In an attempt to identify local mediators which activate mature osteoclasts directly, we found that a stromal cell line derived from a human giant cell tumor of bone was the source of an activity which was a more powerful stimulator of avian and rat osteoclasts (as well as the human osteoclast-like giant cells) than any other source or mediator we have studied. We have undertaken identification of this activity, and found it is due to several products of arachidonic acid metabolism in the 5-lipoxygenase (5-LO) pathway. In this proposal, 1) we plan to identify and characterize all of the compounds of the 5-LO pathway which stimulate osteoclast activity, 2) to determine whether this is a common mechanism by which bone resorption is enhanced by cells in the osteoblast lineage, 3) to study mechanisms by which expression of enzymes in the 5-LO pathway are regulated by osteotropic hormones and cytokines and 4) to identify and characterize the property of C433 conditioned media which prevents degradation of unstable 5-LO metabolites. Identification of the local soluble mediators which stimulate osteoclastic bone resorption should enhance our understanding of the hormonal mechanisms responsible for increased bone resorption in normal bone remodeling and in all pathologic states in which bone resorption is increased.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR042372-02
Application #
2081571
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Project Start
1993-05-01
Project End
1997-04-30
Budget Start
1994-05-01
Budget End
1995-04-30
Support Year
2
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
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