Thesis (Ph. D.)--University of Toronto, 1999. / eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis (MSc. (Physiology)--Faculty of Health Sciences) - University of Pretoria, 2008. / Includes bibliographical references.

Thesis (doctoral)--Karolinska Institutet, Stockholm, 1988. / Extra t.p. with thesis statement inserted. Includes bibliographical references.

Thesis (M.S.)--University of Louisville, 1998. / Includes bibliographical references.

Thesis (doctoral)--Karolinska Institutet, Stockholm, 1988. / Extra t.p. with thesis statement inserted. Includes bibliographical references.

Thesis (Ph. D.)--Rensselaer Polytechnic Institute, Troy, New York, 1992. / Includes bibliographical references (p. 184-200).

Thesis (Ph. D.)--West Virginia University, 2006. / Title from document title page. Document formatted into pages; contains x, 180 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references.

OBJECTIVE: To determine the effect of clinically used zoledronate (ZOL) and docetaxel on breast cancer cells and bone biology under both bone remodeling stages and the rate of tumor dissemination and state of dormancy. METHODS: The effect of clinically used zoledronate (ZOL) was examined on MDA-MB-231 and MDA-BO cells in a roller tube system under bone resorption and formation conditions. Three groups; calvaria alone, calvarial co-cultured with tumor cells, and calvaria with tumor cells treated with four repeat doses of 2 µM of ZOL were cultured for 8, 14 and 20 days. The formation groups were supplemented with 150 µg/ml ascorbic acid. Cell counts were performed on trypsinized calvaria harvested at 2, 8 and 14 days. Media was changed every 2 days and the changed media was re-seeded in a 24-well for 20 days. To test the impact of chemotherapy agents on cancer-bone metastasis the effect of 10 µM of docetaxel was tested on breast cancer cells under formation and resorption conditions using the above design. Tumor burden was assessed at 8 days. RESULTS: Tumor burden: no statistically significant difference between ZOL treated and untreated groups under resorption and formation conditions in both cell lines. Exposure to docetaxel revealed that ~30% of the cells were affected by chemotherapy in formation model, while ~70% was affected in resorption model in both cell types. Dissemination model: the dissemination rate for MDA and BO cells under formation condition is significantly less than for resorption conditions. Fluorescent microscopy: MDA and BO tumor-calvaria were treated with Ki 67 antibody showed that under bone resorption conditions the cancer-bone cells colony were predominantly in proliferation stage while under formation conditions cancer cells were in dormancy. Confocal microscopy: observation confirmed the relation of the mode of cancer cell attachment to bone endosteal cell layer with the dormancy and cell proliferation states. CONCLUSIONS: Both cancer cell lines showed resistance to ZOL under formation and resorption conditions. Drug resistance to docetaxel was more evident under formation condition, where cells are dormant and not proliferating. The dissemination rate is significantly higher in resorption condition, suggesting that cells in formation are dormant with lower dissemination rate. / 2019-07-23T00:00:00Z

Periosteum and bone marrow (BM) contain cells that, after isolation and culture-expansion, exhibit properties of mesenchymal stromal/stem cells (MSCs). However, these cells have not been identified and characterised in situ due to the lack of specific markers. This study aimed to identify and phenotypically characterise long-term label-retaining cells (LT-LRCs), thought to include stem cells (SCs), in mouse periosteum and BM. Two mouse models were used: nucleoside-analogue labelling, and doxycycline (Dox)-inducible expression of histone 2B–green fluorescent fusion protein (H2B-GFP). LRCs were identified and phenotypically characterised by immunostaining, and microscopy or by flow cytometry (FCM). LRCs were detected throughout the periosteum with no apparent focal concentration, and subsets of cells displayed a phenotype compatible with MSCs but not pericytes. Osteoblasts were also labelled, but osteocalcin-expressing osteoblasts were distinct from Low-affinity nerve growth factor receptor (LNGFR)/P75-expressing MSCs. Similarly, BM contained LRCs expressing MSC markers that were distinct from pericytes. For FCM analyses, two cell isolation methods were compared, which revealed that crushing and collagenase digestion of long bones yielded a higher percentage of LRCs compared with flushing. BM analysed 40 days after the end of nucleoside administration showed that LRCs both within the CD45- and CD45low population were enriched for cells expressing Platelet-derived growth factor receptor α (PDGFRα) together with Stem cell antigen-1 (Sca-1) as well as cells expressing LNGFR/P75+. Furthermore, the CD45-PDGFRα+Sca-1+ population showed an increase in the percentage of LRCs with an increasing washout period, suggesting PDGFRα together with Sca-1 is most suitable to identify stromal LRCs in mouse BM. Comparison of the nucleoside label-retaining model with the H2B-GFP-label-retaining transgenic model showed a good correlation between nucleoside and H2B-GFP-label retention, suggesting the suitability of the H2B-GFP model for identification of stromal LRCs in BM. Future studies characterising the MSC niche in-vivo could reveal novel therapeutic targets for promoting bone regeneration/repair.

