Srinivasan Sundar, Balsiger Danica, Huber Phillipe, Ausk Brandon J, Bain Steven D, Gardiner Edith M, Gross Ted S
Department of Orthopaedics and Sports Medicine University of Washington Seattle WA USA.
JBMR Plus. 2018 Oct 11;3(5):e10087. doi: 10.1002/jbm4.10087. eCollection 2019 May.
Nearly all exogenous loading models of bone adaptation apply dynamic loading superimposed upon a time invariant static preload (SPL) in order to ensure stable, reproducible loading of bone. Given that SPL may alter aspects of bone mechanotransduction (eg, interstitial fluid flow), we hypothesized that SPL inhibits bone formation induced by dynamic loading. As a first test of this hypothesis, we utilized a newly developed device that enables stable dynamic loading of the murine tibia with SPLs ≥ -0.01 N. We subjected the right tibias of BALB/c mice (4-month-old females) to dynamic loading (-3.8 N, 1 Hz, 50 cycles/day, 10 s rest) superimposed upon one of three SPLs: -1.5 N, -0.5 N, or -0.03 N. Mice underwent exogenous loading 3 days/week for 3 weeks. Metaphyseal trabecular bone adaptation (μCT) and midshaft cortical bone formation (dynamic histomorphometry) were assessed following euthanasia (day 22). Ipsilateral tibias of mice loaded with a -1.5-N SPL demonstrated significantly less trabecular bone volume/total volume (BV/TV) than contralateral tibias (-12.9%). In contrast, the same dynamic loading superimposed on a -0.03-N SPL significantly elevated BV/TV versus contralateral tibias (12.3%) and versus the ipsilateral tibias of the other SPL groups (-0.5 N: 46.3%, -1.5 N: 37.2%). At the midshaft, the periosteal bone formation rate (p.BFR) induced when dynamic loading was superimposed on -1.5-N and -0.5-N SPLs was significantly amplified in the -0.03-N SPL group (>200%). These data demonstrate that bone anabolism induced by dynamic loading is markedly inhibited by SPL magnitudes commonly implemented in the literature (ie, -0.5 N, -1.5 N). The inhibitory impact of SPL has not been recognized in bone adaptation models and, as such, SPLs have been neither universally reported nor standardized. Our study therefore identifies a previously unrecognized, potent inhibitor of mechanoresponsiveness that has potentially confounded studies of bone adaptation and translation of insights from our field. © 2018 The Authors. Published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.
几乎所有骨适应的外源性加载模型都应用叠加在时间不变的静态预负荷（SPL）上的动态负荷，以确保对骨进行稳定、可重复的加载。鉴于SPL可能会改变骨力传导的某些方面（例如，组织液流动），我们推测SPL会抑制动态负荷诱导的骨形成。作为对这一假设的首次检验，我们使用了一种新开发的装置，该装置能够对小鼠胫骨进行稳定的动态负荷加载，且SPL≥-0.01 N。我们将BALB/c小鼠（4月龄雌性）的右胫骨置于三种SPL之一（-1.5 N、-0.5 N或-0.03 N）上叠加动态负荷（-3.8 N，1 Hz，每天50次循环，休息10 s）。小鼠每周进行3天外源性负荷加载，持续3周。在安乐死（第22天）后评估干骺端小梁骨适应情况（μCT）和骨干皮质骨形成情况（动态组织形态计量学）。加载-1.5 N SPL的小鼠同侧胫骨的小梁骨体积/总体积（BV/TV）明显低于对侧胫骨（-12.9%）。相比之下，叠加在-0.03 N SPL上的相同动态负荷使BV/TV相对于对侧胫骨显著升高（12.3%）以及相对于其他SPL组的同侧胫骨升高（-0.5 N：46.3%；-1.5 N：37.2%）。在骨干处，当动态负荷叠加在-1.5 N和-0.5 N SPL上时诱导的骨膜骨形成率（p.BFR）在-0.03 N SPL组中显著放大（>200%）。这些数据表明，文献中通常采用的SPL大小（即-0.5 N、-1.5 N）会显著抑制动态负荷诱导的骨合成代谢。SPL的抑制作用在骨适应模型中尚未得到认识，因此，SPL既未被普遍报告也未标准化。我们的研究因此确定了一种先前未被认识的、强大的心因性反应抑制剂，它可能混淆了骨适应研究以及我们领域见解的转化。© 2018作者。由Wiley Periodicals, Inc.代表美国骨与矿物质研究学会出版。
