Osteoprotegerin and osteopontin in aortic aneurysm

Summary

Principal Investigator: J Golledge
Affiliation: James Cook University
Country: Australia
Abstract: Weakening and dilation of the main abdominal artery (aortic aneurysm, AAA) affects 5-10% of men and 1% of women aged over 60 years. The weakening process is usually progressive and without surgical repair the artery can burst usually leading to death. Despite improved medical treatment of artery disease the incidence of this problem is increasing. At present no medication has been clearly shown to halt or slow the artery weakening in humans. The aortic weakening results from inflammation, protein degrading enzymes and loss of vascular smooth muscle cells (VSMC). In this study we investigate the role of two calcium-controlling proteins, osteoprotegerin (OPG) and osteopontin (OPN), in human artery weakening. These proteins are of particular interest because preliminary human, animal and cell studies suggest they may be of critical importance in AAA. The role of OPG and OPN in AAA development and progression will be assessed by a combination of human, animal and cell culture experiments. The effect of variation in the OPG and OPN genes on AAA development and progression will be assessed by genetic analysis of DNA from 4045 participants in the Western Australian AAA study. The influence of OPG and OPN on inflammation, protein degrading enzymes and VSMC loss will be studied in cell culture and an animal model of AAA. Finally, two potential medical treatments for AAA will be assessed as to their effect on OPG and OPN utilizing cell culture and animal studies. Understanding the role of these calcium-controlling proteins in artery weakness and how drug therapy can interfere in these effects is an important step in the development of new treatment for aortic aneurysm.
Funding Period: 2005-06-01 - 2010-05-31
more information: NIH RePORT

Top Publications

  1. ncbi Association of statin prescription with small abdominal aortic aneurysm progression
    Craig D Ferguson
    Vascular Biology Unit, Department of Surgery, School of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia
    Am Heart J 159:307-13. 2010
  2. ncbi Acute aortic dissection
    Jonathan Golledge
    Vascular Biology Unit, School of Medicine, James Cook University, Townsville, Australia
    Lancet 372:55-66. 2008
  3. ncbi Role of homocysteine in aortic calcification and osteogenic cell differentiation
    Ann Van Campenhout
    Vascular Biology Unit, School of Medicine, James Cook University, Townsville, QLD4811, Australia
    Atherosclerosis 202:557-66. 2009
  4. ncbi Use of a covered stent to treat two large false aneurysms of the anterior tibial artery
    Jonathan Golledge
    Vascular Biology Unit, James Cook University, Townsville, Queensland, Australia
    J Vasc Surg 47:1090. 2008
  5. ncbi Measurement and determinants of infrarenal aortic thrombus volume
    Jonathan Golledge
    The Vascular Biology Unit, James Cook University, Townsville, Queensland, 4811, Australia
    Eur Radiol 18:1987-94. 2008
  6. ncbi Reduced expansion rate of abdominal aortic aneurysms in patients with diabetes may be related to aberrant monocyte-matrix interactions
    Jonathan Golledge
    Vascular Biology Unit, Department of Surgery, School of Medicine, James Cook University, Townsville, Qld 4811, Australia
    Eur Heart J 29:665-72. 2008
  7. ncbi Determinants of endothelial function in a cohort of patients with peripheral artery disease
    J Golledge
    Vascular Biology Unit, James Cook University, Townsville, Australia
    Cardiology 111:51-6. 2008
  8. ncbi Angiotensin II type 1 receptor 1166C polymorphism is associated with abdominal aortic aneurysm in three independent cohorts
    Gregory T Jones
    Department of Surgery, University of Otago, New Zealand
    Arterioscler Thromb Vasc Biol 28:764-70. 2008
  9. ncbi Meta-analysis of whole-genome linkage scans for intracranial aneurysm
    Erik Biros
    Vascular Biology Unit, Department of Surgery, School of Medicine, James Cook University, Townsville, 4811 QLD, Australia
    Neurosci Lett 431:31-5. 2008
  10. ncbi Relationship between two sequence variations in the gene for peroxisome proliferator-activated receptor-gamma and plasma homocysteine concentration. Health in men study
    Jonathan Golledge
    The Vascular Biology Unit, Department of Surgery, School of Medicine, James Cook University, Townsville, QLD, 4811, Australia
    Hum Genet 123:35-40. 2008

