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Permanent link (DOI): https://doi.org/10.7939/R3ZT16

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Novel Imaging Tracers of Bone Turnover for the Early Diagnosis of Osteoarthritis Open Access

Descriptions

Other title
Subject/Keyword
Osteoarthritis
Animal model
Synchrotron
micro-CT
Celecoxib
Iron oxide nanoparticles
MRI
Diagnosis
Strontium ranelate
Bisphosphonate
Glucosamine
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Panahifar, Arash
Supervisor and department
Walter Maksymowych (Division of Rheumatology)
Robert Lambert (Radiology & Diagnostic Imaging)
Michael Doschak (Faculty of Pharmacy)
Examining committee member and department
Michael Doschak (Faculty of Pharmacy and Pharmaceutical Sciences)
Walter Maksymowych (Division of Rheumatology)
Benjamin Boyd (Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Australia)-External examiner
Robert Lambert (Radiology & Diagnostic Imaging)
Afsaneh Lavasanifar (Faculty of Pharmacy and Pharmaceutical Sciences)
Jacob Jaremko (Radiology & Diagnostic Imaging))
Department
Faculty of Pharmacy and Pharmaceutical Sciences
Specialization
Pharmaceutical Sciences
Date accepted
2014-08-14T10:50:59Z
Graduation date
2014-11
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Osteoarthritis (OA) is characterized by progressive destruction of articular cartilage, subchondral bone sclerosis, and osteophyte formation. Currently there is no disease modifying drug for treatment of OA. Usually OA is not diagnosed until the advanced stages, where palliative treatment is the only option. Early diagnosis of OA is thought to play a critical role in the management of OA. The etiology of OA is not well-understood, however, studies suggest that early increased turnover in the subchondral bone precedes the degeneration of overlying articular cartilage. The objectives of this thesis were firstly to develop and characterize an animal model of post-traumatic OA (PTOA), and secondly to develop and characterize novel tracers of bone turnover for early diagnosis of OA. PTOA was surgically induced in skeletally mature rats. Pathological changes were monitored and characterized utilizing micro-MRI, micro-CT and histology; resulting in development of a comprehensive scoring system for evaluation of OA in pre-clinical animal models. Secondary to the objectives of the thesis, this system was used to evaluate the efficacy of several therapeutic compounds. The feasibility of using stable strontium as a surrogate for calcium and a tracer of bone turnover was evaluated. After OA induction rats received strontium ranelate as a bioavailable source of elemental strontium at sub-therapeutic doses. Distribution of strontium on bony tissues were assessed ex vivo at 2D and 3D using electron probe micro-analysis (EPMA), and synchrotron dual energy K-edge subtraction micro-CT (KES), respectively. The main bone adaptations detected were formation of osteophytes and subchondral bone sclerosis. Although very sensitive and accurate, these methodologies remain mainly as ex vivo methods. Therefore, we further aimed to develop a bone-targeting MRI contrast agent with potential for in vivo application in humans. For that purpose superparamagnetic iron oxide nanoparticles (SPIONs) were synthesized and subsequently conjugated with bisphosphonate molecules. In vivo micro-MRI revealed accumulation of the tracer in the subchondral bone plate at the early stages of OA progression (i.e., 2-3 weeks post-surgery) before manifestation on radiography. This non-ionizing MR-based bone tracer can provide information on the cellular events at bone (i.e., functional imaging) while providing anatomical information about the cartilage-bone compartment.
Language
English
DOI
doi:10.7939/R3ZT16
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Panahifar A, Mahmoudi M, Doschak MR. Synthesis and in vitro evaluation of bone-seeking superparamagnetic iron oxide nanoparticles as contrast agents for imaging bone metabolic activity. ACS Appl Mater Interfaces. 2013 Jun 12;5(11):5219-26.Panahifar A, Maksymowych WP, Doschak MR. Potential mechanism of alendronate inhibition of osteophyte formation in the rat model of post-traumatic osteoarthritis: evaluation of elemental strontium as a molecular tracer of bone formation. Osteoarthritis Cartilage. 2012 Jul;20(7):694-702.

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