Thesis (doctoral)--Københavns Universitet. / Summary in Danish. Bibliography: p. 44-48.

Thesis (Ph. D.)--University of Lund, 1995. / Published dissertation.

Thesis (doctoral)--Lund University, 1998. / Added t.p. with thesis statement inserted.

Thesis (Ph. D.)--Oregon State University, 2005. / Includes bibliographical references. Also available online (PDF file) by a subscription to the set or by purchasing the individual file.

Thesis (Ph. D.)--Oregon State University, 2005. / Includes bibliographical references.

Osteoporosis is characterized by chronic bone loss and deterioration of microarchitecture that can leave patients more susceptible to costly and debilitating fractures. A variety of treatment options have been developed that target different cells and pathways to disrupt its progression. In addition to pharmaceutical options, regular exercise is recommended, as external, mechanical loading has long been recognized as a stimulus bone can use to regulate its size and shape to meet mechanical demands. While bone cell signaling is undoubtedly multifaceted, meaningful changes in bone mass ultimately result from the actions of bone-forming osteoblasts and bone-resorbing osteoclasts. To this end, therapies are most traditionally described through their impacts on these cells, and are broadly categorized as anabolic (activating osteoblasts and having bone-building effects, such as parathyroid hormone injections and sclerostin antibody treatment), or anti-resorptive (targeting osteoclasts and slowing resorption, such as bisphosphonates and denosumab). Bone formation and resorption are rooted in two overarching processes: coupled bone remodeling (resorption followed by formation in the same space) and uncoupled bone modeling (formation or resorption occurring independently). Hematopoietic-lineage cells have an inherent, established role in bone remodeling, as descendent osteoclasts perform the resorption to initiate remodeling, but have only more recently been implicated as potential orchestrators of anabolic bone modeling in their preosteoclastic states, suggesting the extent of their differentiation may be a mechanism steer the bone response between maintenance remodeling and adaptive modeling regimes. Understanding how pharmaceutical treatments and mechanical loading work through these regimes, augment intrinsic sensing mechanisms, or tilt local signals to favor one or the other may provide valuable insight into optimizing or combining current treatments, and potentially suggest new therapeutic avenues. We first establish a method for quantifying modeling and remodeling in vivo using image registration on weekly micro-computed tomography scans. This technique is implemented in a study to assess the independent and combined effects of daily mechanical loading and parathyroid hormone injections in mice. We found that both resulted in significant increases in bone formation through anabolic modeling and remodeling, and while the modeling effects were usually additive or independent, the remodeling response was synergistic. Additionally, while PTH tended to exert its influence indiscriminately, the loading response was more targeted and pronounced in ways that mirrored local mechanical strains. Interestingly, this held true for catabolic modeling as well, where we observed a previously unreported phenomenon of load-induced increases in catabolic modeling in areas of low strain on the endosteal surface of cortical bone. We then began targeted interventions into the hematopoietic lineage cells, starting at their most terminally differentiated state in bone, the osteoclast. Using an injectable osteoclast maturation inhibitor, osteoprotegerin (OPG), we observed how arresting this process influenced modeling and remodeling in response to loading in normal mice, and in mice genetically modified to reduce sclerostin expression. We observed the expected reductions in catabolic modeling regardless of genotype. We also found that in sclerostin-depleted mice treated with OPG, anabolic modeling was elevated, and there was no added benefit of mechanical loading to the response in trabecular and endosteal compartments, suggesting the controlled manipulation of these factors can fully recapitulate the intrinsic mechanosensing capabilities. Since the loading response is largely modeling-based, these findings support the hypothetical determinant of the modeling/remodeling response being the preosteoclast/osteoclast ratio in these areas. In contrast, however, on the periosteal surface a pronounced load-induced anabolic modeling response persisted in all treatment conditions, suggesting the unique cell populations in the periosteum may have more robust, more finely tuned, or differentially regulated mechanosensing mechanisms. Finally, to probe the hematopoietic lineage further upstream and address the other side of the preosteoclast/osteoclast hypothesis, we utilized a novel genetically modified mouse model that allows for inducible macrophage (preosteoclast) ablation. Modeling and remodeling dynamics in response to loading were quantified in mice with normal or depleted macrophage quantities with concurrent normal or genetically-reduced sclerostin expression. In agreement with our hypothesis linking these cells to the anabolic modeling response, macrophage ablation resulted in significantly less anabolic modeling on trabecular and endosteal surfaces, which was not recovered by mechanical loading in either wild type or sclerostin deficient mice. Again, however, the periosteal surface was unique. Macrophage ablation did not reduce anabolic modeling on the periosteal surface, and loading still significantly increased it, regardless of sclerostin expression. Thus, similar to our findings with osteoprotegerin, a unique contrast existed between macrophage/preosteoclast ablation drastically reducing anabolic modeling and nullifying any mechanoresponse on trabecular and endosteal surfaces, but not the periosteal surface. Taken together, these studies outline and implement a novel method to quantify modeling and remodeling in response to loading and clinically relevant treatments, with an emphasis on perturbations of the hematopoietic lineage. Concurrent stimuli are used to observe and quantify overlaps and augmentations in treatment efficacies, with a focus on mechanisms related to mechanoadaptation. Future work will focus on targeted approaches to identify unique mechanosensing factors driving the periosteal response, more sophisticated data analysis tools to observe to what extent localized bone metabolism can be predicted by strain and morphology, and the protein and cellular-level dynamics that underlie our findings. As an addendum, a novel bone morphological parameter is described. A trabecular-cortical interface surface area metric (iSAM) is quantified on a set of cadaver bone segments from clinical high-resolution peripheral quantitative computed-tomography scans (a clinical analog to micro-computed tomography). iSAM is shown to correlate with stiffness and ultimate force derived from mechanical testing of the same samples, and improve correlations gleaned from traditional morphometric parameters alone.

