Sitagliptin, An Anti-diabetic Drug, Suppresses Estrogen Deficiency-Induced OsteoporosisIn Vivo and Inhibits RANKL-Induced Osteoclast Formation and Bone Resorption In Vitro.
Sitagliptin, An Anti-diabetic Drug, Suppresses Estrogen Deficiency-Induced OsteoporosisIn Vivo and Inhibits RANKL-Induced Osteoclast Formation and Bone Resorption In Vitro.
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西他列汀是一种抗糖尿病药物，可在体内抑制雌激素缺乏引起的骨质疏松症，并在体外抑制 RANKL 诱导的破骨细胞形成和骨吸收
DOI：
10.3389/fphar.2017.00407
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发表时间：
2017
影响因子：
5.6
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Wang C;Xiao F;Qu X;Zhai Z;Hu G;Chen X;Zhang X
绝经后骨质疏松症是一种以破骨细胞过度骨吸收为特征的疾病。一些抗糖尿病药物被证明具有抗破骨细胞骨质流失的作用。本研究调查了长期服用西他列汀（一种二肽基肽酶 IV (DPP IV) 抑制剂，越来越多地用于 2 型糖尿病治疗）对雌激素缺乏引起的骨质疏松症的骨骼影响，并阐明了相关机制。这项研究表明，西格列汀可有效预防卵巢切除术引起的骨质流失并减少体内破骨细胞数量。还表明西格列汀以剂量依赖性方式抑制核因子κB配体受体激活剂（RANKL）介导的破骨细胞分化、骨吸收和F-肌动蛋白环形成。此外，西格列汀显着降低小鼠骨髓源性巨噬细胞中破骨细胞特异性标志物的表达，包括降钙素受体（Calcr）、树突细胞特异性跨膜蛋白（Dc-stamp）、c-Fos和活化T细胞胞质核因子1（Nfatc1）。进一步的研究表明，西格列汀通过抑制 AKT 和 ERK 信号通路、清除 ROS 活性和抑制 Ca2+ 振荡来抑制破骨细胞生成，从而影响破骨细胞特异性转录因子 c-Fos 和 NFATc1 的表达和/或活性。总的来说，这些发现表明西格列汀对骨骼具有有益作用，并且破骨细胞数量的抑制意味着该作用直接作用于破骨细胞生成。
Postmenopausal osteoporosis is a disease characterized by excessive osteoclastic bone resorption. Some anti-diabetic drugs were demonstrated for anti-osteoclastic bone-loss effects. The present study investigated the skeletal effects of chronic administration of sitagliptin, a dipeptidyl peptidase IV (DPP IV) inhibitor that is increasingly used for type 2 diabetes treatments, in an estrogen deficiency-induced osteoporosis and elucidated the associated mechanisms. This study indicated that sitagliptin effectively prevented ovariectomy-induced bone loss and reduced osteoclast numbers in vivo. It was also indicated that sitagliptin suppressed receptor activator of nuclear factor-κB ligand (RANKL)-mediated osteoclast differentiation, bone resorption, and F-actin ring formation in a manner of dose-dependence. In addition, sitagliptin significantly reduced the expression of osteoclast-specific markers in mouse bone-marrow-derived macrophages, including calcitonin receptor (Calcr), dendrite cell-specific transmembrane protein (Dc-stamp), c-Fos, and nuclear factor of activated T-cells cytoplasmic 1 (Nfatc1). Further study indicated that sitagliptin inhibited osteoclastogenesis by suppressing AKT and ERK signaling pathways, scavenging ROS activity, and suppressing the Ca2+ oscillation that consequently affects the expression and/or activity of the osteoclast-specific transcription factors, c-Fos and NFATc1. Collectively, these findings suggest that sitagliptin possesses beneficial effects on bone and the suppression of osteoclast number implies that the effect is exerted directly on osteoclastogenesis.