Dual Targeting of Bile Acid Receptor-1 (TGR5) and Farnesoid X Receptor (FXR) Prevents Estrogen-Dependent Bone Loss in Mice
Dual Targeting of Bile Acid Receptor-1 (TGR5) and Farnesoid X Receptor (FXR) Prevents Estrogen-Dependent Bone Loss in Mice
复制标题
胆汁酸受体 1 (TGR5) 和法尼醇 X 受体 (FXR) 的双重靶向可防止小鼠雌激素依赖性骨质流失。
DOI：
10.1002/jbmr.3652
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发表时间：
2019-04-01
影响因子：
6.2
通讯作者：
Xiao, Jianru
中科院分区：
文献类型：
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作者：
Li, Zhenxi;Huang, Jinping;Xiao, Jianru
骨质疏松症是一种全球性的骨骼疾病，其特征是骨矿物质密度（BMD）降低和骨折风险增加。患骨质疏松症的风险随着年龄的增长而增加，尤其是女性绝经后。发现在衰老和绝经诱导的骨质疏松症中起重要作用的信号通路应该加速骨质疏松症药物的发现。在这项研究中，我们发现，胆汁酸膜受体Tgr 5敲除C57 BL/6 J小鼠在早期和中期（4个月以前）骨重建过程中具有与野生型小鼠相似的骨量;然而，与野生型小鼠相比，Tgr 5（-/-）显著降低老年（7个月以上）和卵巢切除（OVX）小鼠的骨量。此外，Tgr 5敲除强烈诱导破骨细胞分化，但对成骨细胞活性没有影响。用不同的TGR 5激动剂处理一致地抑制破骨细胞分化。重要的是，我们的研究结果表明，Tgr 5通过AMP活化蛋白激酶（AMPK）信号通路调节破骨细胞生成，AMPK信号通路是参与衰老和年龄相关疾病病理生理学的中心代谢通路。胆汁酸核受体FXR是骨代谢的既定调节剂。我们筛选了桦木酸（BA）的衍生物，一种已知的TGR 5激动剂，以确定新的FXR和TGR 5双重激动剂。衍生物SH-479是一种五环三萜酸，可激活TGR 5和FXR，与单独激活FXR或TGR 5的激动剂相比，对破骨细胞生成具有更好的抑制作用，并额外增强成骨细胞生成。此外，SH-479通过骨重建途径在治疗上消除了C57 BL/6 J小鼠的骨丢失。总之，我们的研究结果表明，双重靶向胆汁酸膜受体TGR 5和核受体FXR是骨质疏松症的一个有前途的策略。(c)2018年美国骨与矿物质研究学会。
Osteoporosis is a global bone disease characterized by reduced bone mineral density (BMD) and increased risk of fractures. The risk of developing osteoporosis increases with aging, especially after menopause in women. Discovering the signaling pathways that play a significant role in aging-and menopause-induced osteoporosis should accelerate osteoporosis drug discovery. In this study, we found that bile acid membrane receptor Tgr5 knockout C57BL/6J mice had similar bone mass as wild-type mice during early and middle-age (before 4 months old) bone remodeling; however, Tgr5(-/-) markedly decreased bone mass in aged (more than 7 months old) and ovariectomized (OVX) mice compared with wild-type mice. Moreover, Tgr5 knockout strongly induced osteoclast differentiation but had no effect on osteoblast activity. Treatment with different TGR5 agonists consistently inhibited osteoclast differentiation. Importantly, our results showed that Tgr5 regulates osteoclastogenesis by the AMP-activated protein kinase (AMPK) signaling pathway, which is a central metabolic pathway involved in the pathophysiology of aging and age-related diseases. The bile acid nuclear receptor FXR is an established regulator of bone metabolism. We screened the derivatives of betulinic acid (BA), a known TGR5 agonist, to identify novel dual agonists of FXR and TGR5. The derivative SH-479, a pentacyclic triterpene acid, could activate both TGR5 and FXR, with a better inhibitory effect on osteoclastogenesis compared with agonists solely activating FXR or TGR5 and additionally enhanced osteoblastogenesis. Furthermore, SH-479 therapeutically abrogated bone loss in C57BL/6J mice through the bone remodeling pathways. Together, our results demonstrate that dual targeting the bile acid membrane receptor TGR5 and nuclear receptor FXR is a promising strategy for osteoporosis. (c) 2018 American Society for Bone and Mineral Research.