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1
Mason, Rachel Ann. "Effects of estrogens and androgens on bone cell metabolism /." Title page, table of contents and abstract only, 1997. http://web4.library.adelaide.edu.au/theses/09PH/09phm411.pdf.
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Secreto, Frank. "The regulation of arachidonic acid metabolism in human osteoblast-like cells." Morgantown, W. Va. : [West Virginia University Libraries], 2003. http://etd.wvu.edu/templates/showETD.cfm?recnum=2970.
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Thesis (Ph. D.)--West Virginia University, 2003.<br>Title from document title page. Document formatted into pages; contains vi, 123 p. : ill. Includes abstract. Includes bibliographical references (p. 110-123).
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Macoritto, Michael. "Mechanisms of vitamin D receptor and retinoid X receptor mediated hormone resistance and cell differentiation in normal and cancer cells." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111887.
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Vitamin D is a precursor to a steroid hormone, 1,25 dihydroxyvitamin D (1,25(OH)2D). After its discovery and the characterization of its receptor, the vitamin D receptor (VDR), it was initially thought only to be involved in calcium homeostasis, but further research revealed an important role for vitamin D in the regulation of cell growth and differentiation of such cells as osteoblasts and bone marrow adipocytes. 1,25(OH)2D has also been shown to be a strong inhibitor and pro-differentiator of keratinocytes. The anti-proliferative and pro-differentiative properties of this hormone have led to studies where 1,25(OH)2D anticancer properties were assessed and initial findings that showed a requirement of other factors beyond VDR to induce 1,25(OH)2D signaling led to the identification of the retinoid X receptor, a common heterodimeric partner for several hormone receptors. The focus of thesis was to further elucidate the structure-function relationship of both the vitamin D receptor and the retinoid X receptor. Additionally, contributions to work directed towards further identifying the effects of vitamin D on osteoblast differentiation and survival. Interactions of 1,25(OH) 2D3 with its cognate receptor, identifying a key amino acid (Tryptophan 286) required for ligand contact and transcriptional activation, are described in Chapter 2. Mechanisms of vitamin D action on mesenchymal stem cell differentiation, promotion of osteoblast induction and maturation, and inhibition of adipocyte differentiation, are eluicidated in Chapter 3. Chapter 4 illustrates the effects of RAS/RAF/Mitogen-activated protein kinase mediated RXRalpha phosphorylation on the three-dimensional structure of the RXR/nuclear receptor partner heterodimers. Furthermore, this chapter reveals the inhibitory effect of the phosphorylation of a critical amino acid (serine 260) on the interaction of the AF-2 domain of the RXR with several coactivators, resulting in a decrease in the signaling potential of multiple steroid hormone receptors. The findings of this thesis further the knowledge of several areas of vitamin D biology, including both the canonical areas of bone formation, and the non-canonical area of vitamin D and cancer.
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Star, Gregory. "The effects of bone morphogenic proteins and transforming growth factor [beta] on in-vitro endothelin-1 production by human pulmonary microvascular endothelial cells /." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111942.
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Introduction: Idiopathic Pulmonary arteriole hypertension (IPAH) is a rare but severely debilitating disease that strikes women to men at a ratio of 3:1. Endothelial cell (EC) dysfunction is a hallmark of the disease. This includes rapid growth of the ECs until the occlusion of the vasculature as well as decreased blood levels of vasodilators. Markedly increased levels of endothelin-1, a potent vasoconstrictor and smooth muscle mitogen, have been noted in IPAH patients.<br>Recently mutations in the bone morphogenic protein receptor type II (BMPRII) have been linked to the disease. Interestingly mutations in activin-like kinase-1 (ALK-1) and endoglin have been linked to hereditary haemorrhagic telangiectasia (HHT), a disease that results in PAH clinically indistinguishable from IPAH. All of these proteins are either receptors or co-receptors to members of the TGFbeta superfamily. The connection of these mutations to the disease still remains largely a mystery to researchers and the effects of either bone morphogenic proteins 2, 4, 7 or TGFbeta levels on endothelin-1(ET-1) production in human microvascular endothelial cells cultured from normal lungs (HMVEC-LBI) are unknown.<br>Methods: HMVEC-LBI cells were cultured in the presence of various concentrations of BMP 2,4,7 and TGFbeta, in complete media or serum starved conditions. After allotted time points the media was collected and assayed by ELISA, meanwhile the cells were lysed and protein content assayed for normalization purposes. Small Mothers against Decapentaplegic (SMAD) 1/5 phosphorylation was also measured.<br>Results and Conclusions: Despite evidence that all BMPs used were biologically active, namely through SMAD phosphorylation studies, only BMP7 at very high dosages increased ET-1 production levels. TGFbeta had a more pronounced effect at earlier time points with lower concentrations. The results provide insights on the effects of an important group of proteins, the BMPs and TGFbeta, on lung microvascular ECs and which are likely the key cellular player In IPAH development. These findings may have clinical relevance in terms of control of the disease and understanding the normal response of these cells BMPs and TGFbeta.
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Ren, Song. "Metabolism of cyclophosphamide : implications for hematopoietic stem cell transplantation /." Thesis, Connect to this title online; UW restricted, 1999. http://hdl.handle.net/1773/7968.
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Pan, Beiqing. "Mechanisms of skeletal disease mediated by haematological malignancies /." Title page, table of contents and abstract only, 2004. http://web4.library.adelaide.edu.au/theses/09PH/09php1871.pdf.
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Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine and The Hanson Centre, Institute of Medical and Veterinary Science, 2004.<br>"August 2004" Errata inside front cover. Bibliography: leaves 126-159.
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Zarrinkalam, Krystyna. "Characterisation of osteoblast function in a feline model of mucopolysaccharidosis type VI." Title page, contents and introduction only, 2001. http://web4.library.adelaide.edu.au/theses/09PH/09phz38.pdf.
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Addenda slip inserted in back. Includes bibliographical references (leaves 178-231). To further the understanding of the molecular mechanisms that contribute to the skeletal pathology of mucopolysaccharidosis type VI and to investigate the production of organic matrix by mucopolysaccharidosis VI osteoblasts
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Pan, Beiqing. "Molecular and cellular studies of zoledronic acid : a potent inhibitor of multiple myeloma-induced osteolysis." Title page, contents and abstract only, 2002. http://web4.library.adelaide.edu.au/theses/09MSM/09msmp187.pdf.
