Targeting Sclerostin and Dkk1 at Optimized Proportions of Low-Dose Antibody Achieves Similar Skeletal Benefits to Higher-Dose Sclerostin Targeting in the Mature Adult and Aged Skeleton.
Targeting Sclerostin and Dkk1 at Optimized Proportions of Low-Dose Antibody Achieves Similar Skeletal Benefits to Higher-Dose Sclerostin Targeting in the Mature Adult and Aged Skeleton.
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DOI：
10.14336/ad.2022.0315
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发表时间：
2022-12-01
影响因子：
7.4
通讯作者：
Robling, Alexander G
中科院分区：
文献类型：
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作者：
Choi, Roy B;Hoggatt, April M;Horan, Daniel J;Rogers, Emily Z;Hong, Jung Min;Robling, Alexander G
在美国，与年龄相关的低骨量疾病是一个日益严重的问题。治疗骨骼脆弱的骨合成代谢疗法的发展落后于抗分解代谢疗法，但是一些造骨分子在临床上是可用的。我们之前报道了Lrp5/Lrp6抑制剂Dkk1的抗体中和对骨增重的影响很小，但可以增强硬化蛋白抑制（另一种由骨细胞高度表达的Lrp5/Lrp6抑制剂）已经有效的骨合成代谢作用。在这篇文章中，我们测试了在成年（6个月大）和老年（20个月大）野生型小鼠中，低剂量给药的硬化蛋白和Dkk1抗体（分别为scll - mab和Dkk1- mab）的优化比例是否能保持与高剂量Scl-mAb相同的建骨效果。使用放射学（DXA，µCT），生物力学（三点弯曲试验）和组织学（基于荧光色的骨形成参数）结果测量，12.5 mg/kg剂量的Scl-mAb:Dkk1-mAb的3:1剂量与25 mg/kg的Scl-mAb在两个年龄组中同样有效。对于一些骨骼特性，包括脊柱小梁厚度和骨矿物质密度，以及股骨皮质内骨形成率，3:1的治疗与两倍剂量的Scl-mAb相比，显著改善了骨骼特性。Scl-mAb和低剂量3:1处理也可减少老年小鼠的皮质孔隙度。总的来说，这两种治疗方法对成年（6个月）和老年（20个月）骨骼都有效，这表明Wnt靶向治疗是改善老年人骨骼脆弱性的可行策略。此外，数据表明，低剂量的联合治疗至少可以与高剂量的Scl-mAb单药治疗同样有效。
Age-associated low bone mass disease is a growing problem in the US. Development of osteoanabolic therapies for treating skeletal fragility has lagged behind anti-catabolic therapies, but several bone-building molecules are clinically available. We reported previously that antibody-based neutralization of the Lrp5/Lrp6 inhibitor Dkk1 has minimal effects on bone gain, but can potentiate the already potent osteoanabolic effects of sclerostin inhibition (another Lrp5/Lrp6 inhibitor highly expressed by osteocytes). In this communication, we test whether an optimized ratio of sclerostin and Dkk1 antibodies (Scl-mAb and Dkk1-mAb, respectively), administered at low doses, can maintain the same bone-building effects as higher dose Scl-mAb, in adult (6 months of age) and aged (20 months of age) wild-type mice. A 3:1 dose of Scl-mAb:Dkk1-mAb at 12.5 mg/kg was equally efficacious as 25 mg/kg of Scl-mAb in both age groups, using radiographic (DXA, µCT), biomechanical, (3-point bending tests), and histological (fluorochrome-based bone formation parameters) outcome measures. For some bone properties, including trabecular thickness and bone mineral density in the spine, and endocortical bone formation rates in the femur, the 3:1 treatment was associated with significantly improved skeletal properties compared to twice the dose of Scl-mAb. Cortical porosity in aged mice was also reduced by both Scl-mAb and low-dose 3:1 treatment. Overall, both treatments were efficacious in the mature adult (6 mo.) and aged (20 mo.) skeletons, suggesting Wnt targeting is a viable strategy for improving skeletal fragility in the very old. Further, the data suggest that low dose of combination therapy can be at least equally efficacious as higher doses of Scl-mAb monotherapy.