Scientific Experts

  • J Golledge
  • Gregory T Jones
  • Paul E Norman
  • Robert G Crowther
  • Catherine M Rush
  • Ann Van Campenhout
  • Paula Clancy
  • Craig D Ferguson
  • J V Moxon
  • Alexandra L V Golledge
  • Andrew R Thompson
  • E Biros
  • Lisa N Oliver
  • Jun D Parker
  • Simone Mangan
  • Erik Biros
  • L Smallwood
  • Simone H Mangan
  • Paul Moroz
  • Rumal W Jayalath
  • Tim Buckenham
  • Anthony Dear
  • Philip J Walker
  • Bernard Bourke
  • Adam Parr
  • B R Herbert
  • M P Padula
  • Hieronim Jakubowski
  • Philip Walker
  • P Clancy
  • Jackie A Cooper
  • Steve E Humphries
  • Corey S Moran
  • Hany Hafez
  • B Iacopetta
  • Petra G Buttner
  • Helen Hobson
  • L J Palmer
  • R Allcock
  • F van Bockxmeer
  • N Warrington
  • Max T Q Le
  • Lisa Oliver
  • Rumal Jayalath
  • Peter Jackson
  • Petra Buttner

Detail Information

Publications48

  1. ncbi Association of statin prescription with small abdominal aortic aneurysm progression
    Craig D Ferguson
    Vascular Biology Unit, Department of Surgery, School of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia
    Am Heart J 159:307-13. 2010
    ..Statins have been suggested to reduce expansion of abdominal aortic aneurysms (AAAs) independent of lipid-lowering effects...
  2. ncbi Acute aortic dissection
    Jonathan Golledge
    Vascular Biology Unit, School of Medicine, James Cook University, Townsville, Australia
    Lancet 372:55-66. 2008
    ..Open surgical repair remains the main treatment for dissection in the ascending aorta, whereas endovascular treatment is increasingly being used in dissection that is limited to other parts of the aorta...
  3. ncbi Role of homocysteine in aortic calcification and osteogenic cell differentiation
    Ann Van Campenhout
    Vascular Biology Unit, School of Medicine, James Cook University, Townsville, QLD4811, Australia
    Atherosclerosis 202:557-66. 2009
    ..We examined the relationship between plasma homocysteine and infrarenal aortic calcification, the presence of homocysteine in human atheroma and the influence of homocysteine on osteogenic differentiation in vitro...
  4. ncbi Use of a covered stent to treat two large false aneurysms of the anterior tibial artery
    Jonathan Golledge
    Vascular Biology Unit, James Cook University, Townsville, Queensland, Australia
    J Vasc Surg 47:1090. 2008
  5. ncbi Measurement and determinants of infrarenal aortic thrombus volume
    Jonathan Golledge
    The Vascular Biology Unit, James Cook University, Townsville, Queensland, 4811, Australia
    Eur Radiol 18:1987-94. 2008
    ..Infrarenal aortic thrombus volume can be measured reproducibly on CT. Serum HDL, which can be therapeutically raised, may play a role in discouraging aortic thrombus accumulation with implications in terms of delaying progression of AAA...
  6. ncbi Reduced expansion rate of abdominal aortic aneurysms in patients with diabetes may be related to aberrant monocyte-matrix interactions
    Jonathan Golledge
    Vascular Biology Unit, Department of Surgery, School of Medicine, James Cook University, Townsville, Qld 4811, Australia
    Eur Heart J 29:665-72. 2008
    ..The reason for this difference is unknown. We examined the role of diabetes and glycation on AAA expansion and extracellular matrix-monocyte interactions...
  7. ncbi Determinants of endothelial function in a cohort of patients with peripheral artery disease
    J Golledge
    Vascular Biology Unit, James Cook University, Townsville, Australia
    Cardiology 111:51-6. 2008
    ..The aim of this study was to examine determinants of FMD in a homogenous cohort of patients with PAD...
  8. ncbi Angiotensin II type 1 receptor 1166C polymorphism is associated with abdominal aortic aneurysm in three independent cohorts
    Gregory T Jones
    Department of Surgery, University of Otago, New Zealand
    Arterioscler Thromb Vasc Biol 28:764-70. 2008
    ..This study was undertaken, using the largest case series yet reported, to determine whether common genetic variants of the RAS are associated with either susceptibility or severity of AAA...
  9. ncbi Meta-analysis of whole-genome linkage scans for intracranial aneurysm
    Erik Biros
    Vascular Biology Unit, Department of Surgery, School of Medicine, James Cook University, Townsville, 4811 QLD, Australia
    Neurosci Lett 431:31-5. 2008
