Osteonectin
- Not to be confused with Osteocalcin or Osteopontin.
Osteonectin (ON) also known as secreted protein acidic and rich in cysteine (SPARC) or basement-membrane protein 40 (BM-40) is a protein that in humans is encoded by the SPARC gene.
Osteonectin is a glycoprotein in the bone that binds calcium. It is secreted by osteoblasts during bone formation, initiating mineralization and promoting mineral crystal formation. Osteonectin also shows affinity for collagen in addition to bone mineral calcium. A correlation between osteonectin over expression and ampullary cancers and chronic pancreatitis has been found.
Gene
The human SPARC gene is 26.5 kb long, and contains 10 exons and 9 introns and is located on chromosome 5q31-q33.
Structure
Osteonectin is a glycoprotein of 40 kD. Osteonectin is an acidic, cysteine-rich glycoprotein consisting of a single polypeptide chain that can be broken into 4 domains: 1) an Ca++ binding domains near the glutamic acidic-rich region at the amino terminus (domain I), 2) a cysteine- rich (domain II), 3) a hydrophilic region (domain III) and 4) an EF hand motif at the carboxy terminus region (domain IV).[1]
At least the domains at the amino and carboxy terminus appear to contain calcium-binding regions.
Function
Osteonectin is an acidic extracellular matrix glycoprotein that plays a vital role in bone mineralization, cell-matrix interactions, and collagen binding. Osteonectin also increases the production and activity of matrix metalloproteinases, a function important to invading cancer cells within bone. Additional functions of osteonectin beneficial to tumor cells include angiogenesis, proliferation and migration. Overexpression of osteonectin is reported in many human cancers such as breast, prostate and colon.[2]
This molecule has been implicated in several biological functions, including mineralization of bone and cartilage, inhibiting mineralization, modulation of cell proliferation, facilitation of acquisition of differentiated phenotype and promotion of cell attachment and spreading.
A number of phosphoproteins and glycoproteins are found in bone. The phosphate is bound to the protein backbone through serine or threonine amino acid residues. The best characterized of these bone protein is osteonectin. It binds collagen and hydroxyapatite through separate areas of its molecule, is found in relatively large amounts in immature bone and promotes mineralization of collagen. Thus it is possible that osteonectin plays a crucial role in mineralization.
Tissue distribution
Fibroblasts, including periodontal fibroblasts, synthesize osteonectin.[3] This protein is synthesized by macrophages at sites of wound repair and platelet degranulation so it may play an important role in wound healing. SPARC does not support cell attachment and like thrombospondin and tenascin, it antiadhesive and an inhibitor of cell spreading. It distrupt focal adhesion in fibroblasts. Also regulates the proliferation of some cells especially the endothelial cells, and it mediate this effect through its ability to bind to cytokines and growth factors.[4] Osteonectin has also been found decrease DNA synthesis in cultured bone.[5]
High levels of immunodetectable osteonectin are found in active osteoblasts and marrow progenitor cells, odontoblasts, periodontal ligament and gingival cells and some chondrocytes and hypertrophic chondrocytes. Osteonectin is also detectable in osteoid, bone matrix proper and dentin. Osteonectin has been localized in a variety of tissues, it is found in greatest abundance in osseous tissue, tissues characterized by high turnover (such as intestinal epithelium), basement membranes and certain neoplasms. Osteonectin is expressed by a wide variety of cells including chondrocytes, fibroblasts, platelets, endothelial cells, epithelial cells, Leydig cells, Sertoli cells, luteal cells, adrenal cortical cells and numerous neoplastic cell lines (such as SaOS-2 cells from human osteosarcoma).
Model organisms
| Characteristic | Phenotype |
|---|---|
| Homozygote viability | Normal |
| Homozygous Fertility | Normal |
| Body weight | Normal |
| Anxiety | Normal |
| Neurological assessment | Normal |
| Grip strength | Normal |
| Hot plate | Normal |
| Dysmorphology | Abnormal[6] |
| Indirect calorimetry | Normal |
| Glucose tolerance test | Normal |
| Auditory brainstem response | Normal |
| DEXA | Abnormal[7] |
| Radiography | Abnormal[8] |
| Body temperature | Normal |
| Eye morphology | Abnormal[9] |
| Clinical chemistry | Normal |
| Plasma immunoglobulins | Normal |
| Haematology | Normal |
| Peripheral blood lymphocytes | Normal |
| Micronucleus test | Normal |
| Heart weight | Normal |
| Brain histopathology | Normal |
| Eye Histopathology | Abnormal |
| MicroCT & Quantitative Faxitron | Abnormal |
| Salmonella infection | Normal[10] |
| Citrobacter infection | Normal[11] |
| All tests and analysis from[12][13] |
Model organisms have been used in the study of SPARC function. A conditional knockout mouse line, called Sparctm1a(EUCOMM)Wtsi[14][15] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[16][17][18]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[12][19] Twenty six tests were carried out on mutant mice and six significant abnormalities were observed.[12] Homozygous mutant animals had unusually white incisors, decreased bone mineral density, abnormal lens morphology, cataracts and a decreased length of long bones.[12]
References
- ↑ Villarreal XC, Mann KG, Long GL (July 1989). "Structure of human osteonectin based upon analysis of cDNA and genomic sequences". Biochemistry 28 (15): 6483–91. doi:10.1021/bi00441a049. PMID 2790009.
