Research for the mechanisms of anabolic action of parathyroid hormone(PTH) on bone and interaction between PTH and estrogen in osteoblasts

虽然一些研究表明，甲状旁腺激素（PTH）对骨的合成代谢作用和雌激素增强其对骨的合成代谢作用，其确切的机制一直是未知的。TGFβ在体内刺激骨形成，并通过两种受体调节的Smads（Smad 2和Smad 3）调节靶基因的转录应答。我们的研究表明Smad 3是骨形成的重要分子。接下来，我们研究了PTH对Smad 3的影响及其在成骨细胞中的生理意义。PTH通过PKA和PKC途径促进小鼠成骨细胞MC 3 T3-E1和大鼠成骨细胞UMR-106中Smad 3 mRNA和蛋白水平的升高。接下来，我们检查了PTH和Smad 3的抗凋亡作用。PTH预处理或Smad 3过表达可减少地塞米松或足叶乙甙诱导的凋亡细胞数。此外，一个显性负突变体，Smad 3deltaC，废除PTH诱导的抗凋亡作用。另一方面，PTH可增强TGFβ-inducible ...更多信息 测定Smad 3的转录活性。此外，PTH还能促进TGFβ诱导的1型胶原的生成。这些观察结果表明，PTH通过加速Smad 3的转录活性来放大TGFβ的合成代谢作用。我们首先证明PTH-Smad 3轴发挥抗凋亡作用，并加强TGFβ在成骨细胞中的合成代谢作用。最近有证据表明Wnt信号在骨形成中的重要性，我们获得了关于PTH和Smad 3过表达对成骨细胞中β-连环蛋白表达的刺激作用的数据。因此，PTH-Smad-3轴可能参与PTH的骨合成作用。关于PTH和雌激素在成骨细胞中相互作用的研究，在人成骨细胞SaOS-2中，雌激素预处理减弱PTH诱导的成骨细胞增殖抑制和PTH刺激成骨细胞功能。IGF-1和/或IGF-结合蛋白-5参与了雌激素对PTH对成骨细胞增殖和功能的调节作用。少

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 … More 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