Kato Norihiko, Kitahara Keiichiro, Rittling Susan R, Nakashima Kazuhisa, Denhardt David T, Kurosawa Hisashi, Ezura Yoichi, Noda Masaki
Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, 3-10 Kanda-Surugadai 2-Chome, Tokyo, Japan.
J Endocrinol. 2007 Apr;193(1):171-82. doi: 10.1677/joe.1.06917.
Osteoporosis is one of the most widespread and destructive bone diseases in our modern world. There is a great need for anabolic agents for bone which could reverse this disease, but few are available for clinical use. Prostaglandin E receptor (EP4) agonist (EP4A) is one of the very few anabolic agents for bone in rat, but its systemic efficacy against bone loss at sub-optimal dose is limited in mice. As osteoblasts are regulated by extracellular matrix proteins, we tested whether deficiency of osteopontin (OPN), a secreted phosphorylated protein, could modulate the effects of EP4A (ONO-AE1-329) treatment at 30 microg/kg body weight, a sub-optimal dose, for 5 days/week for 4 weeks. OPN deficiency enhanced the anabolic effects of EP4A on bone volume. Histomorphometric analysis indicated that EP4A increased mineral apposition rate as well as bone formation rate in OPN-deficient but not in wild-type mice. Neither OPN deficiency nor EP4A altered osteoclast parameters. Importantly, OPN deficiency enhanced the direct anabolic action of EP4A locally injected onto the parietal bone in inducing new bone formation. Combination of OPN deficiency and EP4A treatment caused an increase in mineralized nodule formation in the cultures of bone marrow cells. Finally, OPN deficiency enhanced anabolic action of EP4A in the mice subjected to ovariectomy. These data indicate that OPN deficiency enhances the actions of EP4A at sub-optimal dose.
骨质疏松症是现代社会中最为普遍且具有破坏性的骨病之一。对于能够逆转这种疾病的骨合成代谢药物有着巨大需求,但临床上可用的此类药物却很少。前列腺素E受体(EP4)激动剂(EP4A)是大鼠中极少数的骨合成代谢药物之一,但其在次优剂量下对小鼠骨质流失的全身疗效有限。由于成骨细胞受细胞外基质蛋白调节,我们测试了骨桥蛋白(OPN)(一种分泌型磷酸化蛋白)缺乏是否能调节EP4A(ONO-AE1-329)在30微克/千克体重(次优剂量)下每周5天、连续4周治疗的效果。OPN缺乏增强了EP4A对骨体积的合成代谢作用。组织形态计量学分析表明,EP4A在OPN缺乏的小鼠中增加了矿物质沉积率以及骨形成率,而在野生型小鼠中则没有。OPN缺乏和EP4A均未改变破骨细胞参数。重要的是,OPN缺乏增强了局部注射到顶骨上的EP4A诱导新骨形成的直接合成代谢作用。OPN缺乏与EP4A治疗相结合导致骨髓细胞培养物中矿化结节形成增加。最后,OPN缺乏增强了EP4A在去卵巢小鼠中的合成代谢作用。这些数据表明,OPN缺乏在次优剂量下增强了EP4A的作用。