Rapidly growing Brtl/+ mouse model of osteogenesis imperfecta improves bone mass and strength with sclerostin antibody treatment.
Rapidly growing Brtl/+ mouse model of osteogenesis imperfecta improves bone mass and strength with sclerostin antibody treatment.
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DOI：
10.1016/j.bone.2014.10.012
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发表时间：
2015-02
期刊：
影响因子：
4.1
通讯作者：
Kozloff, Kenneth M.
中科院分区：
文献类型：
--
作者：
Sinder, Benjamin P.;Salemi, Joseph D.;Ominsky, Michael S.;Caird, Michelle S.;Marini, Joan C.;Kozloff, Kenneth M.
关键词：
成骨不全症（Osteogenesis imperfecta， OI）是一种遗传性的与胶原蛋白相关的骨质发育不良，其特征是骨质脆性，骨折风险增加，在儿童中表现最为严重。抗吸收双膦酸盐经常用于治疗儿童成骨不全症，对照临床试验表明，双膦酸盐治疗可改善椎体预后，但对长骨骨折率几乎没有好处。增加儿童成骨不全骨骼骨量的新疗法将是有益的。硬化蛋白抗体（Sclerostin antibody, Scl-Ab）是治疗儿童成骨不全症的潜在候选合成代谢疗法，通过典型的wnt信号通路刺激成骨细胞骨形成。为了探索Scl-Ab对快速生长的OI骨骼的影响，我们用Scl-Ab治疗了快速生长的3周龄Brtl/+小鼠，这些小鼠具有典型的杂合子，可引起col1a1上的Gly->Cys替换。Scl-Ab在Brtl/+中具有合成代谢作用，导致新的皮质骨形成和皮质骨量增加。这种合成代谢作用导致机械强度提高到WT Veh水平，而不会改变材料的潜在脆性。虽然Scl-Ab在两种基因型的股骨远端小梁骨中都有合成代谢，但与WT相比，在这些快速生长的Brtl/+小鼠中的作用较弱。总之，Scl-Ab能够刺激快速生长的Brtl/+小鼠成骨模型中的骨形成，代表了一种改善骨量和降低儿童成骨风险的潜在新疗法。
Osteogenesis imperfecta (OI) is a heritable collagen-related bone dysplasia, characterized by brittle bones with increased fracture risk that presents most severely in children. Anti-resorptive bisphosphonates are frequently used to treat pediatric OI and controlled clinical trials have shown bisphosphonate therapy improves vertebral outcomes but has little benefit on long bone fracture rate. New treatments which increase bone mass throughout the pediatric OI skeleton would be beneficial. Sclerostin antibody (Scl-Ab) is a potential candidate anabolic therapy for pediatric OI and functions by stimulating osteoblastic bone formation via the canonical wnt signaling pathway. To explore the effect of Scl-Ab on the rapidly growing OI skeleton, we treated rapidly growing 3 week old Brtl/+ mice, harboring a typical heterozygous OI-causing Gly->Cys substitution on col1a1, for 5 weeks with Scl-Ab. Scl-Ab had anabolic effects in Brtl/+ and led to new cortical bone formation and increased cortical bone mass. This anabolic action resulted in improved mechanical strength to WT Veh levels without altering the underlying brittle nature of the material. While Scl-Ab was anabolic in trabecular bone of the distal femur in both genotypes, the effect was less strong in these rapidly growing Brtl/+ mice compared to WT. In conclusion, Scl-Ab was able to stimulate bone formation in a rapidly growing Brtl/+ murine model of OI, and represents a potential new therapy to improve bone mass and reduce fracture risk in pediatric OI.
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