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Bibliography: leaves 86-103. Investigates the effect of zoledronic acid on myeloma cells and osteoblast-like cells to establish the molecular and cellular mechanisms responsible for the clinical effectiveness of bisphosphonates in the treatment of patients with myelomatosis. Concludes that zoledronic acid inhibits myelomatosis-induced osteolysis thorugh the mechanisms of myeloma cell death and proliferation and maturation of osteoblasts.
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Freitas, Claudia Mercedes. "Regulation of Immune Cell Activation and Functionby the nBMPp2 Protein andthe CD5 Co-Receptor." BYU ScholarsArchive, 2019. https://scholarsarchive.byu.edu/etd/8257.
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According to the centers for disease control and prevention (CDC) and the world healthorganization (WHO), heart disease and immune related diseases such as diabetes and cancer areamong the leading causes of death around the world. Thus, the regulation of the function ofimmune cell plays a key role in health and disease. Calcium (Ca2+) ions play a critical role inimmune cell activation, function and in a robust immune response. Defects in Ca2+ signalinginfluences the development of cardiac disease, Alzheimer disease, immune cell metabolism,muscle dysfunction, and cancer. Each immune cell is unique in its activation and function,making it relevant to understand how activation of each type of immune cell is regulated. Herewe describe the role of the nBMP2 protein in macrophage activation and function and the role ofthe CD5 co-receptor in helper T cell activation and function.The nuclear bone morphogenetic protein 2 (nBMP2) is the nuclear variant of the bonemorphogenetic protein 2 (BMP2), a growth factor important in heart development, neurogenesis,bone, cartilage and muscle development. To better understand the function of nBMP2, transgenicnBMP2 mutant mice were generated. These mice have a slow muscle relaxation and cognitivedeficit caused in part by abnormal Ca2+ mobilization. Mutant nBMP2 mice also have an impairedsecondary immune response to systemic bacterial challenge. Here we have further characterizedmacrophage activation and function from mutant nBMP2 mice before and after bacterialinfection. We describe how nBMP2 influences the Ca2+ mobilization response and phagocytosisin macrophages, revealing a novel role of the nBMP2 protein in immune cell regulation.CD5 is a surface marker on T cells, thymocytes, and the B1 subset of B cells. CD5 isknown to play an important role during thymic development of T cells. CD5 functions as anegative regulator of T cell receptor (TCR) signaling and fine tunes the TCR signaling response.Here we describe our characterization of CD5 regulation of Ca2+ signaling in naïve helper Tcells. We also outline our findings examining how CD5-induced changes in helper T cellactivation influence other biological processes such as immune cell metabolism, the diversity ofthe gut microbiome, and cognitive function and behavior. Thus, this work elucidates theinfluence of the CD5 co-receptor on the functional outcomes in multiple systems when CD5 isaltered.
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Laketic-Ljubojevic, Ira. "Glutamate signalling in bone cells." Thesis, University of York, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.311080.
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Hayes, Sandra C. "Exercise, functional capacity and quality of life in peripheral blood stem cell transplant patients." Thesis, Queensland University of Technology, 2001. https://eprints.qut.edu.au/36758/7/36758_Digitised%20Thesis.pdf.
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Rondeau, Vincent. "Rôle de la désensibilisation de CXCR4 dans la spécification lympho-myéloïde des progéniteurs hématopoïétiques multipotents. Lymphoid differentiation of hematopoietic stem cells requires efficient Cxcr4 desensitization New method to obtain lymphoid progenitors CXCR4-driven mitochondrial metabolic pathways shape the lympho-myeloid fate of hematopoietic multipotent progenitors." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASQ022.
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Les cellules souches et progéniteurs hématopoïétiques (CSPHs), incluant les progéniteurs multipotents (MPPs), sont responsables de la production des cellules immunes circulantes. Ils résident dans la moelle osseuse (MO) au sein de structures spécialisées, les niches endostéale et (péri)-vasculaire, qui régulent la spécification et l'engagement lymphoïde versus myéloïde des CSPHs. Dans la MO, le couple formé par la chimiokine CXCL12 et l’un de ses récepteurs, CXCR4, exerce un rôle clé dans la régulation de la rétention et la quiescence des CSPHs. Ces processus sont dérégulés dans le Syndrome WHIM (SW), une maladie immuno-hématologique rare liée à des mutations autosomiques dominantes du gène codant CXCR4, qui altèrent la désensibilisation du récepteur et conduisent à un gain de fonction en réponse à CXCL12. Cliniquement, le SW se caractérise notamment par une profonde leucopénie circulante qui affecte les lignages lymphoïde et myéloïde et dont les mécanismes restent à déterminer. Grâce à un modèle murin génétiquement modifié du SW et à l'accès à des prélèvements biologiques de patients atteints du SW, nous avons testé l'hypothèse que la lymphopénie circulante associée au SW résultait de défauts hématopoïétiques dans la MO. Nous avons révélé un rôle clé de la désensibilisation de CXCR4 dans la différenciation lymphoïde des CSPHs et identifié les MPPs comme étant le stade défectueux dans le SW. La divergence entre les lignages lymphoïde et myeloïde se produit précisément à ce stade au sein duquel règne une hétérogénéité : les MPP2/3 sont biaisés myéloïde et les MPP4 sont orientés lymphoïde. Notre compréhension de la façon dont les signaux extrinsèques (niches) et intrinsèques aux MPPs déterminent leur devenir lymphoïde versus myéloïde est encore parcellaire. Dans ce contexte, l’objectif de ma thèse a été de déterminer si et comment la signalisation de CXCR4 régule la dépendance énergétique des MPPs et à comprendre comment les voies métaboliques façonnent leur spécification lympho-myéloïde. Dans la MO des souris porteuses de la mutation gain de fonction de Cxcr4, nous avons observé une diminution du nombre de MPP4 qui contrastait avec l'augmentation des MPP2/3. L’analyse de prélèvements médullaires de patients a également permis de rapporter une diminution de la fréquence des progéniteurs lymphoïdes et une augmentation de celle des progéniteurs myéloïdes. Chez la souris mutantes, ce biais myéloïde du compartiment de MPPs s'avèrait associé à une expansion anormale et une reprogrammation moléculaire et métabolique des MPP4. Fait marquant, un traitement chronique par l’AMD3100, un antagoniste de CXCR4, permettait de normaliser le nombre de MPP4 dans la MO, de restaurer leurs propriétés métaboliques, et de corriger la lymphopénie des souris mutantes. Par conséquent, nos résultats