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

甲状旁腺激素（PTH）对骨具有合成代谢作用，经典的Wnt和TGFβ-smad 3途径在骨形成中很重要。我们证明PTH通过Smad 3激活Wnt-β-catenin信号，导致成骨细胞凋亡的抑制。接下来，我们研究了Smad 3在不同分化阶段如何影响成骨细胞。Smad 3抑制多能间充质细胞向成骨细胞定向分化，促进成骨定向细胞早期分化成熟。另一方面，他汀类药物具有多效性作用，其中，其骨合成代谢作用已被注意到。我们研究了他汀类药物是否会影响成骨细胞TGF-β-Smad 3通路和凋亡。匹伐他汀通过Smad 3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，二磷酸盐（BP）和甲状旁腺素（PTH）可有效治疗。然而，GC抑制骨坏死的确切机制 ...更多信息 血压和甲状旁腺素是否减轻GIO尚不清楚。目前的研究表明，GC抑制成骨细胞的分化，通过抑制BMP和Wnt信号通路，通过增强表达的拮抗剂，卵泡抑素/丹和sFRP，分别，和BP和PTH的有效性可能部分解释了取消这些过程。我们最近的研究表明脂联素通过AdipoR 1和AMP激酶（AMPK）信号通路以自分泌和/或旁分泌方式刺激成骨细胞增殖、分化和矿化。已知AMPK和Rho激酶（ROK）都调节甲羟戊酸途径。AICAR抑制HMG-CoA还原酶和羟基法舒地尔抑制ROK可刺激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。锶通过激活钙敏感受体（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激动剂作为骨形成剂治疗老年性骨质疏松症提供了理论依据。

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