Cytokines & Cells Online Pathfinder Encyclopaedia
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ALTERNATIVE NAMES
The name osteopontin was proposed for the bone-specific sialoprotein following isolation of its cDNA. This protein has been isolated from various species and has been described under a variety of different names:
2ar,
2B7 mRNA,
44K BPP (44 kDa bone phosphoprotein),
66 kDa BPP (66 kDa bone phosphoprotein),
bone sialoprotein-1 (bone sialoprotein; abbr. BSP, BSPI),
Calcium oxalate crystal growth inhibitor protein,
Eta-1 [early T-lymphocyte activation protein 1],
M11
Nephropontin
Spp-1 (Secreted Phosphoprotein-1),
OTS5
transformation-associated secreted phosphoprotein,
transformation-related phosphoprotein,
tumor-secreted phosphoprotein,
urinary stone protein,
Uropontin
SOURCES
Osteopontin is an extracellular matrix cell adhesion protein which is abundant in bone and which is synthesized by preosteoblasts, osteoblasts and osteoclastic cells that are localized in the mineralized phase of bone matrix. In osteoblastic cells expression of Osteopontin mRNA is upregulated by growth and differentiation factors (PDGF, EGF, TGF-beta and BMP7) and by mechanical stress, which promote bone formation, as well as by osteotropic hormones (retinoic acid and vitamin D3), which can promote bone resorption and remodelling. Calcitonin has been shown to inhibit osteopontin mRNA expression in isolated rabbit osteoclasts. The protein is abundant also in milk, and urine and is found also in malignant tissues. Osteopontin mRNA expression is not restricted to tissues involved in phosphate metabolism.
In the rat osteopontin is found also in considerable amounts in kidney. In the mouse high levels of osteopontin expression are also seen in the bone marrow-derived granulated metrial gland cells of the deciduum and placenta, and in a number of specialized epithelial tissues, including embryonic and postnatal kidney tubules, uterine epithelium and sensory epithelium of the embryonic ear. It is synthesized also by odontoblasts, certain bone marrow cells and hypertrophic chondrocytes.
PROTEIN CHARACTERISTICS
Osteopontin is an acidic, phosphorylated, sialic acid-rich Ca2+ binding protein. Osteopontin contains a signal sequence and is a secreted protein. Multiple interactions with Ca2+ most likely influence protein conformation and may be important in processes mediate or dependent on Ca2+.
Osteopontin probably exists in tissue-specific isoforms that may correspond to particular cellular functions. Multiple truncated forms of the protein, generated among other things, by cleavage by thrombin, and forms with different post-translational modifications have been described. Several lines of evidence suggest that cleavage of Osteopontin by thrombin occurs in vivo, such as in tumors and at sites of tissue injury, and such cleavage may be important in the regulation of Osteopontin function. Bone osteopontin is extremely heterogeneous with respect to post-translational modification. It differs from bovine milk osteopontin in which 28 residues are completely phosphorylated. Normal rat kidney cells secrete both phosphorylated and nonphosphorylated forms of osteopontin into the conditioned medium. These forms also show different physiological properties.
The several forms of the protein appear to be regulated differentially in normal and transformed cells through both transcriptional and posttranscriptional mechanisms by osteotropic hormones, growth factors and tumor promoters such as 12-O-tetradecanoyl-phorbol-13-acetate.
GENE STRUCTURE
The human gene has been mapped to chromosome 4q. The murine gene maps to a locus on murine chromosome 5 (see: Eta-1).
RECEPTORS
The protein contains an Arg-Gly-Asp sequence, which serves as a cell adhesion sequence that recognizes integrin-alpha-V / integrin-beta-3. Mutagenesis of this sequence in recombinant osteopontin causes it to lose its cell adhesion ability. Osteopontin also appears to bind to various other integrins. Osteopontin also binds to components of the extracellular matrix but the sequence motif involved has been characterized only insufficiently.
In addition to integrin-alpha-V / integrin-beta-3 (a vitronectin receptor), integrin-alpha-V / integrin-beta-5 and integrin-alpha-V / integrin-beta-1 are osteopontin receptors. Osteopontin has been identified as a ligand for CD44. The receptor-ligand interaction mediates chemotaxis or attachment, depending on presentation of osteopontin in soluble or immobilized form. Secretion of osteopontin and expression of CD44 may cause migration of tumor cells to specific sites of metastasis formation.
BIOLOGICAL ACTIVITIES
The wide spectrum of biological activities is revealed by the plethora of different names. The protein plays a wider role in processes that are not confined to bone development, remodeling, and resorption. Osteopontin has been shown to inhibit the growth of calcium oxalate crystals by disruption of the growing crystal lattice (see also: Calcium oxalate crystal growth inhibitor protein). The presence of osteopontin in normal artery walls and its increased expression after injury suggests a role for this protein in the vascular system.