suggèrent que l’axe CXCL12/CXCR4 est requis au maintien du potentiel lymphoïde des MPP4 au travers de la modulation de leur activité métabolique mitochondriale<br>Hematopoietic stem and progenitor cells (HSPCs), including the multipotent progenitors (MPPs), are responsible for replenishing immune cells. They reside in bone marrow (BM) endosteal and (peri)-vascular niches, which provide all cellular and molecular components required for their lifelong maintenance and fate. Among them, the CXCL12 chemokine and one of its receptor, CXCR4, exert a dominant role in promoting HSPC retention and quiescence. These processes are deregulated in the WHIM Syndrome (WS), a rare immunodeficiency caused by inherited heterozygous autosomal gain-of-function CXCR4 mutations that affect homologous desensitization of the receptor. Clinically, WS is notably characterized by severe, chronic circulating lymphopenia whose mechanisms remain to be elucidated. Using a mouse model carrying a naturally occurring WS-linked Cxcr4 mutation as well as human BM and blood samples, we explored the possibility that the lymphopenia in WS originates from defects at the HSPC level in BM. We reported that Cxcr4 desensitization is required for lymphoid differentiation of HSPCs and further identified the MPP stage as defective in mutant mice. The divergence between lymphoid and myeloid lineages occurs at the MPP stage, which is composed of distinct subpopulations, i.e., MPP2 and MPP3 are reported as distinct myeloid-biased MPP subsets that operate together with lymphoid-primed MPP4 to control blood leukocyte production. Our understanding of how cell-extrinsic niche-related and cell-intrinsic cues drive the lymphoid versus myeloid fate decision of MPPs is still fragmentary. Therefore, my PhD project aimed at determining whether and how CXCR4 signaling regulates bioenergetics demands of MPPs and at understanding how these metabolic pathways shape the lympho-myeloid fate of MPPs. We unraveled a myeloid skewing of the HSPC compartment in BM of WS mice and patients. In mutant mice, this partly relied on the contraction of the MPP4 pool and on cell-autonomous molecular and metabolic changes that reprogramed MPP4 away from lymphoid differentiation. Interestingly, chronic treatment with the CXCR4 antagonist AMD3100 normalized mitochondrial metabolism and fate of MPP4, while correcting circulating lymphopenia in WS mice. This study provides evidence that CXCR4 signaling acts as an essential gatekeeper for integrity of the mitochondrial machinery, which in turn controls lymphoid potential of MPP4
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Mason, Shelley S. "Exploring Tissue Engineering: Vitamin D3 Influences on the Proliferation and Differentiation of an Engineered Osteoblast Precursor Cell Line During Early Bone Tissue Development." PDXScholar, 2013. https://pdxscholar.library.pdx.edu/open_access_etds/1000.
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Most of the load-bearing demand placed on the human body is transduced by skeletal tissue, and the capacity of the skeleton to articulate in various opposing directions is essential for body movement and locomotion. Consequently, cartilage and bone defects due to trauma, disease, and developmental abnormalities result in disabling pain and immobility for millions of people worldwide. A novel way of promoting cartilage and bone regeneration is through the incorporation of either primary cells or multipotent progenitor cells in a three-dimensional (3D) biomaterial scaffold, and/or the addition of exogenous growth and differentiation factors. The first part of this study reports a protocol for using freshly isolated mature chondrocytes seeded in a 3D hydrogel biomaterial scaffold, developed to explore mechanotransduction of engineered cartilage constructs cultured in a designed bioreactor. The bioreactor was designed to allow the application of physiological mechanical forces (compression and fluid flow), as well as a non-invasive/non-destructive method for analyzing regenerating tissue in real time through ultrasound transducers and a computerized monitoring system. In the second part of this study, an engineered immortalized osteoprecursor cell line, designated OPC1 (osteoblastic precursor cell line 1), was used as a culture model system for exploring the effects of exogenous growth and differentiation factors, mainly vitamin D, on early bone development. OPC1 was previously designed to provide a consistent reproducible culture system for direct comparisons of engineered bone constructs, evaluating bone development and cell/biomaterial interactions, and for investigating putative bone differentiating factors. One of the objectives of this research effort was to explore tissue development and regeneration by culturing OPC1 in the presence of vitamin D metabolites vitaD3 and 1,25OH2D3, while assaying the concomitant biological response. Results indicate that OPC1 is capable of metabolizing the parental metabolite vitaD3, and thus 25OHD3, to the active vitamin D form 1,25OH2D3. The metabolism of vita3 resulted in an anti-proliferative and pro-differentiative influence on OPC-1. These results support the hypothesis that extra-endocrine synthesis of 1,25OH2D3 functions in a tissue specific manner to regulate growth and differentiation, in addition to the classic calcimic actions of the vitamin D endocrine pathway. Understanding the influence of vitamin D on bone development will have significant implications on healthy aging, including the susceptibility to skeletal disorders involved in development and aging, such as osteoarthritis (OA) and osteoporosis.
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Ford, Lorna. "An investigation into the effects of endocannabinoids and the COX-2 metabolite of 2-Arachidonyl glycerol on bone cells." Thesis, Available from the University of Aberdeen Library and Historic Collections Digital Resources, 2009. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?application=DIGITOOL-3&owner=resourcediscovery&custom_att_2=simple_viewer&pid=33596.
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Mason, Rachel Ann. "Effects of estrogens and androgens on bone cell metabolism / Rachel Ann Mason." Thesis, 1997. http://hdl.handle.net/2440/19065.
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Bibliography: leaves 298-334.<br>xxxi, 334, [3] leaves, [18] leaves of plates : ill. ; 30 cm.<br>Provides insight into the mechanism by which dihydrotestosterone (DHT) and estrogen effect osteoblast and osteoclast bone cell activities. Also demonstrates the differential effects of DHT on bone cell activities in estrogen sufficient and estrogen deficient rats suggesting that there is an interaction of estrogens and androgens on bone cell metabolism in the female rat.<br>Thesis (Ph.D.)--University of Adelaide, Dept. of Physiology, 1998?
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Corry, Kylie A. "Novel insights into the mechanistic gene regulation of STAT3 in bone cells." Thesis, 2015. http://hdl.handle.net/1805/7956.
