| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2003: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2002: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Research Abstract |
Although several studies indicated that parathyroid hormone (PTH) exerted anabolic action on bone and estrogen augmented its anabolic action on bone, their precise mechanisms have been unknown. TGFβ stimulates bone formation in vivo and regulates the transcriptional response of the target genes through the two receptor -regulated Smads, Smad2 and Smad3. Our study revealed that Smad3 was an important molecule for bone formation. Next, we examined the effects of PTH on Smad3 and its physiological significance in osteoblasts. PTH promoted Smad3 mRNA and protein levels though PKA and PKC pathways in mouse osteoblastic MC3T3-E1 cells and rat osteoblastic UMR-106 cells. We, next, examined anti-apoptotic effects of PTH and Smad3. Pretreatment with PTH or overexpression of Smad3 decreased the number of apoptotic cells induced by dexamethasone or etoposide. Moreover, a dominant negative mutant, Smad3deltaC, abrogated PTH-induced anti-apoptotic effects. On the other hand, PTH augmented TGFβ-indu
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ced transcriptional activity of Smad3. Furtheremore, PTH enhanced TGFβ-induced production of type1collagen. These observations indicate that PTH amplified the anabolic effects of TGFβ by accelerating the transcriptional activity of Smad3. We first demonstrated that PTH-Smad3 axis exerts anti-apoptotic effects and reinforces the anabolic action by TGFβ in osteoblasts. There is recent evidence about the importance of Wnt signaling in bone formation and we obtained data about stimulatory effects of PTH and Smad3 overexpression on β-catenin expression in osteoblasats. Hence, PTH-Smad-3 axis would be involved in bone anabolic action of PTH. As for studies about the interaction between PTH and estrogen in osteoblasts, estrogen attenuated PTH-induced inhibition of osteoblast proliferation and PTH stimulated osteoblast function in the presence of estrogen pretreatment in human osteoblastic SaOS-2 cells. And, IGF-I and/or IGF-binding protein-5 were involved in the estrogen-induced modulation of PTH action on osteoblast proliferation and function. Less
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