| Budget Amount *help |
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 1999: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1998: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 1997: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
Inflammatory cytokines, matrix metalloproteinase-9 and-2(MMP-9, -2)have been thought to play a crucial role in the odontogenic jaw cyst expansion. At first, we investigated the expression of interleukin-lα. (IL-lα), interleukin-1β(IL-lβ), and tumor necrosis factor-α(TNF-α)in the cysts, and secondary we investigated the regulatory mechanisms of MMP-9 and MMP-2 expression and activation in the cysts.
In situ hybridization and immunohistochemical studies revealed that the grade of expression of IL-lα mRNA and protein was more abundant in odontogenic keratocysts than dentigerous cysts and radicular cysts, while there was no significant difference in the grade of expression of IL-lβ and TNF-α mRNAs between the different types of the cysts. The cell proliferating activity of the epithelial cells were well associated with the grade of IL-lα mRNA expression.
Secandary, we found that exogenously added recombinant human IL-lα(rhIL-1α)increased the secretion and activation of proMMP-9 in the fragme
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nts of odontogenic jaw cysts. Under the cultivation of the epithelial cells isolated from odontogenic keratocysts on a fibronectin-coated dish, rhIL-lα increased the secretion of proMMP-9 from the cells in a dose-dependent manner. Moreover, rhIL-lα induced the secretion of proMMP-3 and plasminogen activator urokinase(u-PA)from the epithelial cells, and converted the secreted proMMP-3 to the active form in the presence of plasminogen. The secreted proMMP-9 was also activated in the presence of rhIL-lα and plasminogen.
Finally, the fibroblasts isolated from odontogenic keratocysts secreted 72 kDa MMP-2(proMMP-2)spontaneously in serum-free DMEM. The expression of membrane-type MMP-1(MT1-MMP), but not MT2-MMP nor MT3-MMP was induced on the fibroblasts by rhIL-1α, and the expression of MT-1(MT1-MMP), but not MT2-MMP nor MT3-MMP was induced on the fibroblasts by rhIL-1α, and the expression of MT1-MMP mRNA was also increased about 10-fold of the control by 10 nM rhIL-1α when the cells were cultured on type I collagen, and rhIL-1α activated the proMMP-2 in a dose-dependent manner.
Thus, we conclude that 1) IL-1α may play a crucial role for the regulation of epithelial cell proliferation in odontogenic jaw cysts. 2)IL-1α may up-regulate not only proMMP-9 secretion but also proMMP-9 activation by inducing proMMP-3 and u-PA production in the cyst epithelial cells in autocrine/paracrine regulatory mechanisms. 3) IL-1α may up-regulate proMMP-2 activation by inducing MT1-MMP expression on the fibroblasts synergistically with type I collagen. Less
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