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Indiana University-Purdue University Indianapolis (IUPUI)<br>Many cells are involved in the orchestra that is bone homeostasis--particularly osteoclasts and osteoblasts, which mediate remodeling of bones. This creates a balance that must be kept in check, otherwise pathologies arise. The JAK-STAT signaling pathway is crucial to maintaining this balance. It has long been known that the transcription factor STAT3 has more profound effects on bone homeostasis than other members of the STAT family of proteins. Recently, a genetic condition called Job’s Syndrome has been specifically linked to point mutations in the Stat3 gene. These patients present with severe bone abnormalities, including prominent foreheads, broad nasal bridges, and abnormal eye spacing. For this reason, our lab has extensively studied conditional knockouts of Stat3 in all three types of bones cells in mice and observed severe deficiencies in numerous parameters of normal bone phenotypes. STAT3 seems to play a principal role in the signaling that takes place upon mechanical loading of bone tissues and calling cells into action where they are needed. Furthermore,
STAT3 has been found to be up-regulated in the early-response gene cluster following mechanical loading.
Our current approach to studying STAT3’s effects on bone includes both in vivo and in vitro comparisons of WT and KO STAT3 models. The conditional knock-out of STAT3 in 8-week old mice revealed significant phenotypic variations as compared to the WT controls, while no significant differences were observed in cKO newborn pups. We also looked at immortalized WT and STAT3 KO cell lines. The STAT3 KO cells had diminished proliferation rates and decreased differentiation capabilities. Furthermore, STAT3 KO cells showed significantly reduced mRNA levels of both Wnt3a and Wnt5a when exposed to fluid shear stress.
By employing available ChIP-seq data, we were able to elucidate the genome-wide binding patterns of STAT3. From the peak distribution, we can begin to uncover novel downstream effectors of STAT3 signaling that are responsible for the observed phenotypes in our conditional knockout mouse model. A preliminary look at the ChIP-seq data reveals Wnt and Nrf2 signaling to be under the putative control of STAT3. In our further research, we endeavor to experimentally confirm the ChIP-seq data for STAT3 with RNA-seq experiments in the hopes of finding potential therapeutic targets for bone pathologies.
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Anuradha, Valiya Kambrath. "Testing the reliability and selectivity of different bone-cell-specific Cre- expressing mouse models for studying bone cell metabolism." Thesis, 2015. http://hdl.handle.net/1805/7942.
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Indiana University-Purdue University Indianapolis (IUPUI)<br>The Cre/loxP system is a tool for targeted recombination of DNA. For applying Cre recombinase-mediated genome modifications, there is a requirement for reliable, high-fidelity, and specific transgenic expression of the Cre recombinase. This study focuses on the reliability of different bone cell specific Cre models in the Cre/loxP system. In this study, DMP1-Cre transgenic mouse which has a transgene driven by DMP1 promotor that allows Cre-expression only in late stage osteoblasts and osteocytes was used. Ctsk-Cre mouse with a driven by Ctsk promoter was used so that only osteoclasts would undergo Cre-mediated recombination. E2A-Cre mouse where the Cre recombinase is driven by a global promoter E2A was also included in this study as a control line to test the Cre reporter line Ai9. Dmp1-Cre, Ctsk-Cre and E2A-Cre mice were crossed to the fluorescent Cre-reporter line—Ai9, which harbors a floxed stop codon, followed by the fluorophoremTomato, inserted into the Rosa26 locus. This construct is expected to give red fluorescence when it recombines with Cre-expressing mouse cells and no fluorescence in non-recombinant mouse cells. Double positive (Ai9+/Cre+) offspring selected by PCR were perfused, and 5mu-m thick section of bone and soft tissues were examined for red fluorescent expression. Cre positive cells were quantitated using ‘ImageJ’ software program. The DMP1-vi Cre mouse results showed significant expression in the targeted osteocytes and osteoblasts. In addition, skeletal muscle tissue also showed significant Cre- expression. Ctsk-Cre mice showed significant expression in targeted osteoclasts. But brain tissue was positive in Cre-expression. Bone-Cre mouse models are expected to express Cre recombinase only in their respective bone cells and they have been used for gene deletion studies in bone cells. However, this study has revealed that the bone cell specific Cre mouse models DMP1-Cre and Ctsk-Cre have unexpected expression in muscle and brain respectively. In order to use these models for targeted gene deletion in bone cells, further testing and studies have to be conducted.
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Algate, Kent. "Epigenetic Regulation of Cells Involved in Periodontal Bone Destruction through Targeted Histone Deacetylase Inhibition." Thesis, 2018. http://hdl.handle.net/2440/127113.
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Periodontitis (PD) is one of the most common bone loss pathologies in adults and currently affects more than 60% of the population in its destructive form. Ineffective or surgically invasive treatment options can result in patient noncompliance, gingival recession, alveolar bone destruction and eventual loss of teeth. Aside from the psychosocial effects of poor dental health, PD has been associated with a variety of systemic conditions, such as rheumatoid arthritis and cardiovascular disease, exacerbating their onset and severity. Histone deacetylase (HDAC) enzymes are molecules that control cellular activity through modifications to gene expression and protein function at an epigenetic level. Alterations to HDAC expression or function can cause diminished physiological cell regulation, thought to be an essential factor in the pathogenesis of disease. The use of selective HDAC inhibitors (HDACi) targeting candidate HDACs may be an effective, non-invasive therapeutic tool to treat both inflammation and bone loss in PD. The aim of this research was to investigate the effects of novel HDACi designed to target individual HDAC isoforms as a PD treatment. In vitro investigations identified therapeutic potential for targeting HDAC 1 and HDAC 2 during the inflammatory response and catabolic actions of human monocytes and osteoclasts. Whereas HDAC 5 inhibition holds regenerative potential, as osteoblastogenesis and matrix mineralisation was induced by its suppression. With the additional identification and characterisation of candidate HDAC isoforms in an in vivo mouse model of PD, the results of this thesis will provide a strong foundation for future investigations and clinical translation of HDACi.<br>Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 2018
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Pan, Beiqing. "Mechanisms of skeletal disease mediated by haematological malignancies / Beiqing Pan." Thesis, 2004. http://hdl.handle.net/2440/22124.
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"August 2004"<br>Errata inside front cover.<br>Bibliography: leaves 126-159.<br>xi, 159, [12] leaves : ill., plates ; 30 cm.<br>Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine and The Hanson Centre, Institute of Medical and Veterinary Science, 2004
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Singh, Suman K., Waqas A. Abbas, and Desmond J. Tobin. "Bone morphogenetic proteins differentially regulate pigmentation in human skin cells." 2012. http://hdl.handle.net/10454/6194.