    ..The new locus contains a number of potential gene candidates including kininogen-1 precursor, fibroblast growth factor-12 and endothelin converting enzyme 2...
  10. ncbi Relationship between two sequence variations in the gene for peroxisome proliferator-activated receptor-gamma and plasma homocysteine concentration. Health in men study
    Jonathan Golledge
    The Vascular Biology Unit, Department of Surgery, School of Medicine, James Cook University, Townsville, QLD, 4811, Australia
    Hum Genet 123:35-40. 2008
    ..005). Our findings demonstrate a new genotypic association with plasma homocysteine. Replication will be required in other cohorts...
  11. ncbi Polymorphisms of the matrix metalloproteinase 9 gene and abdominal aortic aneurysm
    L Smallwood
    Schools of Surgery, University of Western Australia, Fremantle, Western Australia
    Br J Surg 95:1239-44. 2008
    ..Increased matrix metalloproteinase (MMP) 9 activity has been implicated in the formation of abdominal aortic aneurysm (AAA). The aim was to explore the association between potentially functional variants of the MMP-9 gene and AAA...
  12. ncbi Sequence variant on 9p21 is associated with the presence of abdominal aortic aneurysm disease but does not have an impact on aneurysmal expansion
    Andrew R Thompson
    Department of Cardiovascular Genetics, Rayne Building, UCL, UK
    Eur J Hum Genet 17:391-4. 2009
    ..38 (1.04-1.82) P=0.03), an effect size completely consistent with that originally reported. rs10757278 was not significantly associated with altered AAA growth rate in either cohort...
  13. ncbi A single-nucleotide polymorphism in the gene encoding osteoprotegerin is associated with diastolic blood pressure in older men
    Jonathan Golledge
    Vascular Biology Unit, School of Medicine, James Cook University, Townsville, Australia
    Am J Hypertens 22:1167-70. 2009
    ..We examined the association between single nucleotide polymorphisms (SNPs) in the gene encoding OPG (tumor necrosis factor receptor superfamily, member 11b, TNFRSF11B), with blood pressure in a large cohort of elderly men...
  14. ncbi A systematic review of studies examining inflammation associated cytokines in human abdominal aortic aneurysm samples
    Alexandra L V Golledge
    Vascular Biology Unit, School of Medicine, James Cook University, Townsville, Australia
    Dis Markers 26:181-8. 2009
    ..The aim of this review was to systemically assess previous studies investigating the relative expression of inflammation associated cytokines within human AAA samples...
  15. ncbi Pathophysiology of abdominal aortic aneurysm relevant to improvements in patients' management
    Jonathan Golledge
    The Vascular Biology Unit, School of Medicine, James Cook University, Townsville, Australia
    Curr Opin Cardiol 24:532-8. 2009
    ..In this review recent developments in identifying new diagnostic, prognostic and therapeutic strategies for AAA are discussed...
  16. ncbi A genetic polymorphism in transforming growth factor beta receptor-2 is associated with serum osteopontin
    E Biros
    Vascular Biology Unit, School of Medicine, James Cook University, Townsville, Queensland 4811, Australia
    Int J Immunogenet 36:241-4. 2009
    ..0007) after adjusting for multiple testing. This study suggests that polymorphism in TGFBR2 are associated with altered secretion of OPN, supporting a role for transforming growth factor beta in OPN production...
  17. ncbi Whole genome expression analysis within the angiotensin II-apolipoprotein E deficient mouse model of abdominal aortic aneurysm
    Catherine Rush
    The Vascular Biology Unit, School of Medicine, James Cook University, Townsville, Australia
    BMC Genomics 10:298. 2009
    ..The aim of this study was to investigate genes differentially expressed in aneurysms forming within this mouse model in order to assess the relevance of this model to human AAA...
  18. ncbi Challenges, current status and future perspectives of proteomics in improving understanding, diagnosis and treatment of vascular disease
    J V Moxon
    Vascular Biology Unit, School of Medicine and Dentistry, James Cook University, Townsville, Queensland 4811, Australia
    Eur J Vasc Endovasc Surg 38:346-55. 2009
    ..In this review we outline currently available proteomics techniques, the challenges to using these approaches and modifications which may improve the utilization of proteomics in the study of vascular diseases...