- ↑ Guweidhi A, Kleeff J, Adwan H, Giese NA, Wente MN, Giese T, Büchler MW, Berger MR, Friess H (August 2005). "Osteonectin influences growth and invasion of pancreatic cancer cells". Ann. Surg. 242 (2): 224–234. doi:10.1097/01.sla.0000171866.45848.68. PMC 1357728. PMID 16041213.
- ↑ Wasi S, Otsuka K, Yao KL, Tung PS, Aubin JE, Sodek J, Termine JD (June 1984). "An osteonectinlike protein in porcine periodontal ligament and its synthesis by periodontal ligament fibroblasts". Can. J. Biochem. Cell Biol. 62 (6): 470–8. PMID 6380686.
- ↑ Young MF, Kerr JM, Ibaraki K, Heegaard AM, Robey PG (August 1992). "Structure, expression, and regulation of the major noncollagenous matrix proteins of bone". Clin. Orthop. Relat. Res. (281): 275–94. PMID 1499220.
- ↑ Lane TF, Sage EH (February 1994). "The biology of SPARC, a protein that modulates cell-matrix interactions". FASEB J. 8 (2): 163–73. PMID 8119487.
- ↑ "Dysmorphology data for Sparc". Wellcome Trust Sanger Institute.
- ↑ "DEXA data for Sparc". Wellcome Trust Sanger Institute.
- ↑ "Radiography data for Sparc". Wellcome Trust Sanger Institute.
- ↑ "Eye morphology data for Sparc". Wellcome Trust Sanger Institute.
- ↑ "Salmonella infection data for Sparc". Wellcome Trust Sanger Institute.
- ↑ "Citrobacter infection data for Sparc". Wellcome Trust Sanger Institute.
- ↑ 12.0 12.1 12.2 12.3 Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x.
- ↑ Mouse Resources Portal, Wellcome Trust Sanger Institute.
- ↑ "International Knockout Mouse Consortium".
- ↑ "Mouse Genome Informatics".
- ↑ Skarnes, W. C.; Rosen, B.; West, A. P.; Koutsourakis, M.; Bushell, W.; Iyer, V.; Mujica, A. O.; Thomas, M.; Harrow, J.; Cox, T.; Jackson, D.; Severin, J.; Biggs, P.; Fu, J.; Nefedov, M.; De Jong, P. J.; Stewart, A. F.; Bradley, A. (2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature 474 (7351): 337–342. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
- ↑ Dolgin E (2011). "Mouse library set to be knockout". Nature 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
- ↑ Collins FS, Rossant J, Wurst W (2007). "A Mouse for All Reasons". Cell 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
- ↑ van der Weyden L, White JK, Adams DJ, Logan DW (2011). "The mouse genetics toolkit: revealing function and mechanism.". Genome Biol 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC 3218837. PMID 21722353.
Further reading
- Yan Q, Sage EH (1999). "SPARC, a matricellular glycoprotein with important biological functions". J. Histochem. Cytochem. 47 (12): 1495–506. doi:10.1177/002215549904701201. PMID 10567433.
- Altura BM (1975). "Pharmacological effects of alpha-methyldopa, alpha-methylnorepinephrine, and octopamine on rat arteriolar, arterial, and terminal vascular smooth". Circ. Res. 36 (6 Suppl 1): 233–40. PMID 1093755.
- Raines EW, Lane TF, Iruela-Arispe ML et al. (1992). "The extracellular glycoprotein SPARC interacts with platelet-derived growth factor (PDGF)-AB and -BB and inhibits the binding of PDGF to its receptors". Proc. Natl. Acad. Sci. U.S.A. 89 (4): 1281–1285. doi:10.1073/pnas.89.4.1281. PMC 48433. PMID 1311092.