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Bone morphogenetic proteins (BMPs) are a large family of multi-functional secreted signalling molecules. Previously BMP2/4 were shown to inhibit skin pigmentation by downregulating tyrosinase expression and activity in epidermal melanocytes. However, a possible role for other BMP family members and their antagonists in melanogenesis has not yet been explored. In this study we show that BMP4 and BMP6, from two different BMP subclasses, and their antagonists noggin and sclerostin were variably expressed in melanocytes and keratinocytes in human skin. We further examined their involvement in melanogenesis and melanin transfer using fully matched primary cultures of adult human melanocytes and keratinocytes. BMP6 markedly stimulated melanogenesis by upregulating tyrosinase expression and activity, and also stimulated the formation of filopodia and Myosin-X expression in melanocytes, which was associated with increased melanosome transfer from melanocytes to keratinocytes. BMP4, by contrast, inhibited melanin synthesis and transfer to below baseline levels. These findings were confirmed using siRNA knockdown of BMP receptors BMPR1A/1B or of Myosin-X, as well as by incubating cells with the antagonists noggin and sclerostin. While BMP6 was found to use the p38MAPK pathway to regulate melanogenesis in human melanocytes independently of the Smad pathway, p38MAPK, PI3-K and Smad pathways were all involved in BMP6-mediated melanin transfer. This suggests that pigment formation may be regulated independently of pigment transfer. These data reveal a complex involvement of regulation of different members of the BMP family, their antagonists and inhibitory Smads, in melanocytes behaviour.
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Zarrinkalam, Krystyna Helena. "Characterisation of osteoblast function in a feline model of mucopolysaccharidosis type VI / by Krystyna Zarrinkalam." Thesis, 2001. http://hdl.handle.net/2440/21750.
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Addenda slip inserted in back.<br>Includes bibliographical references (leaves 178-231).<br>xiv, 234, [19] leaves, [56] leaves of plates : ill. (chiefly col.) ; 30 cm.<br>To further the understanding of the molecular mechanisms that contribute to the skeletal pathology of mucopolysaccharidosis type VI and to investigate the production of organic matrix by mucopolysaccharidosis VI osteoblasts<br>Thesis (Ph.D.)--University of Adelaide, Dept. of Paediatrics, 2001
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Himes, Evan Robert. "The role of STAT3 in osteoclast mediated bone resorption." Thesis, 2014. http://hdl.handle.net/1805/4841.
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Indiana University-Purdue University Indianapolis (IUPUI)<br>Signal Transducer and Activator of Transcription 3 (STAT3) is known to be related to bone metabolism. Mutation of STAT3 causes a rare disorder in which serum levels of IgE are elevated. This causes various skeletal problems similar to osteoporosis.
To examine the effect of STAT3 in the osteoclast, we obtained two osteoclast specific STAT3 knockout mouse models: one using the CTSK promoter to drive Cre recombinase and another using a TRAP promoter. Examination of these mice at 8 weeks of age revealed a decreased trabecular bone volume in CTSK specific STAT3 knockout mice along with a slight decrease in osteoclast number in both CTSK and TRAP specific STAT3 knockout females. We also noticed changes in bone mineral density and bone mechanical strength in females. These data suggest that STAT3 plays a part in the function of the osteoclast.
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Zhou, Hongkang. "The essential role of Stat3 in bone homeostasis and mechanotransduction." Thesis, 2014. http://hdl.handle.net/1805/6190.
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Indiana University-Purdue University Indianapolis (IUPUI)<br>Signal Transducer and Activator of Transcription 3 (Stat3) is a transcription factor expressed in bone and joint cells that include osteoblasts, osteocytes, osteoclasts, and chondrocytes. Stat3 is activated by a variety of cytokines and growth factors, including IL-6/gp130 family cytokines. These cytokines not only regulate the differentiation of osteoblasts and osteoclasts, but also regulate proliferation of chondrocytes through Stat3 activation. In 2007, mutations of Stat3 have been confirmed to cause a rare human immunodeficiency disease – Job syndrome which presents skeletal abnormalities like: reduced bone density (osteopenia), scoliosis, hyperextensibility of joints, and recurrent pathological bone fractures. Changes in the Stat3 gene alter the structure and function of the Stat3 proteins, impairing its ability to control the activity of other genes. However, little is known about the effects of Stat3 mutations on bone cells and tissues.
To investigate the in vivo physiological role of Stat3 in bone homeostasis, osteoblast/osteocyte-specific Stat3 knockout (KO) mice were generated via the Cre-LoxP recombination system. The osteoblast/osteocyte-specific Stat3 KO mice showed bone abnormalities and an osteoporotic phenotype because of a reduced bone formation rate.
Furthermore, inactivation of Stat3 decreased load-driven bone formation, and the disruption of Stat3 in osteoblasts suppressed load-driven mitochondrial activity, which led to an elevated level of reactive oxygen species (ROS) in cultured primary osteoblasts.
Stat3 has been found to be responsive to mechanical stimulation, and might play an important role in mechanical signal transduction in osteocytes. To investigate the role Stat3 plays in mechanical signaling transduction, osteocyte-specific Stat3 knockout (KO) mice were created. Inactivation of Stat3 in osteocytes presented a significantly reduced load-driven bone formation. Decreased osteoblast activity indicated by reduced osteoid surface was also found in osteocyte-specific Stat3 KO mice. Moreover, sclerostin (SOST) protein which is a critical osteocyte-specific inhibitor of bone formation, its encoded gene SOST expression has been found to be enhanced in osteocyte-specific Stat3 KO mice.
Thus, these results clearly demonstrated that Stat3 plays an important role in bone homeostasis and mechanotransduction, and Stat3 is not only involved in bone-formation-important genes regulation in the nucleus but also in mediation of ROS and oxidative stress in mitochondria.
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Ben-awadh, Abdullah Nasser. "CONTRIBUTION OF RANKL REGULATION TO BONE RESORPTION INDUCED BY PTH RECEPTOR ACTIVATION IN OSTEOCYTES." 2012. http://hdl.handle.net/1805/3015.