  19. ncbi Possible association between genetic polymorphisms in transforming growth factor beta receptors, serum transforming growth factor beta1 concentration and abdominal aortic aneurysm
    J Golledge
    Vascular Biology Unit, School of Medicine, James Cook University, Townsville, Queensland, Australia
    Br J Surg 96:628-32. 2009
    ..This study examined the possible association between TGF-beta receptor 1 and 2 (TGFBR-1 and -2) single nucleotide polymorphisms (SNPs) and serum TGF-beta1 with AAA...
  20. ncbi Outcome of endovascular treatment of acute type B aortic dissection
    Jun D Parker
    Vascular Biology Unit, School of Medicine, James Cook University, Townsville, Australia
    Ann Thorac Surg 86:1707-12. 2008
    ..Further study of long-term outcomes is required...
  21. ncbi Osteoprotegerin, vascular calcification and atherosclerosis
    Ann Van Campenhout
    Vascular Biology Unit, Department of Surgery, School of Medicine, James Cook University, Townsville, Qld 4811, Australia
    Atherosclerosis 204:321-9. 2009
    ..By integrating the results of recent experimental research, animal models and clinical studies, this review summarises the present understanding of the role of OPG in vascular disease and calcification...
  22. ncbi Identifying the carotid 'high risk' plaque: is it still a riddle wrapped up in an enigma?
    J Golledge
    The Vascular Biology Unit, James Cook University, Townsville, Queensland 4811, Australia
    Eur J Vasc Endovasc Surg 35:2-8. 2008
    ....
  23. ncbi Regarding "Duplex surveillance following carotid surgery: effect of management policy"
    Jonathan Golledge
    J Vasc Surg 46:1087-8; author reply 1088. 2007
  24. ncbi The outcome of endovascular repair of small abdominal aortic aneurysms
    Jonathan Golledge
    Vascular Biology Unit, James Cook University, Townsville, Queensland, Australia
    Ann Surg 245:326-33. 2007
    ..To assess the outcome of endovascular repair (EVAR) of small abdominal aortic aneurysms (AAA, <or=5.5 mm maximum diameter) in Australia...
  25. ncbi Association between osteopontin and human abdominal aortic aneurysm
    Jonathan Golledge
    The Vascular Biology Unit, School of Medicine, James Cook University, Townsville, Queensland, 4811 Australia
    Arterioscler Thromb Vasc Biol 27:655-60. 2007
    ..The relationship between serum concentration of OPN and variants of the OPN gene with human abdominal aortic aneurysm (AAA) was investigated...
  26. ncbi Association of obesity and metabolic syndrome with the severity and outcome of intermittent claudication
    Jonathan Golledge
    Vascular Biology Unit, James Cook University, Townsville, Queensland, Australia
    J Vasc Surg 45:40-6. 2007
    ..The aim of this study was to assess the association between obesity and the severity and outcome of intermittent claudication...
  27. ncbi Assessment of a serum assay for quantification of abdominal aortic calcification
    Paula Clancy
    Arterioscler Thromb Vasc Biol 26:2574-6. 2006
  28. ncbi Abdominal aortic aneurysm: pathogenesis and implications for management
    Jonathan Golledge
    The Vascular Biology Unit, School of Medicine, James Cook University, Townsville, Queensland 4811, Australia
    Arterioscler Thromb Vasc Biol 26:2605-13. 2006
    ..Well designed large multicenter randomized controlled trials are required to examine the medical treatment of AAA...
  29. ncbi The small abdominal aortic aneurysm: conservative management or endovascular repair
    J Golledge
    Eur J Vasc Endovasc Surg 32:333. 2006
  30. ncbi Screening for abdominal aortic aneurysms: more benefit than cost
    P E Norman
    Eur J Vasc Endovasc Surg 32:7-8. 2006
  31. ncbi Quantification of abdominal aortic calcification on CT
    Rumal W Jayalath
    Arterioscler Thromb Vasc Biol 26:429-30. 2006
  32. ncbi The small abdominal aortic aneurysm
    J Golledge
    The Vascular Biology Unit, James Cook University, Townsville, Qld 4811, Australia
    Eur J Vasc Endovasc Surg 31:237-8. 2006
  33. ncbi Outcome assessment for intermittent claudication
    J Golledge
    Eur J Vasc Endovasc Surg 31:44-5. 2006
  34. ncbi A meta-analysis of randomised controlled trials assessing drug-eluting stents and vascular brachytherapy in the treatment of coronary artery in-stent restenosis
    Lisa N Oliver
    The Vascular Biology Unit, James Cook University, Townsville, Queensland, 4811, Australia
    Int J Cardiol 126:216-23. 2008
