| While it is well documented that bone can adapt its mass and architecture to its mechanical environment, the underlying mechanisms of mechanotransduction, the process by which bone cells sense and respond to external mechanical loadings, are still poorly understood. Furthermore, studies from inbred mice have shown that mechanosensitivity---the ability of bone tissue to detect mechanical loads---could be under genetic control, but how genes exert their influence on bone's mechanotransduction are unclear. There is a consensus emerging that osteocytes may indeed function as sensors of local mechanical environment in bone. This dissertation aims to examine the two aspects of bone mechanotransduction from a view point of bone fluid flow in the lacunar-canalicular porosity.;Chapter 1 gives a state-of-the-art review on flow induced mechanotransduction and genetic influences on bone.s sensitivity in response to mechanical loadings.;The structural and mathematical model developed in Chapter 2 predicts that the membrane strains on osteocyte processes around newly identified attachment complexes are two orders of magnitude larger than overall tissue strains. Immunohistochemical studies in Chapter 3 show that paxillin is present along osteocyte processes, particularly with a punctate distribution, suggesting tiny focal attachments between membranes of osteocyte processes and conical protrusions from canalicular wall that might be comparable to the normal cytoskeletal elements characteristic of focal adhesions. Given several lines of evidence, results from Chapter 2 and 3 imply that tiny focal attachments along osteocyte processes could function as mechanotransducer sites regulated by mechanical stimuli generated by load-induced fluid flow in the lacunar-canalicular porosity.;Morphological studies in Chapter 4 show that the ultrastructures and transport rates of the lacunar-canalicular system are related to mechanosensitivities of inbred mice, suggesting the genetic regulation of mechanotransduction could be partially controlled through the lacunar-canalicular porosity.;Chapter 5 summarizes the major accomplishments and suggests directions for future research.;Abbreviations: B6---C57BL/6J, BMD---bone mineral density, C3H---C3H/HeJ, ECM---extracellular matrix, EM---electron microscopy, FAK---focal adhesion kinase, FSS---fluid shear stress, IHC---immunohistochemistry, IIAP---integrin intracellular anchoring protein, LCP---lacunar-canalicular porosity, LCS---lacunar-canalicular system, OPN---osteopontin, PGE2---prostaglandin E2... |
