The Tenth People's Hospital of Tongji University, Shanghai, 200027, People's Republic of China.
J Bone Miner Metab. 2011 Mar;29(2):168-73. doi: 10.1007/s00774-010-0208-x. Epub 2010 Aug 11.
TAK-778, a derivative of ipriflavone, has been shown to induce bone growth both in vitro and in vivo. Recently, it has been shown that TAK-778 can enhance osteoblast differentiation of human bone marrow cells via an estrogen receptor (ER)-dependent pathway. However, the mechanism by which TAK-778 exerts its effect in vivo has not been determined. Considering the evidence that TAK-778 acts via ER-mediated signaling in vitro, in the present study we tested if TAK-778 induced osteogenesis via an ER-dependent pathway using an ovariectomized (OVX) rat model. Two weeks after test animals underwent ovariectomy, TAK-778 and/or tamoxifen was administered orally over 3 months. Vehicle-treated and sham-operated rats served as controls. The bone mineral density (BMD) of the lumbar vertebrae and sagittal two-dimensional images of the L3 vertebral body were measured. In addition, bone formation rates (BFR) and serum calcium and osteocalcin levels were measured. The results indicated that TAK-778 significantly increased BMD, serum calcium and osteocalcin levels, and BFR when compared to that of the vehicle-treated group. However, tamoxifen, a well-known ER antagonist, clearly inhibited the increase in these parameters induced by TAK-778. In addition, micro-computed tomography scans showed that treatment with TAK-778 increased the structure model index, bone volume/tissue volume, and trabecular thickness parameters and decreased the trabecular separation/spacing in OVX rats. Tamoxifen suppressed these effects when administered in combination with TAK-778. Taken together, the present study showed that TAK-778 enhanced bone formation in OVX rats and that this effect was dependent on an ER-mediated pathway.
TAK-778 是伊普黄酮的衍生物，已被证明在体外和体内均能促进骨生长。最近的研究表明，TAK-778 可以通过雌激素受体（ER）依赖性途径增强人骨髓细胞的成骨分化。然而，TAK-778 在体内发挥作用的机制尚未确定。鉴于 TAK-778 在体外通过 ER 介导的信号通路发挥作用的证据，在本研究中，我们使用去卵巢（OVX）大鼠模型测试了 TAK-778 是否通过 ER 依赖性途径诱导成骨。在测试动物接受卵巢切除术 2 周后，TAK-778 和/或他莫昔芬通过口服给药 3 个月。接受载体处理和假手术的大鼠作为对照。测量腰椎的骨密度（BMD）和 L3 椎体的矢状二维图像。此外，还测量了骨形成率（BFR）和血清钙和骨钙素水平。结果表明，与载体处理组相比，TAK-778 显著增加了 BMD、血清钙和骨钙素水平以及 BFR。然而，他莫昔芬，一种众所周知的 ER 拮抗剂，明显抑制了 TAK-778 引起的这些参数的增加。此外，微计算机断层扫描扫描显示，TAK-778 治疗增加了结构模型指数、骨体积/组织体积和小梁厚度参数，并减少了 OVX 大鼠的小梁分离/间距。当与 TAK-778 联合使用时，他莫昔芬抑制了这些作用。总之，本研究表明 TAK-778 增强了 OVX 大鼠的骨形成，并且这种作用依赖于 ER 介导的途径。
