Osteocytes, the cells that reside within bone matrix, are the most abundant bone cells. They function as the mechanical sensors in bone, and are critical to activation and coordination of osteoclastic and osteoblastic activities by which bone adapts to mechanical usage, maintains its health and prevents fractures. The mechanisms underlying osteocyte mechanotransduction are not well understood, though changes osteocyte mechanosensitivity have been implicated in regulating the effect of both bone anabolic agents and sex hormones. We have developed engineering models which show that small whole bone strains can be amplified locally around osteocyte processes by focal attachments to the canalicular wall. Osteocyte cell bodies cannot see similar high strains as they are too compliant and lack the cellular attachments needed for local strain amplification. These mathematical models argue that the osteocyte cell process may be uniquely designed to function as a detector of small tissue strains. To test this hypothesis, we developed a broad-based multiple-PI program that combines expertise in ion channel physiology, in vivo osteocyte structure/biomechanics and bioengineering/modeling to understand how osteocytes perceive and transduce their local mechanical environment. This program will a) examine the functional polarity of osteocyte mechano- responsiveness using electrophysiological approaches on cultured osteocytes (Aim 1), b) identify the molecular components of mechanotransduction complexes in osteocytes (Aim 2), c) characterize the structure of the mechanotransduction complex in osteocytes in vivo (Aim 3) and d) build integrative mathematical models relating local hydrodynamic forces and membrane strains at osteocyte processes and cell bodies to cellular responses in vitro and in vivo (Aim 4). We have also developed a novel technology (""""""""Stokesian"""""""" Fluid Stimulus probe) that allows us to hydrodynamically load osteocyte processes vs. cell bodies at extremely low forces (<10pN) typical of what bone cells actually experience in vivo. Expansion of this technology to interrogate mechano-responsiveness in a broad range of cell types is a developmental goal of this grant. Significance: Understanding how osteocytes """"""""perceive"""""""" and transduce mechanical signals may provide key new insights into bone physiology leading to the identification of novel therapeutic targets against bone loss due to aging and disease.
Osteocytes are the cells in bone that sense mechanical loading and translate mechanical strain into biochemical signals that initiate modeling and remodeling through which bone adapts its structure to its mechanical loading environment. This ability is key to skeletal health;failure to adapt results in bone in fragility. Increases and decreases in osteocyte mechanosensitivity have been implicated in regulating the bone response to anabolic agents, and conversely the bone loss resulting from estrogen loss, respectively. Thus understanding how osteocytes perceive and transduce mechanical signals may provide key new insights into bone physiology leading to the identification of novel therapeutic targets against bone loss due to aging and disease.
|Cabahug-Zuckerman, Pamela; Stout Jr, Randy F; Majeska, Robert J et al. (2018) Potential role for a specialized ?3 integrin-based structure on osteocyte processes in bone mechanosensation. J Orthop Res 36:642-652|
|Liu, Zhongbo; Han, Tianzhen; Werner, Haim et al. (2018) Reduced Serum IGF-1 Associated With Hepatic Osteodystrophy Is a Main Determinant of Low Cortical but Not Trabecular Bone Mass. J Bone Miner Res 33:123-136|
|Kennedy, Oran D; Lendhey, Matin; Mauer, Peter et al. (2017) Microdamage induced by in vivo Reference Point Indentation in mice is repaired by osteocyte-apoptosis mediated remodeling. Bone 95:192-198|
|Kaya, Serra; Basta-Pljakic, Jelena; Seref-Ferlengez, Zeynep et al. (2017) Lactation-Induced Changes in the Volume of Osteocyte Lacunar-Canalicular Space Alter Mechanical Properties in Cortical Bone Tissue. J Bone Miner Res 32:688-697|
|McCutcheon, Sean; Majeska, Robert; Schaffler, Mitchell et al. (2017) A multiscale fluidic device for the study of dendrite-mediated cell to cell communication. Biomed Microdevices 19:71|
|Lewis, Karl J; Frikha-Benayed, Dorra; Louie, Joyce et al. (2017) Osteocyte calcium signals encode strain magnitude and loading frequency in vivo. Proc Natl Acad Sci U S A 114:11775-11780|
|Frikha-Benayed, Dorra; Basta-Pljakic, Jelena; Majeska, Robert J et al. (2016) Regional differences in oxidative metabolism and mitochondrial activity among cortical bone osteocytes. Bone 90:15-22|
|Cabahug-Zuckerman, Pamela; Frikha-Benayed, Dorra; Majeska, Robert J et al. (2016) Osteocyte Apoptosis Caused by Hindlimb Unloading is Required to Trigger Osteocyte RANKL Production and Subsequent Resorption of Cortical and Trabecular Bone in Mice Femurs. J Bone Miner Res 31:1356-65|
|Liu, Zhongbo; Kennedy, Oran D; Cardoso, Luis et al. (2016) DMP-1-mediated Ghr gene recombination compromises skeletal development and impairs skeletal response to intermittent PTH. FASEB J 30:635-52|
|Cheung, Wing Yee; Fritton, J Christopher; Morgan, Stacy Ann et al. (2016) Pannexin-1 and P2X7-Receptor Are Required for Apoptotic Osteocytes in Fatigued Bone to Trigger RANKL Production in Neighboring Bystander Osteocytes. J Bone Miner Res 31:890-9|
Showing the most recent 10 out of 40 publications