Evaluation of Pharmaceuticals With a Novel 50-Hour Animal Model of Bone Loss
Evaluation of Pharmaceuticals With a Novel 50-Hour Animal Model of Bone Loss
复制标题
DOI：
10.1359/jbmr.090217
复制
发表时间：
2009-07-01
影响因子：
6.2
通讯作者：
Yasuda, Hisataka
中科院分区：
文献类型：
--
作者：
Tomimori, Yoshiya;Mori, Kaoru;Yasuda, Hisataka
骨质疏松症通过其相关的脆性骨折仍然是一个主要的公共卫生问题。用于研究骨质疏松性骨丢失的几种动物模型，如卵巢切除术（OVX）和去神经，需要手术技巧和几周的时间来建立。破骨细胞的分化和活化由RANKL介导。在这里，我们报告了一种新的和快速的骨丢失模型的管理可溶性RANKL（sRANKL）的小鼠。小鼠腹腔注射sRANKL，并用于评估现有的抗骨质疏松药物。sRANKL在50 h内以剂量依赖性方式降低BMD。pQCT和mu CT获得的3D图像显示的股骨骨小梁BMD显著降低与OVX模型中观察到的结果无法区分。组织形态计量学显示，在sRANKL注射小鼠中，骨细胞活性显著增加。此外，在注射sRANKL的小鼠中，骨转换的血清生化标志物，如Ca、1型胶原C端肽（CTX）和TRACP 5 b也以剂量依赖性方式显著增加。二膦酸盐（BPs）、选择性雌激素受体调节剂（SERM）和PTH常用于治疗骨质疏松症。我们成功地评估了抗骨吸收剂如BP、SERM和抗RANKL中和抗体在几周内对骨吸收的影响。我们还评估了PTH对2周骨形成的影响。sRANKL注射和OVX的组合使得有可能评价SERM。sRANKL模型是所有骨质疏松症模型中最简单、最快和最简单的，可用于评价骨质疏松症候选药物。骨矿研究杂志2009;24：1194-1205。在线发表于2009年2月16日; doi：10.1359/JBMR.090217
Osteoporosis remains a major public health problem through its associated fragility fractures. Several animal models for the study of osteoporotic bone loss, such as ovariectomy (OVX) and denervation, require surgical skills and several weeks to establish. Osteoclast differentiation and activation is mediated by RANKL. Here we report the establishment of a novel and rapid bone loss model by the administration of soluble RANKL (sRANKL) to mice. Mice were injected intraperitoneally with sRANKL and used to evaluate existing anti-osteoporosis drugs. sRANKL decreased BMD within 50 h in a dose-dependent manner. The marked decrease in femoral trabecular BMD shown by pQCT and the 3D images obtained by mu CT were indistinguishable from those observed in the OVX model. Histomorphometry showed that osteoclastic activity was significantly increased in the sRANKL-injected mice. In addition, serum biochemical markers of bone turnover such as Ca, C-telopeptide of type 1 collagen (CTX), and TRACP5b were also significantly increased in the sRANKL-injected mice in a dose-dependent manner. Bisphosphonates (BPs), selective estrogen receptor modulators (SERMs), and PTH are commonly used for the treatment of osteoporosis. We successfully evaluated the effects of anti-bone-resorbing agents such as BPs, a SERM, and anti-RANKL-neutralizing antibody on bone resorption in a couple of weeks. We also evaluated the effects of PTH on bone formation in 2 wk. A combination of sRANKL injections and OVX made it possible to evaluate a SERM. The sRANKL model is the simplest, fastest, and easiest of all osteoporosis models and could be useful in the evaluation of drug candidates for osteoporosis. J Bone Miner Res 2009;24:1194-1205. Published online on February 16, 2009; doi: 10.1359/JBMR.090217