Sclerostin antibody improves skeletal parameters in a Brtl/+ mouse model of osteogenesis imperfecta.
Sclerostin antibody improves skeletal parameters in a Brtl/+ mouse model of osteogenesis imperfecta.
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DOI：
10.1002/jbmr.1717
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发表时间：
2013-01
影响因子：
6.2
通讯作者：
Kozloff, Kenneth M.
中科院分区：
文献类型：
--
作者：
Sinder, Benjamin P.;Eddy, Mary M.;Ominsky, Michael S.;Caird, Michelle S.;Marini, Joan C.;Kozloff, Kenneth M.
成骨不全症（Osteogenesis imperfecta， OI）是一种以骨质减少和易骨折为特征的遗传性骨发育不良。症状在儿童时期最为突出。虽然抗吸收双膦酸盐已被广泛用于治疗儿童成骨不全症，但对照试验显示椎体参数得到改善，但对长骨骨折率的影响并不明确。需要新的治疗成骨不全的方法来增加整个骨骼的骨量。硬化蛋白抗体（Sclerostin antibody, Scl-Ab）治疗通过典型的wnt信号通路刺激成骨细胞，在骨骼中进行有效的合成代谢，可能有益于治疗成骨不全症。在这项研究中，研究了Scl-Ab在小鼠杂合中对col1a1中典型的引起oi的Gly- b> Cys替代的治疗。两周的Scl-Ab成功刺激了Brtl/+和WT小鼠的成骨细胞骨形成，导致骨量改善和长骨脆性降低。图像引导纳米压痕显示Scl-Ab对局部组织矿化动力学没有改变。这些结果与先前发现的成骨不全的抗吸收效果在机制和对脆弱性的影响方面形成对比。总之，短期Scl-Ab在成骨细胞中成功地合成代谢了一个典型的导致成骨不全的胶原突变，代表了一个潜在的新疗法来改善骨量和减少儿童成骨不全的骨折。
Osteogenesis imperfecta (OI) is a genetic bone dysplasia characterized by osteopenia and easy susceptibility to fracture. Symptoms are most prominent during childhood. Although anti-resorptive bisphosphonates have been widely used to treat pediatric OI, controlled trials showed improved vertebral parameters but equivocal effects on long-bone fracture rates. New treatments for OI are needed to increase bone mass throughout the skeleton. Sclerostin antibody (Scl-Ab) therapy is potently anabolic in the skeleton by stimulating osteoblasts via the canonical wnt signaling pathway, and may be beneficial for treating OI. In this study, Scl-Ab therapy was investigated in mice heterozygous for a typical OI-causing Gly->Cys substitution in col1a1. Two weeks of Scl-Ab successfully stimulated osteoblast bone formation in Brtl/+ and WT mice, leading to improved bone mass and reduced long-bone fragility. Image-guided nanoindentation revealed no alteration in local tissue mineralization dynamics with Scl-Ab. These results contrast with previous findings of antiresorptive efficacy in OI both in mechanism and potency of effects on fragility. In conclusion, short-term Scl-Ab was successfully anabolic in osteoblasts harboring a typical OI-causing collagen mutation and represents a potential new therapy to improve bone mass and reduce fractures in pediatric OI.
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