-beta | journal = The Journal of Clinical Investigation | volume = 119 | issue = 6 | pages = 1583–94 | date = June 2009 | pmid = 19451692 | pmc = 2689112 | doi = 10.1172/JCI37662 }} A recent study has identified osteopontin as a determinant of disease severity in patients with Duchenne muscular dystrophy.{{cite journal | vauthors = 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 | display-authors = 6 | title = SPP1 genotype is a determinant of disease severity in Duchenne muscular dystrophy | journal = Neurology | volume = 76 | issue = 3 | pages = 219–226 | date = January 2011 | pmid = 21178099 | pmc = 3034396 | doi = 10.1212/WNL.0b013e318207afeb }} 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.

= Hip osteoarthritis =

An increase in Plasma OPN levels has been observed in patients with idiopathic hip OA. Furthermore, a correlation between OPN plasma levels and the severity of the disease has been noted.{{cite journal | vauthors = El Deeb S, Abdelnaby R, Khachab A, Bläsius K, Tingart M, Rath B | title = Osteopontin as a biochemical marker and severity indicator for idiopathic hip osteoarthritis | journal = Hip International | volume = 26 | issue = 4 | pages = 397–403 | date = July 2016 | pmid = 27229171 | doi = 10.5301/hipint.5000361 | s2cid = 40819265 }}

= Fertilized egg implantation =

OPN is expressed in endometrial cells during implantation. Due to the production of progesterone by the ovaries, OPN is up-regulated immensely to aid in this process. The endometrium must undergo decidualization, the process in which the endometrium undergoes changes to prepare for implantation, which will lead to the attachment of the embryo. The endometrium houses stromal cells that will differentiate to produce an optimal environment for the embryo to attach (decidualization). OPN is a vital protein for stromal cell proliferation and differentiation as well as it binds to the receptor αvβ3 to assist with adhesion. OPN along with decidualization ultimately encourages the successful implantation of the early embryo. An OPN gene knock-out results in attachment instability at the maternal-fetal interface.{{cite journal | vauthors = Kang YJ, Forbes K, Carver J, Aplin JD | title = The role of the osteopontin-integrin αvβ3 interaction at implantation: functional analysis using three different in vitro models | journal = Human Reproduction | volume = 29 | issue = 4 | pages = 739–749 | date = April 2014 | pmid = 24442579 | doi = 10.1093/humrep/det433 | doi-access = }}{{cite journal | vauthors = Johnson GA, Burghardt RC, Bazer FW, Spencer TE | title = Osteopontin: roles in implantation and placentation | journal = Biology of Reproduction | volume = 69 | issue = 5 | pages = 1458–71 | date = November 2003 | pmid = 12890718 | doi = 10.1095/biolreprod.103.020651 | doi-access = free }}

References

External links

{{MeshName|Osteopontin}}
{{PDBe-KB2|P10451|Osteopontin}}

Category:Glycoproteins

Category:Extracellular matrix proteins

Category:Matricellular proteins