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The role of bone morphogenetic protein 7 in the pathophysiology and treatment of vascular calcification associated with chronic renal failure.

Davies, M.R.; (2006) The role of bone morphogenetic protein 7 in the pathophysiology and treatment of vascular calcification associated with chronic renal failure. Doctoral thesis , University of London. Green open access

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Abstract

Vascular calcification (VC) is an important complication of chronic renal failure (CRF), and a risk factor for reduced survival. Osteoblast-like cells in the vessel wall derived from resident vascular smooth muscle cells (VSMC) are considered central to the pathogenesis of VC, which is exacerbated by mineral ion abnormalities inherent in renal osteodystrophy (ROD). Nevertheless, its aetiology is incompletely understood, and no effective therapies exist. Recently, CRF has been characterised as a state of Bone Morphogenetic Protein 7 (BMP7) deficiency, and animal studies have shown that administration of this renal morphogen is efficacious in treating several aspects of renal failure, including progressive renal fibrosis and ROD. The hypothesis of this thesis is that BMP7 deficiency contributes to the pathogenesis of VC, by facilitating the emergence of the osteoblast-like cell, and that exogenous BMP7 administration abrogates it by normalising VSMC behaviour. This hypothesis was tested in atherosclerotic Low Density Lipoprotein Receptor Null (ldlf/j) mice. Uraemia was superimposed surgically to generate VC. Animals received BMP7 or vehicle over 15 weeks. Untreated uraemic animals had increased VC on histological and chemical grounds, and demonstrated increased expression of the characteristic osteoblast protein osteocalcin was demonstrated in vascular tissues. Both changes were reversed by BMP7 administration. Uraemic animals were shown to have an adynamic form of ROD, also reversed by BMP7 administration, suggesting that normalisation of mineral ion abnormalities may underlie the benefits of BMP7 on VC in CRF. In addition, in vitro studies showed that BMP7 can act directly on vascular cells to reduce extracellular calcification under conducive conditions. Finally, in an appendix, preliminary data is presented showing that expression of LRP5, a protein involved in the control of normal bone mineralization, may be increased in Idlf1 animals, suggesting that consequences of this genotype may be important to VC pathogenesis in this model.

Type: Thesis (Doctoral)
Title: The role of bone morphogenetic protein 7 in the pathophysiology and treatment of vascular calcification associated with chronic renal failure.
Identifier: PQ ETD:592020
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/1444711
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