- Mundlos S, Schwahn B, Reichert T, Zabel B (1992). "Distribution of osteonectin mRNA and protein during human embryonic and fetal development". J. Histochem. Cytochem. 40 (2): 283–91. doi:10.1177/40.2.1552170. PMID 1552170.
- Kelm RJ, Mann KG (1990). "Human platelet osteonectin: release, surface expression, and partial characterization". Blood 75 (5): 1105–13. PMID 2306517.
- Young MF, Day AA, Dominquez P et al. (1990). "Structure and expression of osteonectin mRNA in human tissue". Connect. Tissue Res. 24 (1): 17–28. doi:10.3109/03008209009152419. PMID 2338025.
- Metsäranta M, Young MF, Sandberg M et al. (1989). "Localization of osteonectin expression in human fetal skeletal tissues by in situ hybridization". Calcif. Tissue Int. 45 (3): 146–152. doi:10.1007/BF02556057. PMID 2505905.
- Sage H, Vernon RB, Funk SE et al. (1989). "SPARC, a secreted protein associated with cellular proliferation, inhibits cell spreading in vitro and exhibits Ca+2-dependent binding to the extracellular matrix". J. Cell Biol. 109 (1): 341–356. doi:10.1083/jcb.109.1.341. PMC 2115491. PMID 2745554.
- Swaroop A, Hogan BL, Francke U (1988). "Molecular analysis of the cDNA for human SPARC/osteonectin/BM-40: sequence, expression, and localization of the gene to chromosome 5q31-q33". Genomics 2 (1): 37–47. doi:10.1016/0888-7543(88)90107-3. PMID 2838412.
- Wewer UM, Albrechtsen R, Fisher LW et al. (1988). "Osteonectin/SPARC/BM-40 in human decidua and carcinoma, tissues characterized by de novo formation of basement membrane". Am. J. Pathol. 132 (2): 345–55. PMC 1880722. PMID 3400777.
- Clezardin P, Malaval L, Ehrensperger AS et al. (1988). "Complex formation of human thrombospondin with osteonectin". Eur. J. Biochem. 175 (2): 275–284. doi:10.1111/j.1432-1033.1988.tb14194.x. PMID 3402455.
- Lankat-Buttgereit B, Mann K, Deutzmann R et al. (1988). "Cloning and complete amino acid sequences of human and murine basement membrane protein BM-40 (SPARC, osteonectin)". FEBS Lett. 236 (2): 352–356. doi:10.1016/0014-5793(88)80054-1. PMID 3410046.
- Stenner DD, Tracy RP, Riggs BL, Mann KG (1986). "Human platelets contain and secrete osteonectin, a major protein of mineralized bone". Proc. Natl. Acad. Sci. U.S.A. 83 (18): 6892–6896. doi:10.1073/pnas.83.18.6892. PMC 386616. PMID 3489235.
- Jundt G, Berghäuser KH, Termine JD, Schulz A (1987). "Osteonectin--a differentiation marker of bone cells". Cell Tissue Res. 248 (2): 409–15. PMID 3581152.
- Fisher LW, Hawkins GR, Tuross N, Termine JD (1987). "Purification and partial characterization of small proteoglycans I and II, bone sialoproteins I and II, and osteonectin from the mineral compartment of developing human bone". J. Biol. Chem. 262 (20): 9702–8. PMID 3597437.
- Sage H, Johnson C, Bornstein P (1984). "Characterization of a novel serum albumin-binding glycoprotein secreted by endothelial cells in culture". J. Biol. Chem. 259 (6): 3993–4007. PMID 6368555.
- Termine JD, Kleinman HK, Whitson SW et al. (1982). "Osteonectin, a bone-specific protein linking mineral to collagen". Cell 26 (1 Pt 1): 99–105. doi:10.1016/0092-8674(81)90037-4. PMID 7034958.
- Xie RL, Long GL (1995). "Role of N-linked glycosylation in human osteonectin. Effect of carbohydrate removal by N-glycanase and site-directed mutagenesis on structure and binding of type V collagen". J. Biol. Chem. 270 (39): 23212–7. doi:10.1074/jbc.270.39.23212. PMID 7559469.
- Maurer P, Hohenadl C, Hohenester E et al. (1995). "The C-terminal portion of BM-40 (SPARC/osteonectin) is an autonomously folding and crystallisable domain that binds calcium and collagen IV". J. Mol. Biol. 253 (2): 347–357. doi:10.1006/jmbi.1995.0557. PMID 7563094.
External links
- Osteonectin at the US National Library of Medicine Medical Subject Headings (MeSH)
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