Focal enhancement of the skeleton to exercise correlates to mesenchymal stem cell responsivity rather than peak external forces

Abstract

Force magnitudes have been suggested to drive the structural response of bone to exercise. As importantly, the degree to which any given bone can adapt to functional challenges may be enabled, or constrained, by regional variation in the capacity of marrow progenitors to differentiate into bone-forming cells. Here, we investigate the relationship between bone adaptation and mesenchymal stem cell (MSC) responsivity in growing mice subject to exercise. First, using a force plate, we show that peak external forces generated by forelimbs during quadrupedal locomotion are significantly higher than hindlimb forces. Second, by subjecting mice to treadmill running and then measuring bone structure with μCT, we show that skeletal effects of exercise are site-specific but not defined by load magnitudes. Specifically, in the forelimb, where external forces generated by running were highest, exercise failed to augment diaphyseal structure in either the humerus or radius, nor did it affect humeral trabecular structure. In contrast, in the ulna, femur and tibia, exercise led to significant enhancements of diaphyseal bone areas and moments of area. Trabecular structure was also enhanced by running in the femur and tibia. Finally, using flow cytometry, we show that marrow-derived MSCs in the femur are more responsive to exercise-induced loads than humeral cells, such that running significantly lowered MSC populations only in the femur. Together, these data suggest that the ability of the progenitor population to differentiate toward osteoblastogenesis may correlate better with bone structural adaptation than peak external forces caused by exercise.

Physical activity alters limb bone structure but not entheseal morphology

“…Each stride generated peak vertical substrate reaction forces between approximately 150% and 250% of the animal’s body weight (Roberts and Scales, 2002). This exercise routine constitutes a substantial increase in high-magnitude limb loading events relative to the normally sedentary activity patterns of laboratory turkeys (Fritton et al, 2000), and it is consistent with prior exercise studies that have revealed statistically significant musculoskeletal tissue changes in galliform birds (Buchanan and Marsh, 2001, 2002), as well as in mammals (Wallace et al, 2015). All subjects were euthanized by 18–19 months of age and their femora were extracted.…”

“…In a diversity of animals including rodents (e.g., Wallace et al, 2015), ruminants (e.g., Lieberman et al, 2003; Barak et al, 2011), swine (e.g., Lieberman, 1996), and now turkeys, loadbearing forms of exercise such as running, particularly if they occur during the growing years, have been shown to enhance bone formation and augment diaphyseal robusticity and trabecular architecture, providing empirical support for the model within which paleoanthropologists commonly infer ancient human activity levels from these structural features of limb bone remains. Diaphyseal and trabecular structure are strongly affected by intrinsic factors such as age, sex, and genetics, but in studies of human skeletal remains in which these non-mechanical factors can be carefully evaluated and convincingly argued to not underlie observed morphological patterns, ample evidence from animal experiments suggests that such patterns may be due to variation in physical activity levels.…”

Effect of Low-Magnitude, High-Frequency Mechanical Stimulation on BMD Among Young Childhood Cancer Survivors

“…These regional differences in the effects of LMS on BMD may relate to the proximity of the device to body region, with potential loss of vibratory energy as the signal travels from the distal lower extremity to the trunk, 47 or to differences in capacity to respond to mechanical signals, with some regions more attuned to functional adaptation than others. 48 …”

Low intensity vibration mitigates tumor progression and protects bone quantity and quality in a murine model of myeloma

“…Given that the marrow volume of the femur is approximately twice that of the tibia, this suggests that an early stage in the pathogenesis of the disease may be to crowd out the healthy marrow, and once that occurs, marrow necrosis begins as aggravated by the absence of a viable marrow to support it. Alternatively, it is entirely possible that spatially distinct marrow populations may account for the differential progression of the tumor in the tibia vs. the femur, as well as the distinct responses of these bones to the mechanical intervention (60). Extrapolating to the clinic, it suggests that any intervention that slows the crowding of the marrow by the tumor would, naturally, slow the inevitable advance of necrosis that follows.…”