L’os subit perpétuellement des contraintes mécaniques et physiologiques, ainsi sa qualité et sa résistance à lafracture évoluent constamment au cours du temps à travers le processus de remodelage osseux. Cependant,certaines pathologies osseuses comme l’ostéoporose ou la maladie de Paget altèrent cette dernière et conduisent àune augmentation du risque de fracture osseuse. La qualité osseuse est non seulement définie par la densitéminérale osseuse (DMO) mais également par les propriétés mécaniques ainsi que la microarchitecture. Au total, onévalue en France à environ 3 millions le nombre de femmes et 1 million le nombre d’hommes souffrantd’ostéoporose, pour un coût estimé à 1 milliard d’euros. La prévention par le développement d’outils de diagnosticest nécessaire. Le diagnostic doit permettre d’estimer la qualité osseuse (propriétés mécaniques, activitéscellulaires, architecture). Ces travaux de thèse proposent un modèle innovant permettant de combiner lesdifférents facteurs agissant sur le remodelage osseux, à savoir : (i) le comportement mécanique, (ii) l’activitécellulaire, (iii) le processus de transduction ; visant à traiter les différentes informations d’origines mécanique etbiochimique. Les lois de comportement mécaniques et cellulaires sont issues de modèles validés dans la littératureet la stratégie d’unification voit sa justification à travers différents travaux sur les mécanismes de transduction.Ainsi, l’implémentation de ces trois acteurs du remodelage dans une analyse par éléments finis permet d’obtenirun modèle mécano-biologique du remodelage de l’os trabéculaire. Le modèle est applicable à différentes échelles etpermet d’étudier le niveau de remodelage local modulé par l’activité physique et la concentration de certains agentsbiochimiques. L’application du modèle sur un volume virtuel de fémur selon différents scénarios cliniques donnedes résultats conformes aux observations faites en imagerie médicale. / By continuously undergoing mechanical and physiological stresses, bone quality and bone strength evolve throughremodeling process. However, osteoporosis and Paget’s disease for instance alter bone quality and increase the risk of bone fracture. Bone quality is mainly defined by its Bone Mineral Density (BMD) but mechanical properties and microarchitecture have also to be taken into account for a proper definition. About 3 million of women and 1 million of men suffer from osteoporosis which costs approximately 1 billion Euros per year in France. This highlights the necessity to develop diagnostic tools in order to enable proper bone quality characterization (mechanical properties, cellular activity and architecture).This thesis proposes an original model combining the main bone remodeling constituents which are : (i) the mechanical behavior, (ii) the cellular activity, (iii) the transduction phase ; enabling mechanical and biochemical information processing. Mechanical and cellular behavior models are taken from already published work and the transduction phase model unifying mechanical and biological information is inspired from the literature. Consequently, the implementation of these three main bone remodeling constituents into a finite element analysis gives a plausible mechano-biological model of trabecular bone remodeling. The developed model can be used at different scales in order to study the local amount of bone remodeled, magnified by physical activity and the concentration of some biochemical agents. Its application on virtual volume of femora under different clinical scenarios gives good results in respect to medical images observations.