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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR057139-04
Application #
8522156
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Sharrock, William J
Project Start
2010-09-06
Project End
2015-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
4
Fiscal Year
2013
Total Cost
$470,767
Indirect Cost
$94,654
Name
City College of New York
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
603503991
City
New York
State
NY
Country
United States
Zip Code
10031
Smaldone, Silvia; Clayton, Nicholas P; del Solar, Maria et al. (2016) Fibrillin-1 Regulates Skeletal Stem Cell Differentiation by Modulating TGFβ Activity Within the Marrow Niche. J Bone Miner Res 31:86-97
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
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
Kaya, Serra; Basta-Pljakic, Jelena; Seref-Ferlengez, Zeynep et al. (2016) Lactation-Induced Changes in the Volume of Osteocyte Lacunar-Canalicular Space Alter Mechanical Properties in Cortical Bone Tissue. J Bone Miner Res :
Seref-Ferlengez, Zeynep; Maung, Stephanie; Schaffler, Mitchell B et al. (2016) P2X7R-Panx1 Complex Impairs Bone Mechanosignaling under High Glucose Levels Associated with Type-1 Diabetes. PLoS One 11:e0155107
Cardoso, Luis; Schaffler, Mitchell B (2015) Changes of elastic constants and anisotropy patterns in trabecular bone during disuse-induced bone loss assessed by poroelastic ultrasound. J Biomech Eng 137:
Coughlin, Thomas R; Voisin, Muriel; Schaffler, Mitchell B et al. (2015) Primary cilia exist in a small fraction of cells in trabecular bone and marrow. Calcif Tissue Int 96:65-72
Stout Jr, Randy F; Snapp, Erik Lee; Spray, David C (2015) Connexin Type and Fluorescent Protein Fusion Tag Determine Structural Stability of Gap Junction Plaques. J Biol Chem 290:23497-514
Burke, Shoshana; Nagajyothi, Fnu; Thi, Mia M et al. (2014) Adipocytes in both brown and white adipose tissue of adult mice are functionally connected via gap junctions: implications for Chagas disease. Microbes Infect 16:893-901
Bejarano, Eloy; Yuste, Andrea; Patel, Bindi et al. (2014) Connexins modulate autophagosome biogenesis. Nat Cell Biol 16:401-14

Showing the most recent 10 out of 30 publications