|Budget Amount *help
¥2,900,000 (Direct Cost : ¥2,900,000)
Fiscal Year 2004 : ¥900,000 (Direct Cost : ¥900,000)
Fiscal Year 2003 : ¥2,000,000 (Direct Cost : ¥2,000,000)
We previously revealed that menin, a product of multiple endocrine neoplasia type I gene, is required for the early differentiation of osteoblast and inhibits it at later stage. Moreover, we proposed that Smad3, TGF-beta-specific signaling molecule, is important for bone formation. On the other hand, parathyroid hormone (PTH) is one of most potent bone formation stimulating agents. However, the mechanism, by which PTH stimulates bone formation, remains unknown. In the present study, we demonstrated that PTH-Smad3 axis exerts anti-apoptotic effects in osteoblasts and might be involved in the bone anabolic action of PTH. In addition, dexamethasone, a glucocorticoid analogue, inhibits alkaline phosphatase activity and type I collagen expression, presumably by suppressing Smad3-induced transcriptional activity but not by modulating Smad3 expression in osteoblasts. This evidence might be partially related to the inhibitory action of glucocorticoid on osteoblastic bone formation. On the other hand, we demonstrated that menin interacts physically and functionally with Runx2 as well as Smad 1/5 in uncommited mesenchymal stem cells, but not in well differentiated osteoblasts. In osteoblasts, the interaction of menin and TGF-beta/Smad3 pathway negatively regulates the BMP-2/Smad1/5- and Runx2-induced transcriptional activities leading to inhibition of late stage differentiation. Moreover, menin suppresses osteoblast maturation, in part, by inhibiting the differentiation actions of JunD, AP-1 factor.