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Indiana University-Purdue University Indianapolis (IUPUI)<br>PTH increases osteoclasts by upregulating RANKL in cells of the osteoblastic lineage, but the precise differentiation stage of the PTH target cell remains undefined. Recent findings demonstrate that PTH regulates gene expression in osteocytes and that these cells are an important source of RANKL. We therefore investigated whether direct regulation of the RANKL gene by PTH in osteocytes is required to stimulate osteoclastic bone resorption. To address this question, we examined bone resorption and RANKL expression in transgenic mice in which PTH receptor signaling is activated only in osteocytes (DMP1-caPTHR1) crossed with mice lacking the distal control region regulated by PTH in the RANKL gene (DCR -/-). Longitudinal analysis of circulating C-terminal telopeptide (CTX) in male mice showed elevated resorption in growing mice that progressively decreased to plateau at 3-5 month of age. Resorption was significantly higher (~100%) in DMP1-caPTHR1 mice and non-significantly lower (15-30%) in DCR -/-mice, versus wild type littermates (WT) across all ages. CTX in compound DMP1-caPTHR1; DCR -/-mice was similar to DMP1-caPTHR1 mice at 1 and 2 months of age, but by 3 months of age, was significantly lower compared to DMP1-caPTHR1 mice (50% higher than WT), and by 5 months, it was undistinguishable from WT mice. Micro-CT analysis revealed lower tissue material density in the distal femur of DMP1-caPTHR1 mice, indicative of high remodeling, and this effect was partially corrected in compound vi mice. The increased resorption exhibited by DMP1-caPTHR1 mice was accompanied by elevated RANKL mRNA in bone at 1 and 5 months of age. RANKL expression levels displayed similar patterns to CTX levels in DMP1-caPTHR1; DCR -/-compound mice at 1 and 5 month of age. The same pattern of expression was observed for M-CSF. We conclude that resorption induced by PTH receptor signaling requires direct regulation of the RANKL gene in osteocytes, but this dependence is age specific. Whereas DCR-independent mechanisms involving gp130 cytokines or vitamin D 3 might operate in the growing skeleton, DCR-dependent, cAMP/PKA/CREB-activated mechanisms mediate resorption induced by PTH receptor signaling in the adult skeleton.
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Reis, Sara Daniela de Sousa. "Characterization of the Effects of Proton Pump inhibitors on bone Metabolism: in vitro study in cocultures of osteoclasts and Breast Cancer Cells and in Cultures of Osteoblasts." Master's thesis, 2013. https://repositorio-aberto.up.pt/handle/10216/70510.
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Reis, Sara Daniela de Sousa. "Characterization of the Effects of Proton Pump inhibitors on bone Metabolism: in vitro study in cocultures of osteoclasts and Breast Cancer Cells and in Cultures of Osteoblasts." Dissertação, 2013. https://repositorio-aberto.up.pt/handle/10216/70510.
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"Hyperglycemic impairment of CGRP-induced cAMP responses in vascular smooth muscle cells (VSMCs) and the role of cGMP/protein kinase G pathway in regulating apoptosis and proliferation of VSMCs and bone marrow stromal stem cells." 2006. http://library.cuhk.edu.hk/record=b5893055.
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Wong Cheuk Ying.<br>Thesis (M.Phil.)--Chinese University of Hong Kong, 2006.<br>Includes bibliographical references (leaves 101-124).<br>Abstracts in English and Chinese.<br>Abstract --- p.i<br>摘要 --- p.iv<br>Acknowledgement --- p.vi<br>List of Abbreviations --- p.vii<br>Chapter Chapter 1. --- General Introduction --- p.1<br>Chapter Chapter 2. --- Methods --- p.4<br>Chapter 2.1 --- Measurement of cAMP and cGMP in VSMCs --- p.4<br>Chapter 2.1.1 --- Cell culture --- p.4<br>Chapter 2.1.2 --- Enzyme-immunoassay colorimetric measurement for cAMP and cGMP --- p.5<br>Chapter 2.1.3 --- Statistical analysis --- p.6<br>Chapter 2.2 --- Measurement of apoptosis in VSMCs and bone marrow-derived stem cells --- p.6<br>Chapter 2.2.1 --- Cell culture --- p.6<br>Chapter 2.2.2 --- Hoechst33258 --- p.7<br>Chapter 2.2.3 --- Cell Death ELISA plus --- p.7<br>Chapter 2.2.4 --- Protein extraction and Western blot analysis of PKG expression --- p.8<br>Chapter 2.2.5 --- Statistical analysis --- p.9<br>Chapter 2.3 --- Measurement of cell proliferation in VSMCs and bone marrow-derived stem cells --- p.9<br>Chapter 2.3.1 --- Cell culture --- p.9<br>Chapter 2.3.2 --- Cell count --- p.10<br>Chapter 2.3.3 --- MTT assay --- p.11<br>Chapter 2.3.4 --- BrdU-(5`Bromo-2-deoxyuridine) ELISA colorimetric assay --- p.11<br>Chapter 2.3.5 --- Statistical analysis --- p.12<br>Chapter Chapter 3. --- Effects of hyperglycemia on CGRP-induced cAMP response in VSMCs<br>Chapter 3.1 --- Introduction --- p.13<br>Chapter 3.2 --- Results --- p.18<br>Chapter 3.3 --- Discussion --- p.22<br>Chapter Chapter 4. --- Role of cGMP and protein kinase G in regulation of apoptosis in VSMCs<br>Chapter 4.1 --- Introduction --- p.26<br>Chapter 4.2 --- Results --- p.30<br>Chapter 4.3 --- Discussion --- p.44<br>Chapter Chapter 5. --- Role of protein kinase G in regulation of proliferation in VSMCs<br>Chapter 5.1 --- Introduction --- p.55<br>Chapter 5.2 --- Results --- p.58<br>Chapter 5.3 --- Discussion --- p.67<br>Chapter Chapter 6. --- Effects of aging and eNOS- and iNOS-gene deletion (using eNOS- and iNOS-knockout mice) on apoptosis of VSMCs<br>Chapter 6.1 --- Introduction --- p.73<br>Chapter 6.2 --- Results --- p.76<br>Chapter 6.3 --- Discussion --- p.79<br>Chapter Chapter 7. --- Role of protein kinase G in regulation of apoptosis and proliferation of bone marrow stromal stem cells<br>Chapter 7.1 --- Introduction --- p.81<br>Chapter 7.2 --- Results --- p.84<br>Chapter 7.3 --- Discussion --- p.92<br>Chapter Chapter 8. --- Overall discussion --- p.95<br>Chapter Chapter 9. --- References --- p.101
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Shakibaei, M., C. Buhrmann, and A. Mobasheri. "Resveratrol-mediated SIRT-1 interactions with p300 modulate receptor activator of NF-kappaB ligand (RANKL) activation of NF-kappaB signaling and inhibit osteoclastogenesis in bone-derived cells." 2011. http://hdl.handle.net/10454/6182.
