Loss of bone mass throughout the body, and especially adjacent to inflamed joints, is a major cause of morbidity and fracture in veterans with rheumatic diseases. Although bisphosphonates are sometimes used to protect bone in veterans with rheumatoid arthritis, there is no evidence-based indication that this therapeutic maneuver is effective. The long- term goal of the studies proposed in this application is to elucidate the mechanisms causing inflammation-associated bone loss. Osteoclasts are the only cells capable of degrading bone and RANKL is a protein produced by cells that support osteoclast differentiation that is essential for this process. Therefore, the studies proposed in this application seek to understand the mechanisms that control RANKL gene expression and identify the cell types that express it during inflammation by addressing the following hypothesis: inflammation- associated bone loss is due to stimulation of the RANKL gene in fibroblasts and stromal/osteoblastic cells, but not in activated T cells, and stimulation of RANKL expression is mediated by distant transcriptional regulatory elements. The studies in Specific Objective 1 will determine whether RANKL expression in lymphocytes contributes to bone loss in murine models of inflammation and sex steroid deficiency by deleting this gene specifically in T cells or B cells. Studies in Specific Objective 2 will identify the mechanisms by which inflammation stimulates RANKL gene transcription in stromal/osteoblastic cells and T lymphocytes by identifying the transcriptional responsive regions of the RANKL gene. Lastly, the studies in Specific Objective 3 will determine the role of a transcriptional enhancer of the RANKL gene, identified previously, in the bone loss associated with murine models of inflammation and sex steroid deficiency. It is important to note that the studies proposed in this application to elucidate the mechanisms causing inflammation-associated bone loss would also be relevant to other bone losing conditions such as periodontal tooth loss (the most common cause of adult loss of dentition), as well as the bone loss that occurs around prosthetic joints and results in their failure. In summary, the studies proposed in this Merit application are relevant to several major causes of localized as well as systemic bone loss and are thus important to the veterans patient health care mission.

Public Health Relevance

Potential Impact on Veterans Health Care. Loss of bone mass throughout the body, and especially adjacent to inflamed joints, is a major cause of morbidity and fracture in veterans with rheumatic diseases. Although bisphosphonates are sometimes used to protect bone in veterans with rheumatoid arthritis, there is no evidence-based indication that this therapeutic maneuver is effective. TNF antagonists are another therapeutic option, but as many as 40% of rheumatoid arthritis patients do not respond to anti-TNF therapy. This, and the high cost and uncertain long- term safety of anti-TNF proteins, suggests that novel approaches are still required. Studies that address the mechanism behind the bone loss that occurs with inflammation are therefore of major clinical importance in the VA healthcare mission. Furthermore, studies proposed in this application to elucidate the mechanisms causing inflammation-associated bone loss would also be relevant to other bone losing conditions such as periodontal tooth loss (the most common cause of adult loss of dentition), as well as the bone loss that occurs around prosthetic joints and results in their failure. In summary, the studies proposed in this Merit application are relevant to several major causes of localized as well as systemic bone loss and are thus important to the veterans patient health care mission.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX000294-04
Application #
8258635
Study Section
Endocrinology B (ENDB)
Project Start
2009-04-01
Project End
2013-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
4
Fiscal Year
2012
Total Cost
Indirect Cost
Name
Central Arkansas Veterans Hlthcare Sys
Department
Type
DUNS #
082573742
City
North Little Rock
State
AR
Country
United States
Zip Code
72114