| Budget Amount *help |
¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 2000: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 1999: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1998: ¥1,200,000 (Direct Cost: ¥1,200,000)
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| Research Abstract |
The pathogenesis of rheumatoid arthritis (RA) has not been clarified yet, however, we have been presented that tumorigenic proliferation of synovium is one of the major etiology of this disease. Synoviocytes obtained from RA often present upregulated proliferative activity compared to normal synoviocytes in vitro, with acquirement of colony forming ability in soft agar, and loss of contact inhibition in the plastic dish. Based on these evidence, we started to investigate immaturity of RA synoviocytes. On the other hand, homeobox gene is essential for the formation of organs during embryonic and fetal stages, so we firstly examined which hox gene is responsible for the bone and joint formation. We examined gene expression of hoxd-9 to -13 in mouse embryos and fetus by RT-PCR and in situ RT assay combined with pathological staining of bone and cartilage. As a result, only Hoxd-9 is highly expressed during the joint forming period, whereas other gene was expressed constantly through embryonic and fetal stages. Then, we focused on hoxd-9 and examined its expression in RA and normal synovium obtained from human RA and osteoarthritis (OA) patients as well as HTLV-I tax transgenic mice (RA model mouse) and normal mice. As a result, synoviocytes from RA and HTLV-I tax transgenic mice showed hoxd-9 expression however OA and normal mice synoviocytes did not. We then transfected hoxd-9 into OA synoviocytes to determine this gene is responsible for the hyperplastic synovial proliferation. The result showed transfectant showed remarkable upregulation of proliferative activity, with also colony forming ability in soft agar. This transfectant showed upregulated expression of bFGF and c-fos. Moreover, its expression was upregulated by bFGF, HTLV-I tax, and also hoxd-9 itself, determined by luciferase assay. From these results, hoxd-9 is considered to be one of the essential genes for the acquirement of hyperplastic proliferative activity of RA synoviocytes.
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