TAKATORI Yoshio The University of Tokyo, Faculty of Medicine, Associate Professor, 医学部附属病院, 助教授 (40179461)
KAWAGUCHI Hiroshi The University of Tokyo, Faculty of Medicine, Associate Professor, 医学部附属病院, 助教授 (40282660)
HOSHI Kazuto The University of Tokyo, Faculty of Medicine, Visiting Associate Professor, 医学部附属病院, 客員助教授 (30344451)
CHUNG Ung-il The University of Tokyo, Faculty of Medicine, Associate Professor, 大学院医学系研究科, 助教授 (30345053)
ISHIHARA Kazuhiko The University of Tokyo, Faculty of Industry, Professor, 大学院医学系研究科, 教授 (90193341)
|Budget Amount *help
¥49,530,000 (Direct Cost: ¥38,100,000、Indirect Cost: ¥11,430,000)
Fiscal Year 2006: ¥9,750,000 (Direct Cost: ¥7,500,000、Indirect Cost: ¥2,250,000)
Fiscal Year 2005: ¥11,960,000 (Direct Cost: ¥9,200,000、Indirect Cost: ¥2,760,000)
Fiscal Year 2004: ¥11,570,000 (Direct Cost: ¥8,900,000、Indirect Cost: ¥2,670,000)
Fiscal Year 2003: ¥16,250,000 (Direct Cost: ¥12,500,000、Indirect Cost: ¥3,750,000)
Osteoarthritis (OA), that affects all joints in the body, is a very common skeletal disorder. It is estimated that more than 10 million persons are suffering from the disease. However, the molecular mechanism of OA remains unclarified, and even the basic epidemiologic index like prevalence rate or incidence rate has not yet been elucidated. This research attempted to clarify the molecular backgrounds and detect the therapeutic target of OA by the following three independent projects.
1)Reverse genetics through using mouse models : We created experimental OA models in mice by producing instability in the knee joints. In these models, type X collagen (Col X) expression and matrix metalloproteinase-13 (MMP-13) expression were induced in the joint cartilage during OA progression (Osteoarthritis Cartilage 13 : 632, 2005). Since chondrocyte hypertrophy is known to be positively regulated by a transcriptional activator Runx2, we found that cartilage destruction was suppressed by the Runx2 hapl
oinsufficiency (Arthritis Rheum 54 : 2462, 2006). In the meantime, we recently identified a novel chondrocyte-specific protein, carminerin, which was up-regulated in association with ectopic ossification of the mouse auricular cartilage (J Biol Chem 278 : 48259, 2003). When OA was induced in the knee joint, osteophyte formation was much milder in the Cmr-l-joints than in the WT (Nature Med 12 : 665, 2006). The facts that Runx2 and carminerin insufficiency prevented cartilage destruction and osteophyte formation, respectively, without affecting physiological skeletal conditions suggest that these molecules can clinically be therapeutic targets of these distinct disorders of OA.
2)Forward genetics from human genomic approach : We established a large-scale nationwide clinical study called ROAD (research on osteoarthritis against disability) in 2005, and created a comprehensive and systemic database including clinical and genetic information in three cohorts of urban, mountainous and seacoast areas. We recruited 3,040 participants in total, from which 2,164 subjects older than 60 years (men : 818, 74.7 yrs., women : 1,470, 74.0 yrs.) were enrolled for investigation of the prevalence of radiographic OA of knee and lumbar spine, as well as its association with the respective local pain. Prevalence of radiographic OA (KL> or = 2) in either knee joint was 47.0% in men and 70.2% in women, while that in either intervertebral space was 84.1% in men and 70.7% in women. Prevalence of radiographic knee OA was higher in female sex (OR=3.28) and mountainous residence (OR=1.62), whereas that of lumbar OA was higher in male sex (OR=2.06). With the progress of the ROAD study, the underlying environmental and genetic backgrounds will be elucidated.
3)Basic study for cartilage regenerative medicine: We established an original real-time monitoring system for chondrogenesis, and identified that a transcription factor SOX9 and its co-activators SOX5 and SOX6 (the SOX trio) induce the early stage of chondrocyte differentiation and suppress its terminal stage (Arthritis Rheum 50 : 3561, 2004). The present microarray analysis identified S100A1 and S100B as the most probable target molecules of the SOX trio. Luciferase-reporter, electrophoretic mobility shift, and chromatin immunoprecipitation analyses revealed the transcriptional induction of both S100 proteins by the SOX trio, and identified the respective enhancer elements in the 5'-end flanking region. S100A1 and S100B mediate the inhibition of terminal differentiation of chondrocytes by the SOX trio as the transcriptional targets (EMBO Rep, in press). We further established a real-time fluorescence monitoring cell line for chondrogenesis ATDC5-S2RD5. Using it, we identified a novel chondrogenic factor SNX19 which was a cytoplasmic protein related to the p38 signaling for chondrogenesis. Further screening of molecules using this monitoring cell line will elucidate the molecular network underlying chondrogenic differentiation leading to a novel cartilage regenerative medicine. Less