Roschger Andreas, Roschger Paul, Keplingter Petra, Klaushofer Klaus, Abdullah Sami, Kneissel Michaela, Rauch Frank
Ludwig Boltzmann Institute of Osteology, Hanusch Hospital of WGKK and AUVA Trauma Center Meidling, 1st Med. Dept., Hanusch Hospital, Vienna, Austria.
Shriners Hospital for Children, Montreal, Quebec, Canada; McGill University, Montreal, Quebec, Canada.
Bone. 2014 Sep;66:182-8. doi: 10.1016/j.bone.2014.06.015. Epub 2014 Jun 19.
Osteogenesis imperfecta (OI) is a heritable bone fragility disorder that is usually caused by mutations affecting collagen type I production in osteoblasts. Stimulation of bone formation through sclerostin antibody treatment (Sost-ab) has shown promising results in mouse models of relatively mild OI. We assessed the effect of once-weekly intravenous Sost-ab injections for 4weeks in male Col1a1(Jrt)/+mice, a model of severe dominant OI, starting either at 4weeks (growing mice) or at 20weeks (adult mice) of age. Sost-ab had no effect on weight or femur length. In OI mice, no significant treatment-associated differences in serum markers of bone formation (alkaline phosphatase activity, procollagen type I N-propeptide) or resorption (C-telopeptide of collagen type I) were found. Micro-CT analyses at the femur showed that Sost-ab treatment was associated with higher trabecular bone volume and higher cortical thickness in wild type mice at both ages and in growing OI mice, but not in adult OI mice. Three-point bending tests of the femur showed that in wild type but not in OI mice, Sost-ab was associated with higher ultimate load and work to failure. Quantitative backscattered electron imaging of the femur did not show any effect of Sost-ab on CaPeak (the most frequently occurring calcium concentration in the bone mineral density distribution), regardless of genotype, age or measurement location. Thus, Sost-ab had a larger effect in wild type than in Col1a1(Jrt)/+mice. Previous studies had found marked improvements of Sost-ab on bone mass and strength in an OI mouse model with a milder phenotype. Our data therefore suggest that Sost-ab is less effective in a more severely affected OI mouse model.
成骨不全症（OI）是一种遗传性骨脆性疾病，通常由影响成骨细胞中I型胶原蛋白生成的突变引起。通过硬化蛋白抗体治疗（Sost-ab）刺激骨形成在相对轻度OI的小鼠模型中已显示出有前景的结果。我们评估了每周一次静脉注射Sost-ab，持续4周，对雄性Col1a1(Jrt)/+小鼠（一种严重显性OI模型）的影响，分别在4周龄（生长中的小鼠）或20周龄（成年小鼠）开始给药。Sost-ab对体重或股骨长度没有影响。在OI小鼠中，未发现骨形成（碱性磷酸酶活性、I型前胶原N端前肽）或吸收（I型胶原C端肽）的血清标志物存在与治疗相关的显著差异。对股骨进行的显微CT分析表明，Sost-ab治疗在两个年龄的野生型小鼠以及生长中的OI小鼠中与更高的骨小梁体积和更高的皮质厚度相关，但在成年OI小鼠中并非如此。对股骨进行的三点弯曲试验表明，在野生型小鼠而非OI小鼠中，Sost-ab与更高的极限负荷和破坏功相关。对股骨进行的定量背散射电子成像未显示Sost-ab对CaPeak（骨矿物质密度分布中最常出现的钙浓度）有任何影响，无论基因型、年龄或测量位置如何。因此，Sost-ab在野生型小鼠中的作用比在Col1a1(Jrt)/+小鼠中更大。先前的研究发现，在具有较温和表型的OI小鼠模型中，Sost-ab对骨量和强度有显著改善。因此，我们的数据表明，Sost-ab在受影响更严重的OI小鼠模型中效果较差。
