Osteoporosis is the most common debilitating bone disease affecting 24 million people in the U.S. An estimated 50 percent of women over 45 and 90 percent of women over 75 years of age have osteoporosis, of which approximately half will suffer osteoporotic fractures. The estimated cost of osteoporosis and related fractures is 7-10 billion dollars per year. Bone resorption by osteoclasts is an energy intensive process, requiring ATP hydrolysis by an H+-ATPase to drive proton secretion. Age-dependent changes in bone mass are accompanied by age-dependent changes in other parameters, including glucose intolerance. Osteoclasts are glucose responsive cells that resorb bone in a glucose concentration dependent manner with a Km of 3 mM. The data presented here indicate that osteoclasts have glucose concentration dependent changes in 1) ATP synthesis, 2) phosphate uptake, 3) tyrosine phosphorylation, and 4) phosphatidylinositol 3-kinase activity. In view of the high metabolic demands of bone resorption, I hypothesize that glucose directly alters the activity of osteoclasts by modulating critical signal transduction processes in these cells. The proposed research will define the molecular mechanisms and metabolic requirements responsible for regulating these signal transduction processes.
The Specific Aims are to: I: Characterize The Expression Of Glucose Transport Protein (S) In Osteoclasts. A. Determine the effect of bone attachment on GLUT2 expression in osteoclasts. B. Determine whether glucose transporters are translocated to the plasma membrane in response to bone attachment. II: Characterize Metabolic Elements That Govern Osteoclast Activity. A. Determine the rate limiting steps in glucose metabolism by osteoclasts. B. Characterize the glucose dependence of metabolic pathways. III: Identify Ket Signaling Pathways That Regulate Osteoclast Metabolism. A. Determine and characterize the role of glucose in osteoclastic phosphatidylinositol-dependent signaling pathways. B. Determine the role of glucose in modulating changes in tyrosine phosphorylation of specific proteins.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG016774-02
Application #
6168925
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Program Officer
Carrington, Jill L
Project Start
1999-05-01
Project End
2000-08-31
Budget Start
2000-05-01
Budget End
2000-08-31
Support Year
2
Fiscal Year
2000
Total Cost
$42,707
Indirect Cost
Name
University of Alabama Birmingham
Department
Pathology
Type
Schools of Medicine
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Falany, M L; Thames 3rd, A M; McDonald, J M et al. (2001) Osteoclasts secrete the chemotactic cytokine mim-1. Biochem Biophys Res Commun 281:180-5