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Research for the elucidation of bone formation signals applied to the development of bone-forming agents

阐明骨形成信号的研究应用于骨形成剂的开发

基本信息

批准号：
18591025
负责人：
SUGIMOTO Toshitsugu
金额：
$ 2.39万
依托单位：
Shimane University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591025/
关键词：
Parathyroid hormone Bisohosohonate Stalin strontium Osteoblast Bone formation Smart Wnt Smad Smad3 Lunt グルココルチコイド TGFβ アポトーシス

项目摘要

Parathyroid hormone (PTH) exerts anabolic action on bone and the canonical Wnt as well as TGFβ-smad3 pathways are important in bone formation. We demonstrated that PTH activates Wnt-β-catenin signal through Smad3, resulting in the inhibition of osteoblast apoptosis. Next, we examined how Smad3 affects osteoblast at the different differentiation stage. Smad3 inhibits osteoblastic commitment of multipotential mesenchymal cells, while it promotes early stage of differentiation and maturation of osteoblastic committed cells. On the other hand, statins possess pleiotropic effects and among them, their bone anabolic action's have been noted. We examined whether statins would affect TGF-β-Smad3 pathway and apoptosis in osteoblasts. Pitavastatin suppressed osteoblast apoptosis through Smad3.Glucocorticoid (GC)-induced osteoporosis (GIO) is caused by the suppression of osteogenesis, and effectively treated by bisphosphonate (BP) and PTH. However, the exact mechanisms by which GC suppresses oste … More oblast functions, or BP and PTH alleviate GIO are still unclear. The present study indicates that GC inhibits osteoblastic differentiation by suppressing BMP and Wnt signaling pathways through enhanced expressions of their antagonists, follistatin/Dan and sFRP, respectively, and that the effectiveness of BP and PTH may be partly explained by the cancellation of these processes. Our recent study indicates that adiponectin stimulates the proliferation, differentiation and mineralization of osteoblasts via the AdipoR1 and AMP kinase (AMPK) signaling pathway in autocrine and/or paracrine fashions. Both AMPK and Rho-kinase (ROK) are known to modulate mevalonate pathway. Inhibition of HMG-CoA reductase by AICAR and that of ROK by hydroxyfasudil stimulated the differentiation and mineralization of osteoblasts, indicating that agents modulating the mevalonate pathway might be candidate drugs that promote bone formation. Strontium stimulates osteoblast differentiation and mineralization via the activation of Ca-sensing receptor (CaSR). The present findings provide the rationale for the therapeutic usefulness of PTH,BP, statin as well as CaSR agonist as bone-forming agents for senile osteoporosis Less

甲状旁腺激素（PTH）对骨具有合成代谢作用，典型的Wnt和tgf - β-smad3通路在骨形成中起重要作用。我们证明PTH通过Smad3激活Wnt-β-catenin信号，从而抑制成骨细胞凋亡。接下来，我们研究了Smad3在不同分化阶段对成骨细胞的影响。Smad3抑制多电位间充质细胞的成骨承诺，同时促进成骨承诺细胞的早期分化和成熟。另一方面，他汀类药物具有多效性，其中已注意到其骨合成代谢作用。我们检测了他汀类药物是否会影响TGF-β-Smad3通路和成骨细胞凋亡。匹伐他汀通过Smad3抑制成骨细胞凋亡。糖皮质激素（GC）诱导的骨质疏松症（GIO）是由成骨抑制引起的，双膦酸盐（BP）和甲状旁腺激素（PTH）能有效治疗。然而，GC抑制心肌梗死的确切机制尚不清楚，更多的细胞功能，或BP和PTH减轻心肌梗死。本研究表明，GC通过增强其拮抗剂卵泡素/丹和sFRP的表达，分别抑制BMP和Wnt信号通路，从而抑制成骨细胞分化，BP和PTH的有效性可能部分归因于这些过程的取消。我们最近的研究表明，脂联素通过AdipoR1和AMP激酶（AMPK）信号通路以自分泌和/或旁分泌的方式刺激成骨细胞的增殖、分化和矿化。已知AMPK和rho激酶（ROK）均可调节甲羟戊酸途径。AICAR对HMG-CoA还原酶的抑制和羟法舒地尔对ROK还原酶的抑制刺激了成骨细胞的分化和矿化，表明调节甲羟戊酸途径的药物可能是促进骨形成的候选药物。锶通过激活钙感应受体（CaSR）刺激成骨细胞分化和矿化。本研究结果为PTH、BP、他汀类药物以及CaSR激动剂作为成骨剂治疗老年性骨质疏松症提供了理论依据

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Smad3 directly affects osteoblast differetiation in amanner dependent upon differentiation stase

Smad3 以取决于分化阶段的方式直接影响成骨细胞分化

DOI：
发表时间：
2006
期刊：
Horm Metab Res 38
影响因子：
0
作者：
Ogawa;N.;Yamaguchi;N.;Yano;S.;Yamauchi;M.;Yamamoto;M.;Sugimoto;T;Yano S;Ogawa N;Tobimatsu T;Kaji H
通讯作者：
Kaji H

Parathyroid hormone increases β-catenin leuels through smad 3 in mouse osteoblastic cells

甲状旁腺激素通过 smad 3 增加小鼠成骨细胞中的 β-catenin leuels