The skeleton in a physical world

Abstract

All organisms exist within a physical space and respond to physical forces as part of daily life. In higher organisms, the skeleton is critical for locomotion in the physical environment, providing a carapace upon which the animal can move to accomplish functions necessary for living. As such, the skeleton has responded evolutionarily, and does in real-time, to physical stresses placed on it to ensure that its structure supports its function in the sea, in the air, and on dry land. In this article, we consider how those cells responsible for remodeling skeletal structure respond to mechanical force including load magnitude, frequency, and cyclicity, and how force rearranges cellular structure in turn. The effects of these forces to balance the mesenchymal stem cell supply of bone-forming osteoblasts and energy storing adipocytes are addressed. That this phenotypic switching is achieved at the level of both gene transactivation and alteration of structural epigenetic controls of gene expression is considered. Finally, as clinicians, we consider this information as it applies to a prescriptive for intelligent exercise.

Keywords: Mechanical force; actin; adipose; cell structure; exercise; mesenchymal stem cell.

Figure 1.

Bone cells are impacted by physical load. Bone cells involved in modeling and remodeling the skeleton include MSC and its output of osteoblast, osteocyte, and adipocyte cells as well as the osteoclast, from a hematopoietic precursor. Each of these cell types responds to physical force which, under physiological conditions, leads to formation and remodeling of bone to improve bone quantity and quality. (A color version of this figure is available in the online journal.)

Figure 2.

Bone marrow adipose tissue (BMAT) regional quantification. The figure demonstrates isolation of bone masks as detailed in McGrath et al., where voxel-wise correspondence allows direct comparison of intensities. Average fat maps for each experimental group were computed in the common space and superimposed on the common, average water image for visualization of group fat maps. (A color version of this figure is available in the online journal.)

Figure 3.

Bone marrow adipose tissue (BMAT) quantification via high-resolution MRI with advanced image analysis. This displays our quantitative method for measuring BMAT via 9.4T MRI with advanced image analysis, validated in Styner et al. Fat map intensities were represented with a colored heat map in 3DSlicer for visualization (open-access: www.slicer.org). For BMAT quantification, we created a regional label map of the femur, excluding cortical bone regions, with regions for the epiphysis, metaphysis, and diaphysis. Intensity-weighted volume of BMAT was then quantified via regional fat histograms. Twelve-week-old male (WT, n = 3), SEIPIN heterozygotes (HET, n = 2), and SEIPIN KO (KO, n = 4) were analyzed. Data are plotted as individual values in violin plots. Total as well as metaphyseal BMAT was quantified relative to bone volume. One-way analysis of the variance demonstrated a significant overall difference between the groups (P = 0.04). The between group differences were obtained via posthoc analysis with *P < 0.05. These data have not appeared in the previous publications. (A color version of this figure is available in the online journal.)

Figure 4.

Parameters of experienced or applied mechanical load in cells and organisms. Exercise generates forces within bones in the form of strain as a cell is stretched between its connections to its substrate, flow of interstitial fluid over the cells causing distortion and, in some cases, electrical fields with flow over charged local molecules, and vibration of the dense nuclear body contained within the less massy cell cytoplasm. These forces are experienced as applied parameters, similar to dosing of drugs, including the magnitude (intensity) of force, and the frequency or strain rate. The force might be repeated within seconds or hours, and re-dosed over days with rest periods respecting the cell’s ability to mount a response. These ideas can be represented at the macro level during exercise in terms of weight lifted, speed of performance, repetitions, and sets – and how many times per week, the individual succeeds in getting back to the gym. (A color version of this figure is available in the online journal.)

Figure 5.

The mechanosensors YAP and β-catenin are activated by different components of force. β-catenin and YAP represent the mechanosensing molecules that, when activated, are translocated into the nucleus where they regulate gene expression. β-catenin entry into the nucleus occurs with dynamic load, but not static load, while YAP responds to static, but not dynamic, load. β-catenin nuclear entry in MSCs depends on the concurrent translocation of actin monomers, which are thought to alter the epigenetic landscape. (A color version of this figure is available in the online journal.)