In vascular endothelial cells expression of Osteopontin and its integrin receptors is induced by VEGF and this probably directly influences migration of endothelial cells during angiogenesis. Osteopontin is involved in recruiting and stimulating macrophages and lymphocytes as part of a nonspecific response to microbial infections. Murine macrophages cell lines and resident macrophages show various levels of expression of the osteopontin gene, which can be enhanced by a variety of macrophage stimulating agents. Tumor-cell-derived Osteopontin may function to protect tumor cells from macrophage mediated destruction since Osteopontin inhibits nitric oxide production and cytotoxicity by activated RAW264.7 macrophages. Osteopontin suppresses nitric oxide synthesis induced by the inflammatory mediators IFN-gamma and bacterial lipopolysaccharides in primary mouse kidney proximal tubule epithelial cells and may thus be an important regulator of the NO signaling pathway and NO mediated cytotoxic processes. Osteopontin is synthesized also by T-lymphocytes after cell activation. Expression of mRNA for Osteopontin has been shown to be upregulated during the activation of NK-cells.
Enhanced secretion of osteopontin is observed after transformation of a wide variety of mammalian fibroblasts and epithelial cells and this is correlated often with tumorigenicity, suggesting a role for osteopontin in carcinogenesis. Osteopontin and fragments obtained by cleavage with thrombin also promote cell migration and the adhesion of a variety of cell types at the tumor/host interface and thereby may influence processes such as invasion and metastasis. Studies with the rat mammary epithelial cell line, Rama 37, which yields benign, non-metastasizing adenomatous tumours in syngeneic Furth-Wistar rats have shown that increasing the expression of Osteopontin appears to be sufficient to produce a metastatic phenotype in this particular rat mammary model. A role for Osteopontin in tumor progression is suggested by the observed association of increased Osteopontin expression with increased malignancy in breast cancer. Overexpression of the osteopontin gene is observed also in 100 % of squamous-cell carcinomas and in 58 % of adenocarcinomas relative to matched normal esophageal mucosa. Osteopontin mRNA and proteins are expressed in human glioma cells, and it has been suggested that the extent of expression may correlate with the malignancy grade of gliomas. Osteopontin overexpression is associated with proliferation of smooth muscle cells (see: M11).
Osteopontin promotes attachment and spreading of fibroblasts and osteoblasts to substratum. Osteopontin promotes vascular cell adhesion and spreading and is chemotactic for smooth muscle cells in vitro. Osteopontin expression in vascular smooth muscle cells is regulated by PDGF through the beta-type PDGF receptor in vitro, and possibly in vivo in situations that involve PDGF released from platelets or other cellular sources.
In several cell lines of fibroblasts and epithelial-derived cell lines in culture the expression of murine osteopontin mRNA is regulated by the osteotropic hormones dexamethasone and 1,25-dihydroxyvitamin D3. TGF-beta-1 and TGF-beta-2 have been shown to increase the rate of transcription of the osteopontin gene in rat osteoblastic osteosarcoma ROS 17/2.8 cells. bFGF increases osteopontin mRNA in ROS 17/2.8 cells, independent of growth stimulation. Expression of the osteopontin gene in ROS17/2.8 cells is elevated also by Endothelin-1. IL1-alpha, TNF-alpha, LIF, bacterial lipopolysaccharides, and 1,25-dihydroxyvitamin D3 have been shown to increase osteopontin mRNA expression in both a mouse osteoblastic cell line (MC3T3-E1) and mouse primary osteoblast-like cells.
Osteopontin has been shown to be a component of the human atherosclerotic plaque and may be a mediator of arterial neointima formation (see also: 2B7). It is synthesized by macrophage, smooth muscle, and endothelial cells in primary and restenotic human coronary atherosclerotic plaques and may contribute to cellular accumulations and dystrophic calcification in atherosclerotic plaques.
In the hamster, osteopontin is expressed in heritably cardiomyopathic hearts under conditions of chronic injury and repair, and the source of ostopontin message appears to be issue macrophage-like cells in foci of inflammation.
Osteopontin may playa role in granulomatous inflammation through the regulation of processes such as migration of histiocytes, cell adhesion, and cellular functions including phagocytosis, as it has been shown to be expressed strongly in histiocytes in granulomas of diverse etiology.
TRANSGENIC ANIMALS, KNOCK-OUT, AND ANTISENSE STUDIES
Tani-Ishii et al (1997) have shown that Osteopontin antisense RNA can inhibit bone resorption by mouse osteoclasts in vitro. The expression of antisense Osteopontin RNA in a murine metastatic, ras-transformed NIH 3T3 cell line (PAP2 cells) shows that in vivo expression of antisense Osteopontin RNA is associated with reduced tumorigenicity. Expression of an Osteopontin antisense mRNA malignant B77 Rat1 fibroblasts expressing high levels of Osteopontin reduces Osteopontin secretion and reduces the ability of these cells to form both lung tumors in nude mice after intravenous injection, and colonies in soft agar (see also: Colony formation assay).
Studies with antisense RNA blocking expression of the Osteopontin gene show that the autocrine secretion of Osteopontin appears to play an important role in adhesion, spreading, and invasion of vascular smooth muscle cells.
LAST MODIFIED: January 2002
See REFERENCES for entry Osteopontin
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