Glutamine is a conditionally essential amino acid that has myriad uses in the cell. Aside from direct incorporation into protein, glutamine can be metabolized to generate nucleotides, other amino acids, ATP after anaplerosis into the TCA cycle, and glutathione to protect against oxidative stress. It is unknown how osteoblasts utilize glutamine and when it is required during differentiation. We recently identified glutaminase (GLS) as a critical regulator of Wnt dependent pathological bone formation. GLS deaminates glutamine to form glutamate, the first step in glutamine metabolism. Using a pharmacological approach, we demonstrated GLS activity was required for bone formation in the LRP5 human high bone mass disease mouse model. Importantly, GLS inhibition did not affect bone mass in otherwise wild type mice indicating GLS and glutamine metabolism may not be required for physiological bone formation in mice. In this proposal, we will 1) establish the necessity and sufficiency of glutaminase (GLS) to regulate osteoblast differentiation and bone formation, 2) determine if the molecular regulation of GLS activity by WNT, and 3) understand how glutamine is metabolized in mesenchymal stem cells. Our findings will have broad implications in bone development, maintenance of bone mass, skeletal repair and regeneration, as well as identify if stimulating glutamine metabolism is a viable osteoanabolic target to stimulate bone formation.

Public Health Relevance

Glutaminase (GLS) activity and glutamine metabolism are required for Wnt-dependent pathological bone formation in mice, although the role of GLS activity in physiological bone formation is unknown. Data generated by this proposal will: 1) establish the necessity and regulation of glutamine metabolism during physiological bone formation, and 2) establish the therapeutic feasibility of stimulating GLS activation to stimulate bone formation in osteoporotic patients. Our findings will have broad implications in bone development and the maintenance and regeneration of bone mass.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR071967-01A1
Application #
9522888
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Nicks, Kristy
Project Start
2018-04-01
Project End
2023-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Duke University
Department
Orthopedics
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705