2001 Fiscal Year Final Research Report Summary
Mechanism of regulation of bone metabolism by insulin receptor substrates (IRS-1 and IRS-2)
| Project/Area Number |
11470301
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Orthopaedic surgery
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| Research Institution | The University of Tokyo |
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Principal Investigator |
KONO Shinjiro Faculty of Medicine, The University of Tokyo, Assistant, 医学部・附属病院, 助手 (40333463)
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| Co-Investigator(Kenkyū-buntansha) |
TOBE Kazuyuki Faculty of Medicine, The University of Tokyo, Assistant, 医学部・附属病院, 助手 (30251242)
NAKAMURA Kozo Faculty of Medicine, The University of Tokyo, Professor, 医学部・附属病院, 教授 (60126133)
KAWAGUCHI Hiroshi Faculty of Medicine, The University of Tokyo, Assistant Professor, 医学部・附属病院, 講師 (40282660)
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| Project Period (FY) |
1999 – 2001
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| Keywords | insulin / IGF / bone / osteoporosis / IRS / osteoblast / 骨粗鬆症 |
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| Research Abstract |
Insulin receptor substrates (IRS-1 and IRS-2) are essential for intracellular signaling by insulin and insulin-like growth factor-I (IGF-I) , anabolic regulators of bone metabolism. To investigate the physiological roles of IRS-1 and IRS-2, weinvestigated the bone tissue of mice lacking IRS-1 or IRS-2 in vivo and in vitro. Mice lacking the IRS-1 gene (IRS-1^<-・-> mice) showed low-turnover osteopenia with the decrease in both bone formation and resorption. This was due to the impairment of the anabolic function and RANKL induction in osteoblasts. IRS-1^<-・-> mice also showed the impairment of the fracture healing ability by inhibiting the proliferation of mesenchymal cells and chondrocytes, suggesting that IRS-1 is essential for bone repair. On the other hand, IRS-2^<-・-> mice showed osteopenia with decreased bone formation and increased bone resorption. This was due to the impaired anabolic function and enhanced RANKL expression in osteoblasts. We propose that these anabolic actions are maintained as an integration of two proteins that have distinct biological roles in osteoblasts: IRS-1 and IRS-2. The former is essential to maintain bone turnover by up-regulating anabolic function and RANKL expression, while the latter is needed to keep the predominance of the anabolic function over the catabolic function.
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