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Date of Award
Doctor of Philosophy (PhD)
Mechanical loading is a potent anabolic stimulus that promotes bone formation. After skeletal development, bone formation occurs when osteoblasts are either activated from lining cells on the bone surface or recruited through differentiation or proliferation. The relative contribution of these different mechanisms to osteoblasts that make bone after mechanical loading remains unknown. The main focus of this dissertation was to better define the origin of cells on the bone surface and find the importance of proliferating cells to loading induced bone formation. For the first aim, we evaluated the role of osterix (Osx, an early transcription factor in osteoblast differentiation) lineage cells in response to mechanical loading. We first evaluated the effects of tamoxifen on loading induced bone formation and found a 3-week clearance following tamoxifen administration is necessary to reduce any effects of tamoxifen on the skeleton. We then used these mice for lineage tracing studies to evaluate the contribution of pre-existing Osx lineage cells, including those that arise due to cell proliferation, to loading induced bone formation. Our results demonstrated in 5- (young-adult) and 12- (middle-aged) month old mice that the initial wave of bone formation that occurs following mechanical loading is due to activation and proliferation of cells already committed to the Osx lineage, not the recruitment of progenitor cells. For the second aim, we evaluated the importance of proliferating osteoblast lineage cells to loading induced bone formation by utilizing a transgenic mouse that allowed for ablation of proliferating osteoblast lineage cells (3.6col1a1-tk). Since cell proliferation has been shown to be modestly increased in response to loads to stimulate lamellar bone formation and substantially increased in response to loads to stimulate woven bone formation, we sought to evaluate the importance of proliferating osteoblasts to both lamellar and woven bone formation. We found mineralizing surfaces to be reduced in both 5- and 12-month old mice loaded to stimulate lamellar and woven bone formation. This data suggests that proliferating osteoblasts are critical for maximal loading induced bone formation in young-adult and middle-aged mice. Overall, this dissertation has enhanced our knowledge of the role of osteoblast activation and proliferation in response to mechanical loading in young-adult (5-months old) and middle aged (12-months old) mice.
Matthew J. Silva
Roberto Civitelli, Fanxin Long, Erica Scheller, Lori Setton,
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