Tomimori Yoshiya, Mori Kaoru, Koide Masanori, Nakamichi Yuko, Ninomiya Tadashi, Udagawa Nobuyuki, Yasuda Hisataka
Nagahama Institute for Biochemical Science, Oriental Yeast Co., Nagahama, Shiga, Japan.
J Bone Miner Res. 2009 Jul;24(7):1194-205. 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 microCT 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.
骨质疏松症因其相关的脆性骨折仍然是一个主要的公共卫生问题。几种用于研究骨质疏松性骨质流失的动物模型，如卵巢切除术（OVX）和去神经支配模型，需要手术技能且要数周才能建立。破骨细胞的分化和激活由核因子κB受体活化因子配体（RANKL）介导。在此，我们报告通过给小鼠注射可溶性RANKL（sRANKL）建立了一种新型快速骨质流失模型。给小鼠腹腔注射sRANKL，并用于评估现有的抗骨质疏松药物。sRANKL在50小时内以剂量依赖性方式降低骨密度（BMD）。定量计算机断层扫描（pQCT）显示的股骨小梁骨密度显著降低以及显微计算机断层扫描（microCT）获得的三维图像与OVX模型中观察到的情况无明显差异。组织形态计量学显示，注射sRANKL的小鼠破骨细胞活性显著增加。此外，注射sRANKL的小鼠中骨转换的血清生化标志物，如钙、1型胶原C末端肽（CTX）和抗酒石酸酸性磷酸酶5b（TRACP5b）也以剂量依赖性方式显著增加。双膦酸盐（BPs）、选择性雌激素受体调节剂（SERMs）和甲状旁腺激素（PTH）常用于治疗骨质疏松症。我们在几周内成功评估了抗骨吸收药物，如BPs、一种SERM和抗RANKL中和抗体对骨吸收的影响。我们还在2周内评估了PTH对骨形成的影响。sRANKL注射与OVX相结合使得评估一种SERM成为可能。sRANKL模型是所有骨质疏松模型中最简单、最快且最容易的，可能有助于评估骨质疏松症候选药物。
