Macrophage colony stimulating factor (CSF-1) is essential for the formation of osteoclasts that, in turn, regulate bone turnover. The long-term goal of this proposal is to determine the role of CSF-1 in osteoclast- and monocyte-mediated bone and cartilage destruction in rheumatoid arthritis (RA) using animal models and whether inhibition of CSF-1 alone or in combination with vascular endothelial growth factor (VEGF) ameliorates the disease. Recently, we identified a -3.3 kb/+183 bp region of the CSF-1 promoter that confers lacZ expression in joint tissues of transgenic mice which will be useful for targeting exogenous genes to joint tissue. Our hypothesis is that CSF-1 acts in concert with VEGF, an angiogenic factor that promotes pannus expansion, to enhance cartilage and bone destruction in RA. Patients with RA show increased levels of CSF-1 and VEGF in synovial tissues and serum. However, whether the soluble (s) and membrane-bound (m) forms of CSF-1 mediate distinct biologic effects in RA is unknown. To address this issue, we will use a knock-out and high throughput knock-in approach to selectively express sCSF-1 or mCSF-1 in mice and examine their effect in collagen-induced arthritis (CIA), a model that mimics the human counterpart of RA. Optimal management of RA would require inhibition of synovial hyperplasia, cartilage and bone destruction. Our plan is to inhibit CSF-1 and VEGF in the joint microenvironment using soluble CSF-1 receptor (CSF-1 R) and soluble VEGF receptor (FLT-1), thereby preventing the onset and/or ameliorating established arthritis. The efficacy of osteoclast antagonists in combination with anti-angiogenic factors in RA has not been explored. For these studies, transgenic mice carrying the CSF-1 R under the control of the -3.3 kb/+183 bp CSF-1 promoter will be generated and assessed for clinical and histologic severity of CIA. The effect of combined treatment with FLT-1 in CIA will be determined by delivering FLT-1 to the joints of CSF-1 R transgenic mice using adenoviral and retroviral based approaches. These studies should elucidate the role of CSF-1 isoforms and the therapeutic efficacy of inhibiting osteoclast activity and angiogenesis in rheumatoid arthritis and perhaps, identify novel strategies for therapeutic intervention in this disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR042306-12
Application #
7472323
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Mancini, Marie
Project Start
1994-01-01
Project End
2010-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
12
Fiscal Year
2008
Total Cost
$208,926
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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