Static Preload Confounds Bone Anabolism

University Of Washington, Seattle WA

Investigators

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Abstract

PROJECT SUMMARY/ABSTRACT During calibration studies for a new in vivo skeletal loading model, we observed that the device required only minimal static preload to achieve stable loading of the murine tibia. Static preload (SPL) is a constant static load upon which dynamic loading is superimposed and is ubiquitous across all in vivo loading models. Given the known catabolic influence of static loading, we speculated that SPL would attenuate the response of bone to dynamic loading. To test this thesis, we exploited the unique ability of our device to superimpose a given dynamic loading intervention upon SPLs that range over two orders of magnitude. Consistent with the literature, our initial study demonstrated that a -3.8 N dynamic loading regimen, when superimposed upon a -1.5 N SPL, induced a catabolic response in proximal tibia trabecular bone (BV/TV reduced -12.8% vs contralateral tibiae, p<0.05). In contrast, when the identical dynamic loading regimen was superimposed on a -0.03 N SPL, trabecular BV/TV was significantly elevated (12.4% vs contralateral tibiae, p<0.05). A second preliminary study then suggested that the inhibitory influence of SPL is independent of mouse strain and loading waveform. We therefore hypothesize that static preload inhibits bone formation induced by dynamic skeletal loading. We will implement two Specific Aims (SA) to explore this thesis. In SA#1, we will demonstrate that as SPL is reduced, the magnitude of skeletal loading that is required to augment trabecular and cortical bone formation will also be reduced. The potential impact of SPL inhibition will then be explored in SA#2 where we will demonstrate that reducing SPLs will reveal differential responses to skeletal loading as a function of loading waveform, age, and mouse strain that would otherwise not be evident in the context of SPL magnitudes implemented in previous studies. Significantly, as SPLs have not previously been controlled and often not even reported (including by our group), we believe that the potential impact of this issue is much broader and deeper than a technical issue with a particular in vivo model. Specifically, the presence of an unintentional inhibitor of bone mechanoresponsiveness in studies exploring bone's response to dynamic loading is likely both to confound broad interpretations (e.g., the effect of aging on bone's response to loading) as well as specific assessments of the mechanisms underlying any observed response (or lack thereof). Analogous to the conceptual basis of anti-sclerostin mAB therapy (i.e., inhibition of an inhibitor of osteoblast function), we believe that an understanding of the mechanism underlying SPL (to be pursued in a subsequent R01) holds potential to reveal new strategies (e.g., transient skeletal unweighting) to transform modest exercise into, for the first time, an effective intervention to focally enhance bone mass and morphology.