Bone adapts readily to its mechanical loading environment. The """"""""mechanosensor"""""""" for this adaptation is widely believed to be the osteocyte, though the actual process is both unknown and critical to understanding the process of new bone formation. However, there is an emerging consensus that strain-induced interstitial fluid flow plays a key role in this mechanical signaling. In this proposal we address a new question: How would the osteocyte """"""""perception"""""""" of fluid flow be influenced by the presence of a pericellular matrix with transverse filaments that both tether the cell process to the canalicular wall and transmit fluid dynamic drag forces on the tethering filaments to the intracellular actin cytoskeleton in the cell processes? Our pilot studies have revealed the first clear identification of such transverse bridging fibers and a new theoretical model (You et al., 2001) has been developed to quantitatively explore this hypothesis. This model makes the remarkable prediction that the very small mechanical strains in live bone can be amplified 100-fold at the cellular level. If validated, the model resolves a fundamental paradox. It explains why tissue level strains in whole bone can be so much smaller than that measured in vitro dynamic substrate strains required to elicit intracellular biochemical responses. In the proposed studies, we will experimentally verify and measure the essential biological elements required by this new model. In particular, we will: (1) characterize the spacing and distribution of the transverse elements that tether the cell process to the canalicular wall; (2) identify, using immunohistochemical staining techniques, the proteoglycans that fill the pericellular space; (3) elucidate the structure of the actin filament bundle that fills the cell process; and (4) refine the theoretical model for predicting the cellular level strain amplification that occurs in the cell process due to the fluid drag on the pericellular matrix.
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