Significance: Although osteocytes make up over 90% of all bone cells, little is known about their function, compared to other bone cells, the osteoblast and the osteoclast. The osteocyte is the cell ideally situated in bone to sense mechanical strain and translate that strain into signals for bone formation and bone resorption. However, the role of osteocytes in modulating strain effects on bone modeling and remodeling is unclear: Approach: This Program Project Application was initiated to develop a time approach to clarify the mechanisms by which osteocytes sense and respond to mechanical strain in a manner that results in either bone loss, remodeling, or pathologic repair. The focus of this application is to determine the role of the osteocyte in signaling bone resorption. The mechanisms whereby osteocytes translate mechanical strain into signals include intracellular and extracellular signaling initiate or controlling osteoblast/osteoclast activity and the expression of genes necessary and specific for osteocyte function.
The specific aims of the program project are: 1) determine the role and regulation of gap junction function in osteocytes, 2) to determine the levels of mechanical strains sensed by the osteocyte resulting from the mechanical stimulation of bone, 3) to identify osteocyte specific genes and their regulation by mechanical strain and 4) to determine the role of the osteocyte in osteoclast formation. Innovation: Novel approaches to answer these questions include the use of an osteocyte-like cell line, the use of bioengineering micro- mechanisms techniques to measure strain sensed by individual osteocytes, fluorescence image analysis to examine gene expression in single cells, novel animal models, and gene array technology to examine genes regulated by mechanical strain. Investigators and Environment: The program project is composed of investigators with specific talents, training and expertise in the areas of molecular biology, cell known for its contributions in the area of bone and cartilage biology. Knowledge gained will lead to identification of ways to regulate or inhibit the osteocytic signals of resorption that can be used towards the prevention and treatment of bone loss due to immobilization, space flight, microdamage, aging and disease states such as osteoporosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Program Projects (P01)
Project #
5P01AR046798-04
Application #
6632760
Study Section
Special Emphasis Panel (ZAR1-AAA-C (O2))
Program Officer
Sharrock, William J
Project Start
2001-04-01
Project End
2005-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
4
Fiscal Year
2003
Total Cost
$1,007,149
Indirect Cost
Name
University of Missouri Kansas City
Department
Dentistry
Type
Schools of Dentistry
DUNS #
010989619
City
Kansas City
State
MO
Country
United States
Zip Code
64110
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Prideaux, Matthew; Dallas, Sarah L; Zhao, Ning et al. (2015) Parathyroid Hormone Induces Bone Cell Motility and Loss of Mature Osteocyte Phenotype through L-Calcium Channel Dependent and Independent Mechanisms. PLoS One 10:e0125731
Riquelme, Manuel A; Burra, Sirisha; Kar, Rekha et al. (2015) Mitogen-activated Protein Kinase (MAPK) Activated by Prostaglandin E2 Phosphorylates Connexin 43 and Closes Osteocytic Hemichannels in Response to Continuous Flow Shear Stress. J Biol Chem 290:28321-8
Kamel-ElSayed, Suzan A; Tiede-Lewis, LeAnn M; Lu, Yongbo et al. (2015) Novel approaches for two and three dimensional multiplexed imaging of osteocytes. Bone 76:129-40
Xu, Huiyun; Gu, Sumin; Riquelme, Manuel A et al. (2015) Connexin 43 channels are essential for normal bone structure and osteocyte viability. J Bone Miner Res 30:436-48
Batra, Nidhi; Riquelme, Manuel A; Burra, Sirisha et al. (2014) Direct regulation of osteocytic connexin 43 hemichannels through AKT kinase activated by mechanical stimulation. J Biol Chem 289:10582-91
Kitase, Y; Lee, S; Gluhak-Heinrich, J et al. (2014) CCL7 is a protective factor secreted by mechanically loaded osteocytes. J Dent Res 93:1108-15

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