Sclerostin-Antibody Treatment Decreases Fracture Rates in Axial Skeleton and Improves the Skeletal Phenotype in Growing oim/oim Mice
Sclerostin-Antibody Treatment Decreases Fracture Rates in Axial Skeleton and Improves the Skeletal Phenotype in Growing oim/oim Mice
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DOI：
10.1007/s00223-019-00655-5
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发表时间：
2020-02-06
影响因子：
4.2
通讯作者：
Manicourt, Daniel H.
中科院分区：
文献类型：
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作者：
Cardinal, Mickael;Dessain, Alicia;Manicourt, Daniel H.
在成骨不全（OI）中，椎骨脆性导致胸廓变形并导致心肺功能衰竭。由于硬化蛋白中和抗体在骨质疏松症动物模型中增加了骨量和强度，因此在两种严重OI小鼠模型中给予它们可以增强生长中的雌性Crtap（-/-）小鼠的椎骨强度，但在生长中的雄性Col 1a 1（Jrt/+）小鼠中则没有。然而，这两项研究忽略了抗体对脊柱生长、骨折率和压缩力学性能的影响。在这里，我们在oim/oim小鼠中进行了一项随机对照试验，这是一种由于Col 1a 2突变而建立的人类严重OI III型模型。五周龄雌性WT和oim/oim小鼠接受PBS或sclerostin抗体（Scl-Ab）9周。分析包括X线摄影、组织形态学、pQCT、显微计算机断层扫描和生物力学测试。尽管Scl-Ab治疗没有改变椎骨轴向生长，但它显著降低了骨盆和尾椎的骨折发生率，增强了成骨细胞活性（L4），增加了颈骶椎BMD，并改善了腰骶椎骨横截面积。Scl-Ab不影响椎体高度和身体大小，但在两个Scl-Ab组中显著增加皮质厚度和松质骨体积。在腰椎和胫骨干骺端，Scl-Ab WT中皮质和松质骨质量的绝对增加高于Scl-Ab oim/oim。对骨小梁骨量的影响主要是由于椎骨骨小梁数量和干骺端骨小梁厚度的变化。此外，Scl-Ab没有恢复标准的骨小梁网络，但改善了骨压缩极限载荷，在椎骨比在干骺端具有更稳健的作用。总的来说，Scl-Ab治疗可能有利于减少重度OI患者的椎体骨折和脊柱畸形。
In osteogenesis imperfecta (OI), vertebrae brittleness causes thorax deformations and leads to cardiopulmonary failure. As sclerostin-neutralizing antibodies increase bone mass and strength in animal models of osteoporosis, their administration in two murine models of severe OI enhanced the strength of vertebrae in growing female Crtap(-/-) mice but not in growing male Col1a1(Jrt/+) mice. However, these two studies ignored the impact of antibodies on spine growth, fracture rates, and compressive mechanical properties. Here, we conducted a randomized controlled trial in oim/oim mice, an established model of human severe OI type III due to a mutation in Col1a2. Five-week-old female WT and oim/oim mice received either PBS or sclerostin antibody (Scl-Ab) for 9 weeks. Analyses included radiography, histomorphometry, pQCT, microcomputed tomography, and biomechanical testing. Though it did not modify vertebral axial growth, Scl-Ab treatment markedly reduced the fracture prevalence in the pelvis and caudal vertebrae, enhanced osteoblast activity (L4), increased cervico-sacral spine BMD, and improved the lumbosacral spine bone cross-sectional area. Scl-Ab did not impact vertebral height and body size but enhanced the cortical thickness and trabecular bone volume significantly in the two Scl-Ab groups. At lumbar vertebrae and tibial metaphysis, the absolute increase in cortical and trabecular bone mass was higher in Scl-Ab WT than in Scl-Ab oim/oim. The effects on trabecular bone mass were mainly due to changes in trabecular number at vertebrae and in trabecular thickness at metaphyses. Additionally, Scl-Ab did not restore a standard trabecular network, but improved bone compressive ultimate load with more robust effects at vertebrae than at metaphysis. Overall, Scl-Ab treatment may be beneficial for reducing vertebral fractures and spine deformities in patients with severe OI.