Estrogen is known to play an important role in longitudinal bone growth and growth plate maturation, but the mechanism by which estrogens exert their effect is not fully understood. In this thesis... Show moreEstrogen is known to play an important role in longitudinal bone growth and growth plate maturation, but the mechanism by which estrogens exert their effect is not fully understood. In this thesis this role is further explored. Chapter 1 contains a general introduction to longitudinal bone growth and the regulation of the growth plate in respect to relevant topics further studied in this thesis. Estrogen can act through a genomic or a nongenomic pathway. Both pathways are explored in rats at the onset of maturation in chapter 2. Estrogen stimulates VEGF expression in uterus and bone, which is an important growth factor for chondrocyte differentiation and chondrocytes survival in the growth plate. In chapter 3 the effect of estrogen on VEGF expression in the growth plate was studied in the rat and human growth plate. Another effect of estrogen is that it accelerates growth plate senescence. Senescence is one of the postulated intrinsic mechanisms by which the growth plate matures and finally fuses. In chapter 4 we investigated senescence in relation to proliferation, by investigating a cell cycle inhibitor p27Kip1. In animal models, catch-up growth is suggested to be caused by delayed growth plate senescence. In chapter 5 this hypothesis was further tested in humans. With puberty estrogen levels increase, the growth plate matures and at the end growth ceases with epiphyseal fusion through mechanisms not yet completely understood. In order to further explore growth plate maturation we subjected two growth plate tissues of the same patient, but with one year and one pubertal Tanner stage in between, to microarray analyses. Gene expression patterns and transcription factor binding sides in relation to pubertal maturation were studied in a longitudinal study within this single patient in chapter 6. In addition, we collected extra prepubertal and pubertal growth plate tissues and studied these samples with microarray techniques as well in chapter 7. In chapter 8 the process of epiphyseal fusion and apoptosis was studied in human growth plates. Animal models are frequently used but not fully representative for the human growth plate. Therefore we investigated a promising human in vitro model with multipotent mesenchymal stem cells (MSCs) that can differentiate into chondrocytes. MSCs can be isolated from various tissues. In chapter 9 we investigated the chondrogenic potential of MSCs from different origins and in chapter 10 we compared this model with the epiphyseal growth plate by analyzing gene expression patterns and pathways with micro-array analyses. Chapter 11 contains general conclusions and a discussion regarding the results. Show less
In this thesis the role of several apoptosis regulating proteins in the development of atherosclerosis and atherosclerotic plaque stability is investigated. Apoptosis of different cell types in... Show moreIn this thesis the role of several apoptosis regulating proteins in the development of atherosclerosis and atherosclerotic plaque stability is investigated. Apoptosis of different cell types in atherosclerotic plaques, such as macrophages and smooth muscle cells may inhibit or promote plaque development or stability depending on the stage of atherosclerosis. As many of these apoptosis regulating proteins also display immune-modulating features, we have particularly investigated effects of modulation of apoptosis regulating proteins on plaque and systemic inflammation. We performed a number of studies in mouse models of atherosclerosis. First gene expression profiles of stable and unstable atherosclerotic plaques were compared in order to identify genes or pathways that are associated with plaque vulnerability. We further developed transgenic mice partially or wholly lacking genes involved in apoptosis and/or inflammation such as Bcl-2 family members and focal adhesion kinase, both systemically or in the leukocyte subset. The studies described in this thesis show amongst other things that Bim and Mcl-1, both members of the Bcl-2 family of apoptosis regulators, regulate specific cell death and inflammatory processes relevant to atherosclerosis. Show less
Colorectal cancer (CRC) is a complicated disease in which both genetic pre-desposition and environmental factors are important. Patients with inflammatory bowel disease (IBD) have an increased risk... Show moreColorectal cancer (CRC) is a complicated disease in which both genetic pre-desposition and environmental factors are important. Patients with inflammatory bowel disease (IBD) have an increased risk of developing CRC, and it is believed that treatment of IBD patients with 5-Aminosalicylic acid (5-ASA) reduces the CRC risk. The general purpose of the studies described in this thesis was to evaluate the effect of 5-ASA on the development of CRC, as well as determining the feasibility of introducing 5-ASA as an adjuvant therapy for CRC patients. Animal research showed that chronic 5-ASA medication has the ability to prevent colitis-associated CRC, confirming results from 5-ASA medication in IBD patients. Although 5-ASA was not able to prevent the development of sporadic CRC, 5-ASA treatment was found to hold a great promise for the treatment of CRC, by exerting CRC growth inhibiting, anti-progression and cell death inducing effects, and should be considered to be implemented in a future treatment strategy to CRC. Besides this, the determination of cell death products in the circulation of CRC patients and within the tumour, holds a great promise for selection of CRC patient treatment and patient folluw-up. Show less
