Differential changes in bone strength of two inbred mouse strains following administration of a sclerostin-neutralizing antibody during growth

Administration of sclerostin-neutralizing antibody (Scl-Ab) treatment has been shown to elicit an anabolic bone response in growing and adult mice. Prior work characterized the response of individual mouse strains but did not establish whether the impact of Scl-Ab on whole bone strength would vary across different inbred mouse strains. Herein, we tested the hypothesis that two inbred mouse strains (A/J and C57BL/6J (B6)) will show different whole bone strength outcomes following sclerostin-neutralizing antibody (Scl-Ab) treatment during growth (4.5–8.5 weeks of age). Treated B6 femurs showed a significantly greater stiffness (S) (68.8% vs. 46.0%) and maximum load (ML) (84.7% vs. 44.8%) compared to A/J. Although treated A/J and B6 femurs showed greater cortical area (Ct.Ar) similarly relative to their controls (37.7% in A/J and 41.1% in B6), the location of new bone deposition responsible for the greater mass differed between strains and may explain the greater whole bone strength observed in treated B6 mice. A/J femurs showed periosteal expansion and endocortical infilling, while B6 femurs showed periosteal expansion. Post-yield displacement (PYD) was smaller in treated A/J femurs (-61.2%, p < 0.001) resulting in greater brittleness compared to controls; an effect not present in B6 mice. Inter-strain differences in S, ML, and PYD led to divergent changes in work-to-fracture (Work). Work was 27.2% (p = 0.366) lower in treated A/J mice and 66.2% (p < 0.001) greater in treated B6 mice relative to controls. Our data confirmed the anabolic response to Scl-Ab shown by others, and provided evidence suggesting the mechanical benefits of Scl-Ab administration may be modulated by genetic background, with intrinsic growth patterns of these mice guiding the location of new bone deposition. Whether these differential outcomes will persist in adult and elderly mice remains to be determined.已有研究表明，给予骨硬化蛋白中和抗体（sclerostin-neutralizing antibody, Scl-Ab）可在生长中和成年小鼠中引发合成代谢性骨应答。过往研究仅对单个小鼠品系的应答进行了表征，尚未明确Scl-Ab对全骨强度的影响是否会因不同近交系小鼠品系而异。本研究验证了如下假说：两种近交系小鼠品系（A/J与C57BL/6J，简称B6）在生长阶段（4.5~8.5周龄）经Scl-Ab处理后，其全骨强度结局会存在差异。与A/J品系相比，经处理的B6小鼠股骨的刚度（stiffness, S）（68.8% vs. 46.0%）与最大载荷（maximum load, ML）（84.7% vs. 44.8%）均显著更高。尽管经处理的A/J与B6小鼠股骨的皮质骨面积（cortical area, Ct.Ar）相较于各自对照组均有相似程度的提升（A/J组为37.7%，B6组为41.1%），但介导骨量增加的新骨沉积位置在两个品系间存在差异，这或许可以解释经处理的B6小鼠全骨强度更高的现象。A/J小鼠股骨表现为骨膜扩张与骨内膜填充，而B6小鼠股骨仅表现为骨膜扩张。经处理的A/J小鼠股骨的屈服后位移（post-yield displacement, PYD）较对照组降低了61.2%（p < 0.001），相较于对照组脆性更高；而B6小鼠未出现该效应。刚度S、最大载荷ML以及屈服后位移PYD的品系间差异，导致了断裂功（work-to-fracture, Work）的变化趋势截然相反。与对照组相比，经处理的A/J小鼠的断裂功降低了27.2%（p = 0.366），而经处理的B6小鼠的断裂功则提升了66.2%（p < 0.001）。本研究的数据验证了此前报道的Scl-Ab合成代谢应答，并提供证据表明，Scl-Ab给药的力学获益或许会受到遗传背景的调控，上述两种小鼠的固有生长模式决定了新骨沉积的位置。上述差异性结局是否会在成年与老年小鼠中持续存在，仍有待进一步研究探明。