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Resveratrol is a polyphenolic phytoestrogen that has been shown to exhibit potent anti-oxidant, anti-inflammatory, and anti-catabolic properties. Increased osteoclastic and decreased osteoblastic activities result in bone resorption and loss of bone mass. These changes have been implicated in pathological processes in rheumatoid arthritis and osteoporosis. Receptor activator of NF-kappaB ligand (RANKL), a member of the TNF superfamily, is a major mediator of bone loss. In this study, we investigated the effects of resveratrol on RANKL during bone morphogenesis in high density bone cultures in vitro. Untreated bone-derived cell cultures produced well organized bone-like structures with a bone-specific matrix. Treatment with RANKL induced formation of tartrate-resistant acid phosphatase-positive multinucleated cells that exhibited morphological features of osteoclasts. RANKL induced NF-kappaB activation, whereas pretreatment with resveratrol completely inhibited this activation and suppressed the activation of IkappaBalpha kinase and IkappaBalpha phosphorylation and degradation. RANKL up-regulated p300 (a histone acetyltransferase) expression, which, in turn, promoted acetylation of NF-kappaB. Resveratrol inhibited RANKL-induced acetylation and nuclear translocation of NF-kappaB in a time- and concentration-dependent manner. In addition, activation of Sirt-1 (a histone deacetylase) by resveratrol induced Sirt-1-p300 association in bone-derived and preosteoblastic cells, leading to deacetylation of RANKL-induced NF-kappaB, inhibition of NF-kappaB transcriptional activation, and osteoclastogenesis. Co-treatment with resveratrol activated the bone transcription factors Cbfa-1 and Sirt-1 and induced the formation of Sirt-1-Cbfa-1 complexes. Overall, these results demonstrate that resveratrol-activated Sirt-1 plays pivotal roles in regulating the balance between the osteoclastic versus osteoblastic activity result in bone formation in vitro thereby highlighting its therapeutic potential for treating osteoporosis and rheumatoid arthritis-related bone loss.
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Nasim, Md Talat, T. Ogo, H. M. Chowdhury, L. Zhao, C.-n. Chen, C. Rhodes, and R. C. Trembath. "BMPR-II deficiency elicits pro-proliferative and anti-apoptotic responses through the activation of TGFbeta-TAK1-MAPK pathways in PAH." 2012. http://hdl.handle.net/10454/6115.
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Pulmonary arterial hypertension (PAH) is a cardiovascular disorder associated with enhanced proliferation and suppressed apoptosis of pulmonary arterial smooth muscle cells (PASMCs). Heterozygous mutations in the type II receptor for bone morphogenetic protein (BMPR2) underlie the majority of the inherited and familial forms of PAH. The transforming growth factor beta (TGFbeta) pathway is activated in both human and experimental models of PAH. However, how these factors exert pro-proliferative and anti-apoptotic responses in PAH remains unclear. Using mouse primary PASMCs derived from knock-in mice, we demonstrated that BMPR-II dysfunction promotes the activation of small mothers against decapentaplegia-independent mitogen-activated protein kinase (MAPK) pathways via TGFbeta-associated kinase 1 (TAK1), resulting in a pro-proliferative and anti-apoptotic response. Inhibition of the TAK1-MAPK axis rescues abnormal proliferation and apoptosis in these cells. In both hypoxia and monocrotaline-induced PAH rat models, which display reduced levels of bmpr2 transcripts, this study further indicates that the TGFbeta-MAPK axis is activated in lungs following elevation of both expression and phosphorylation of the TAK1 protein. In ex vivo cell-based assays, TAK1 inhibits BMP-responsive reporter activity and interacts with BMPR-II receptor. In the presence of pathogenic BMPR2 mutations observed in PAH patients, this interaction is greatly reduced. Taken together, these data suggest dysfunctional BMPR-II responsiveness intensifies TGFbeta-TAK1-MAPK signalling and thus alters the ratio of apoptosis to proliferation. This axis may be a potential therapeutic target in PAH.
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Bonfitto, Anna. "Testing bone cell models responsive to a soluble form of klotho." Thesis, 2016. https://doi.org/10.7912/C2V087.
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Indiana University-Purdue University Indianapolis (IUPUI)<br>Fibroblast growth factor-23 (FGF23) is a hormone produced in bone that acts upon the kidney to control blood phosphate and 1,25-(OH)2 vitamin D concentrations. Chronic kidney disease-mineral bone disorder (CKD-MBD) is a major public health problem, affecting 1 in 8 individuals. These patients can have markedly elevated FGF23 at end stage disease which is associated with metabolic bone anomalies, left ventricular hypertrophy, as well as increased mortality (>6-fold). The FGF23 co-receptor αKlotho (αKL) is a membrane-bound protein (mKL) that forms heteromeric complexes with FGF receptors (FGFRs) to initiate intracellular signaling. It also circulates as a cleavage product of mKL (‘cleaved’, or cKL). Previously, a patient with increased plasma cKL from a balanced translocation between chromosomes 9 and 13 in the KLOTHO gene presented with metabolic bone disease and a complex endocrine profile, despite hypophosphatemia. The lack of a reliable cell model in which to study potential FGF23-cKL interactions is a major hurdle for the field of phosphate metabolism. The goal of the present studies was to test and characterize bone cell lines that may respond to FGF23 and/or cKL, permitting study of novel aspects of phosphate handling and control of FGF23 expression. It was confirmed that stable delivery of cKL via AAV2/8 to wild type (WT) and KL-KO mice resulted in highly elevated bone FGF23 mRNA. MC3T3 (mouse) and ROS (rat) osteoblastic cell lines were tested for p-ERK1/2 responses to control FGFs, as well as FGF23 and cKL, alone or in combination. Importantly, both cell lines demonstrated responsiveness to FGF23+cKL only, and not the individual factors. To test responsiveness at the cell level, EGR1 mRNA was tested as an index of FGFR activity and showed modest increases with the same treatments, supporting that other factors may be required for full transcriptional effects. The present studies show that MC3T3 have FGF-dependent signaling capabilities, and that the combination of FGF23+cKL is required for efficient MAPK signaling. These results demonstrated that cKL provision is permissive for efficient FGF23 signaling in bone, and revealed important implications for the regulation of FGF23 and cKL in Mendelian, and common, genetic disorders of phosphate handling and biomineralization.
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Sun, Shih-Chun, and 孫詩淳. "Effects of Di(2-ethylhexyl) Phthalate and Its Metabolite on Osteoblast and Adipocyte Differentiation from Mouse Bone Marrow-derived Mesenchymal Stem Cells." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/08496907133769368336.
