Sclerostin Antibody Treatment Increases Bone Formation, Bone Mass, and Bone Strength in a Rat Model of Postmenopausal Osteoporosis
Sclerostin Antibody Treatment Increases Bone Formation, Bone Mass, and Bone Strength in a Rat Model of Postmenopausal Osteoporosis
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DOI：
10.1359/jbmr.081206
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发表时间：
2009-04-01
影响因子：
6.2
通讯作者：
Paszty, Chris
中科院分区：
文献类型：
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作者：
Li, Xiaodong;Ominsky, Michael S.;Paszty, Chris
开发骨重建合成代谢剂以用于治疗骨质疏松症等骨质流失疾病，一直是一个长期目标。对人类和小鼠的遗传学研究表明，分泌蛋白硬化素是骨形成的关键负调节因子，尽管硬化素在控制衰老骨骼中骨形成中的作用大小和程度仍不清楚。为了研究硬化素生物学这一未探索的领域并评估硬化素抑制的药理作用，我们使用骨形成的细胞培养模型来鉴定硬化素中和单克隆抗体（Scl-AbII），用于在老年绝经后骨质疏松症切除卵巢大鼠模型中进行测试。六个月大的雌性大鼠被切除卵巢，并在 1 年内不进行任何治疗，以允许雌激素缺乏引起的明显骨质流失，此时给予 Scl-AbII 5 周。 Scl-AbII 治疗这些动物具有强大的合成代谢作用，小梁、骨膜、皮质内和皮质内表面的骨形成显着增加。这不仅使数个骨骼部位完全逆转了雌激素缺乏引起的骨质流失一年的情况，而且还进一步增加了骨量和骨强度，达到高于未切除卵巢的对照大鼠的水平。总而言之，这些临床前结果确立了硬化素作为衰老骨骼中骨形成的关键负调节剂的作用，此外，表明抗体介导的硬化素抑制代表了一种有前途的新治疗方法，用于骨相关疾病（例如绝经后骨质疏松症）的合成代谢治疗。
The development of bone-rebuilding anabolic agents for potential use in the treatment of bone loss conditions, such as osteoporosis, has been a long-standing goal. Genetic studies in humans and mice have shown that the secreted protein sclerostin is a key negative regulator of bone formation, although the magnitude and extent of sclerostin's role in the control of bone formation in the aging skeleton is still unclear. To study this unexplored area of sclerostin biology and to assess the pharmacologic effects of sclerostin inhibition, we used a cell culture model of bone formation to identify a sclerostin neutralizing monoclonal antibody (Scl-AbII) for testing in an aged ovariectomized rat model of postmenopausal osteoporosis. Six-month-old female rats were ovariectomized and left untreated for 1 yr to allow for significant estrogen deficiency-induced bone loss, at which point Scl-AbII was administered for 5 wk. Scl-AbII treatment in these animals had robust anabolic effects, with marked increases in bone formation on trabecular, periosteal, endocortical, and intracortical surfaces. This not only resulted in complete reversal, at several skeletal sites, of the I yr of estrogen deficiency-induced bone loss, but also further increased bone mass and bone strength to levels greater than those found in non-ovariectomized control rats. Taken together, these preclinical results establish sclerostin's role as a pivotal negative regulator of bone formation in the aging skeleton and, furthermore, suggest that antibody-mediated inhibition of sclerostin represents a promising new therapeutic approach for the anabolic treatment of bone-related disorders, such as postmenopausal osteoporosis.