CSF-1 Gene Expression in Osteoclast Biology

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DESCRIPTION (provided by applicant): 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.