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碩士<br>國立臺灣大學<br>毒理學研究所<br>102<br>Di(2-ethylhexyl) Phthalate (DEHP), the most widely used phthalate in Taiwan, is added in polyvinyl chloride plastics to increased flexibility. DEHP is commonly used in medical devices, food package, architectural materials, and surface coating. Besides, DEHP is a well-known endocrine-disrupting chemicals (EDCs). EDCs are estrogenic industrial compound that can disrupt normal hormone signaling systems, which raised considerable concern in recent years. Bone microenvironment is a complex dynamic equilibrium between osteoclasts and osteoblasts and is modulated by a wide variety of hormones. Moreover, factors promote adipogenesis not only lead to fatty marrow but also decrease osteoblastogenesis, and eventually affect bone formation. Therefore, we investigate the effects and mechanisms of DEHP and its metabolites, mono(2-ethylhexyl) phthalate (MEHP),on osteoblast and adipocyte differentiation from mouse bone marrow-derived MSCs. Bone marrow-derived mesenchymal stem cells (MSCs) were isolated from normal mice and DEHP-gavaged mice; the former is cultured with DEHP to evaluate the effects on differentiation and the latter is cultured without DEHP to examine whether 8-week DEHP exposure affect differentiation ability of MSCs. At the end of the experiments, Alizarin Red S stain was conducted to observe mineralization and alkaline phosphatase (ALP) activity were measured to evaluate osteoblast differentiation. The oil deposit formation through adipocyte differentiation was evaluated through Oil Red O stain. Besides, the RNA expression of the osteoblast markers, Runx2 and osteocalcin, and adipogenesis marker, PPAR-γ, were detected. The changes in bone morphology were observed by micro-computed tomography (micro-CT). MTT assay showed that 10-100 μM DEHP have no cytotoxicity to MSCs. After DEHP treatment in vitro, ALP activity and Alizarin Red S stain indicated that osteoblast differentiation was inhibited. Expression of osteoblast- related genes, osteocalcin and runx2, decreased in Real-time PCR results. Expression of Wnt1 and s-catenin were markedly decreased, which indicated that DEHP inhibited osteoblastogenesis through Wnt/s-catenin pathway. The expression of PPAR-γ increased, however the Oil Red O stain showed that DEHP have no effect on adipocyte differentiation. Moreover, the inhibition of ALP activity, Alizarin Red S stain, bone mineral density and osteoblast marker expression revealed that osteoblastogenesis potential decreased after DEHP gavage administration. Reciprocally, the enhancement of Oil Red O stain and the expression of PPAR-γ showed that adipogenesis potential increased. Further, DEHP metabolite, MEHP, had same effects on osteoblast differentiation from MSCs as DEHP. Though DEHP showed no effect on adipogenesis in MSCs in vitro, MEHP enhanced adipogenesis in MSCs. The present study suggested that DEHP decreased osteoblastogenesis through Wnt/s-catenin pathway and which would not promote adipogenesis unless metabolized to MEHP.
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Hum, Julia M. "Signaling mechanisms that suppress the anabolic response of osteoblasts and osteocytes to fluid shear stress." Thesis, 2014. http://hdl.handle.net/1805/4652.
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Indiana University-Purdue University Indianapolis (IUPUI)<br>Bone is a dynamic organ that responds to its external environment. Cell signaling cascades are initiated within bone cells when changes in mechanical loading occur. To describe these molecular signaling networks that sense a mechanical signal and convert it into a transcriptional response, we proposed the mechanosome model. “GO” and “STOP” mechansomes contain an adhesion-associated protein and a nucleocytoplasmic shuttling transcription factor. “GO” mechanosomes functions to promote the anabolic response of bone to mechanical loading, while “STOP” mechanosomes function to suppress the anabolic response of bone to mechanical loading. While much work has been done to describe the molecular mechanisms that enhance the anabolic response of bone to loading, less is known about the signaling mechanisms that suppress bone’s response to loading. We studied two adhesion-associated proteins, Src and Pyk2, which may function as “STOP” mechanosomes. Src kinase is involved in a number of signaling pathways that respond to changes in external loads on bone. An inhibition of Src causes an increase in the expression of the anabolic bone gene osteocalcin. Additionally, mechanical stimulation of osteoblasts and osteocytes by fluid shear stress further enhanced expression of osteocalcin when Src activity was inhibited. Importantly, fluid shear stress stimulated an increase in nuclear Src activation and activity. The mechanism by which Src participates in attenuating anabolic gene transcription remains unknown. The studies described here suggest Src and Pyk2 increase their association in response to fluid shear stress. Pyk2, a protein-tyrosine kinase, exhibits nucleocytoplasmic shuttling, increased association with methyl-CpG-binding protein 2 (MBD2), and suppression of osteopontin expression in response to fluid shear stress. MBD2, known to be involved in DNA methylation and interpretation of DNA methylation patterns, may aid in fluid shear stress-induced suppression of anabolic bone genes. We conclude that both Src and Pyk2 play a role in regulating bone mass, possibly through a complex with MBD2, and function to limit the anabolic response of bone cells to fluid shear stress through the suppression of anabolic bone gene expression. Taken together, these data support the hypothesis that “STOP” mechanosomes exist and their activity is simulated in response to fluid shear stress.
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Linhartová, Jana. "Transplantace kadaverozní kostní dřeně: vliv hypoxie a metabolické starvace na myší krvetvorné kmenové buňky." Doctoral thesis, 2012. http://www.nusl.cz/ntk/nusl-307941.
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Objectives: Hematopoietic stem cell transplantation (HSCT) is a widely used method for treatment of hematological disorders and some other diseases. However, sometimes a suitable donor of hematopoietic stem cells (HSC) is not found for a patient. Because HSC have been described as cells with low proliferative and metabolic activity, their tolerance to the lack of oxygen or metabolic substrates may be assumed. In this study, we explored cadaveric bone marrow as an alternative source of HSC for HSCT, using a mouse experimental model. In addition, the effect of in vitro metabolic inhibition and short-term in vitro storage (1 - 4 days) on functional properties of mouse HSC was investigated. Methods: C57Bl/6 mice (wild-type or p53-/- ) were used in the experiments. To explore cadaveric HSC, bone marrow (BM) was left in intact femurs at 37řC, 20řC and 4řC under the conditions of ischemia. The bone marrow cells were harvested after defined time periods ranging 0 - 48 hours. For metabolic inhibition, the electron transport chain inhibitor potassium cyanide (KCN) and inhibitor of glycolysis 2-deoxy-D-glucose (2-DG) were used in vitro. To determine the impact of ischemia, metabolic inhibition, or in vitro storage on transplantability of HSC, the competitive repopulation assay using Ly5.1/Ly5.2 congenic model...