The effect of restricting energy intake (ad libitim vs. 75% ad libitum) elevation of vitamin and mineral levels (150% NRC vs 100% NRC) and the effects of aging on bone growth, histological lesioning and biochemical composition of articular cartilage from growing boars was examined. Growth of the radius and tibia was characterized by radiography at eight equal time points from 110 to 330 d of age. Although ad libitum-fed boars had larger bones in most cases, calculation of weight corrected differences suggested that restriction of energy resulted in lover weight gain but that reduced energy intake slightly increased the rate of bone growth of the restrict-fed boars. Although elevation of vitamin and mineral levels resulted in a few scattered differences in bone size, no consistent trends were evident. Neither restriction of energy intake nor elevation of vitamins and minerals had any consistent effect on the reduction of histological lesion severity. Age, expressed as days on test, produced no definite trends toward increasing or decreasing frequency of histological lesions. The frequency and severity of gross lesions were unaffected by altered energy or vitamin-mineral levels, however, a sevenfold age-related increase in frequency of gross lesions was observed over time. Uronic acid content of the articular cartilage from the femur was greater for the restrict-fed boars, however, uronic acid content of cartilage from the humerus and radius tended to be greater for the ad libitum fed boars. Elevation of vitamins and minerals had no effect on uronic acid content of articular cartilage from the femur, humerus or radius. Uronic acid content of articular cartilage decreased consistently with age throughout the trial period. Galactose and hydroxyproline levels in cartilage samples from the femur, humerus and radius were generally unaffected by the imposed dietary treatments. Galactose levels were unaffected by age. Hydroxyproline content of cartilage from the radius and humerus increased with age, whereas, cartilage from the femur remained unchanged throughout the experimental period. No changes in percentage fat-free dry weight of articular cartilage samples from the femur, humerus, or radius due to treatment or age were evident. Articular cartilage from the radius had a higher percentage of fat-free dry weight than either the humerus or femur. Articular cartilage from the radius also contained less uronic acid than the femur or humerus. Galactose content of the radius was less than that of the humerus, however, galactose levels of the femur and radius did not differ. Hydroxyproline levels were similar among all areas sampled. In summary, skeletal growth rate was slightly greater for restrict-fed boars after weight correction, however, elevation of vitamins and minerals had no overall impact on any parameters measured. Age had a more pronounced, though inconsistent influence on lesion frequency, severity, and biochemical composition of the articular cartilage than the imposed dietary treatments. / Master of Science

published_or_final_version / Chinese / Master / Master of Arts

No description available.

In recent decades anthropologists and archaeologists have divided hunter-gatherer groups into two types; "simple" and "complex". However, many documented foraging communities display traits associated with both types, and the placement of past and present hunter-gatherers into either category is problematic. The substantial house remains of the late Younger Stone Age hunter-gatherers of Varangerfjord, North Norway, have been connected by many archaeologists with sedentism and, by extension, with "complexity" and permanent social hierarchies. This analysis takes a more direct approach social organisation, using faunal remains to better define the social relationships between households within this community. The large mammal remains from a series of houses are compared to determine whether all households had equal access to prey species and to different parts of large mammal carcasses. Towards this end, the climate and available resources are established for North Norway during the Younger Stone Age. Previous interpretations of the archaeology of the period, including the argument for "complexity" are then discussed. The study sites and associated faunal assemblages are presented. Seal hunting patterns are compared between households in terms of both the choice of species and the age breakdown of each hunted seal population. Local differences in the numbers of ringed seal are attributed to the preference of ringed seal for certain types of coastline. Strong similarities are noted between all sites in terms of both the season of seal hunting activity and the selection of adult versus juvenile harp seal and ringed seal. Distribution of seal and reindeer body parts are also compared between and within houses. Again, there are more similarities than differences between households. Seals were returned whole to all houses and reindeer body part representation appears to be mediated by the utility of each part for artefact manufacture. The implication of these results are discussed in terms of the structure of social relationships, symbolic behaviour and territoriality. The utility of this approach in a broader context is also considered.