| Budget Amount *help |
¥18,850,000 (Direct Cost: ¥14,500,000、Indirect Cost: ¥4,350,000)
Fiscal Year 2010: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2009: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2008: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000)
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| Research Abstract |
To clarify the in vivo function of CILP, which was identified as a susceptibility gene associated with cartilage degenerative disease, we firstly established conditional Tg mouse line expressing the gene specifically in cartilage or nucleus pulposus. X-ray, MRI and histochemical analysis of the mice lines indicated that the specific overexpression of the CILP in the nucleus pulposus was responsible for the accelerated intervertebral disc degeneration. This was apparently caused by in vivo binding of the TGFβwith CILP, reduced receptor binding and TGF. signaling that leads to the inhibition of the cartilage matrix gene expression. In addition there was enhanced matrix proteinase expression and disc cell apoptosis that also generated matrix homeostasis imbalance. Based on these observations, we then tried to block the factors associated with the CILP signaling pathway. Inhibition of aggrecanase by injection of ADAMTS5 siRNA in vivo using intervertebral disc degeneration model resulted in the protection of the progression. We also started to block the upstream signal of c-fos/AP-1 using newly developed specific inhibitor. Administration of the c-fos/AP-1 inhibitor to mouse DMM model dramatically prevented the progression of articular cartilage degeneration, partly through inhibition of proteinase expression. Thus, these observations suggested possible strategic targets for cartilage degeneration.
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