    ..We undertook a meta-analysis of randomised trials assessing the outcome of vascular brachytherapy (VBT) or DES for the treatment of coronary artery ISR...
  35. ncbi Homocysteine and abdominal aortic aneurysms
    Paul Moroz
    School of Surgery and Pathology, University of Western Australia, Fremantle Hospital, Perth, Western Australia, Australia
    ANZ J Surg 77:329-32. 2007
    ..Further research is needed, given the potential benefit that simple vitamin supplementation may have for patients with AAA...
  36. ncbi Obesity, adipokines, and abdominal aortic aneurysm: Health in Men study
    Jonathan Golledge
    Vascular Biology Unit, Department of Surgery, School of Medicine, James Cook University, Townsville, QLD, Australia 4811
    Circulation 116:2275-9. 2007
    ..Obesity is associated with occlusive artery disease but is not considered a risk factor for abdominal aortic aneurysm (AAA). We investigated the association between anthropometric measures of obesity, serum adipokines, and AAA...
  37. ncbi Asymptomatic carotid stenosis
    Jonathan Golledge
    Stroke 38:e150. 2007
  38. ncbi Modulation of endothelial cell thrombomodulin by PPAR ligands--variation according to environment
    Simone Mangan
    Vascular Biology Unit, School of Medicine, James Cook University, Townsville, Queensland, 4811, Australia
    Thromb Res 121:827-34. 2008
    ..We investigated the effects of the peroxisome proliferator-activated receptor (PPAR) ligands, fenofibrate and rosiglitazone, on the expression of TM ex vivo by advanced carotid atheromas, and in vitro by endothelial cells...
  39. ncbi Bone marrow-derived cells and arterial disease
    Jonathan Golledge
    Vascular Biology Unit, School of Medicine, James Cook University, Townsville, Queensland, Australia
    J Vasc Surg 46:590-600. 2007
    ..Further understanding of the link between bone and artery pathophysiology is likely to be of significant value in developing new therapies for vascular disease...
  40. ncbi Osteoprotegerin upregulates endothelial cell adhesion molecule response to tumor necrosis factor-alpha associated with induction of angiopoietin-2
    Simone H Mangan
    Vascular Biology Unit, Department of Surgery, School of Medicine, James Cook University, Townsville, 4811 Australia
    Cardiovasc Res 76:494-505. 2007
    ..We studied the influence of OPG and OPN on endothelial adhesion molecule expression and monocyte binding...
  41. ncbi Relationship between CT anthropometric measurements, adipokines and abdominal aortic calcification
    Jonathan Golledge
    Vascular Biology Unit, School of Medicine, James Cook University, Townsville, Qld 4811, Australia
    Atherosclerosis 197:428-34. 2008
    ..Visceral obesity and aortic calcification are both associated with cardiovascular events. The purpose of this study was to examine if visceral obesity was associated with the severity of abdominal aortic calcification...
  42. ncbi Serum osteoprotegerin as a biomarker for vascular disease
    Ann Van Campenhout
    Am J Cardiol 100:561. 2007
  43. ncbi Relationship between temporal-spatial gait parameters, gait kinematics, walking performance, exercise capacity, and physical activity level in peripheral arterial disease
    Robert G Crowther
    Institute of Sport and Exercise Science, James Cook University, Townsville Hospital, Queensland, Australia
    J Vasc Surg 45:1172-8. 2007
    ....
  44. ncbi Medical management of abdominal aortic aneurysm
    J Golledge
    Vascular Biology Unit, School of Medicine, James Cook University, Townsville, Australia 4811
    Eur J Vasc Endovasc Surg 34:267-73. 2007
    ..Medical management also is required to reduce peri-operative risks and stabilise endovascular aneurysm repair. Whilst some of the therapies targeting cardiovascular risk reduction may be helpful, other emerging strategies are discussed...
  45. ncbi Matrix biology of abdominal aortic aneurysms in diabetes: mechanisms underlying the negative association
    Paul E Norman
    School of Surgery and Pathology, University of Western Australia, Fremantle, Western Australia
    Connect Tissue Res 48:125-31. 2007
    ..The aim of our present minireview is to compare the changes in matrix biology seen in diabetes and AAA and to explore molecular mechanisms that may explain the negative association and identify possible therapeutic implications...
  46. ncbi Local therapy for restenosis
    J Golledge
    Eur J Vasc Endovasc Surg 30:571-2. 2005