|Budget Amount *help
¥3,200,000 (Direct Cost : ¥3,200,000)
Fiscal Year 2000 : ¥600,000 (Direct Cost : ¥600,000)
Fiscal Year 1999 : ¥900,000 (Direct Cost : ¥900,000)
Fiscal Year 1998 : ¥1,700,000 (Direct Cost : ¥1,700,000)
Many factors, such as gene or sex, are involved in the development of osteoarthritis. Among them, mechanical stress loaded on the cartilage plays a crucial role in this process (9). We demonstrated the expression of c-fos gene, nuclear transcriptional factor, and protein kinase C (PKC) using experimentally induced osteoarthritis (11). We focused on this c-fos and PKC cascade (12), because an enhancement of the cytosol calcium [Ca2+] is essential in the PKC activation and [Ca2+] plays an important role in the chondrocyte metabolisms (10) . We also obtained the evidence showing the significance of free radical in the cartilage degradation (8). These observations obtained 1998 clearly indicate the significant role of free radical in the c-fos and PKC cascade in terms of cartilage degradation.
To determine the precise role of this cascade, we set up in vitro experiment in 1999. We loaded cyclic tensile stretch on the cells and determined whether GTP binding protein (G protein), which is a
up-stream regulator of c-fos and PKC cascade, and nitric oxide (NO) . Induction of NO exhibited biphasic pattern, i.e. excessive stress inhibited and small stress enhanced NO synthesis, respectively. We found the involvement of Gi in excessive-stress-inhibited NO synthesis (6) . We also interested in the mechanism of chondrocyte apoptosis and found the role mitogen activated protein kinase (MAPK) in hydrogen peroxide (H2O2)-induced apoptosis (7). regulated by extracellular signal-regulated protein kinase (2). Stress-inhibited NO synthesis, mentioned above, is also regulated with cytoskeleton as well as G protein (1) . From the view point of therapeutic aspect, hyaluronate regulates free radical to prevent the cartilage degradation (4).
These data indicated the involvement of MAPK, PKC, c-fos and [Ca2+] in the signal transduction pathway of the mechanical stress. It is clear that G protein, cytoskeleton and free radical regulate these process.