Osteocytes are skeletal cells responsible for detecting and translating physical signals into biochemical cues to direct bone remodeling; the process known as mechanotransduction. The healthy adult skeleton responds to even miniscule bone deformations resulting from daily activities, e.g. walking and running, and the lack thereof, with increases or decreases in tissue mass, respectively; affecting both fracture resistance and tissue efficiency. Bone deforms to only 0.01-0.3% strain under physiological loading, yet the amount of strain necessary to stimulate a cell in vitro is 1%, which is the yield point of bone – so the precise mechanism as to how bone cells detect physiological stimuli is yet unclear. It has been established that osteocytes are the bone cells responsible for mechanotransduction; our lab has demonstrated that osteocyte processes possess highly mechanosensitive structures, which cause a cellular response to <10 pN fluid forces, structures not present on osteocyte bodies. Mathematical modeling of bone tissue osteocyte membrane strain predicts that αVβ3 integrin foci anchoring along process membranes to conical protrusions on the canalicular wall become areas of high membrane tension during physiological loading that trigger stretch-activated ion channels in the vicinity. We hypothesize that αVβ3-integrin foci form mechanotransductive structures along bone tissue osteocyte processes in association with stretch-activated, purinergic receptor and calcium channels, which alter in response to whole bone mechanical perturbations. Using mice bone tissue, an in situ detection system was developed to detect membrane proteins via double fluorescent immunohistochemistry, visualize and quantify protein staining using Structured Illumination Microscopy and determine the extent of their colocalization. The specific aims of this Thesis are to (1) identify the αVβ3-integrin based osteocyte mechanotransductive structure, distinct from integrin based mechanotransductive focal adhesions, (2) determine the mechanical effects of channel distance from αVβ3-integrin anchoring in the mechanotransductive structure, (3) determine its plasticity with altered loading in disuse and reambulation, and (4) examine the changes after estrogen loss, a model for diminished mechanical sensitivity to contrast with mechanical unloading. A mechanotransductive structure (mechanosome) consisting of β3 integrin, P2X7R, Panx1 and CaV3 along osteocyte processes was detected, not present in cell bodies and concentrated in the proximal region of the processes. Osteocytes responded to changes in mechanical loading differently than to changes in hormonal levels, in terms of the mechanosomes: disuse resulted in decreased mechanosome population, which recovered upon reambulation, whereas in estrogen loss, the population remained unchanged. We show for the first time an integrin-based mechanosome in bone tissue, exhibiting plasticity in response to changes in mechanical loading. These findings suggest the potential protein targets for therapy against disuse and age-related osteoporosis.