Mechanical signals as anabolic agents in bone

Abstract

Aging and a sedentary lifestyle conspire to reduce bone quantity and quality, decrease muscle mass and strength, and undermine postural stability, culminating in an elevated risk of skeletal fracture. Concurrently, a marked reduction in the available bone-marrow-derived population of mesenchymal stem cells (MSCs) jeopardizes the regenerative potential that is critical to recovery from musculoskeletal injury and disease. A potential way to combat the deterioration involves harnessing the sensitivity of bone to mechanical signals, which is crucial in defining, maintaining and recovering bone mass. To effectively utilize mechanical signals in the clinic as a non-drug-based intervention for osteoporosis, it is essential to identify the components of the mechanical challenge that are critical to the anabolic process. Large, intense challenges to the skeleton are generally presumed to be the most osteogenic, but brief exposure to mechanical signals of high frequency and extremely low intensity, several orders of magnitude below those that arise during strenuous activity, have been shown to provide a significant anabolic stimulus to bone. Along with positively influencing osteoblast and osteocyte activity, these low-magnitude mechanical signals bias MSC differentiation towards osteoblastogenesis and away from adipogenesis. Mechanical targeting of the bone marrow stem-cell pool might, therefore, represent a novel, drug-free means of slowing the age-related decline of the musculoskeletal system.

Figure 1

Bone is subjected to a range of mechanical strains. a | A 2-minute recording from a strain gauge attached to a sheep tibia while the animal is standing (top panel) shows peak strains in the order of 200 microstrain. A 20-second section of that strain record (middle panel) shows peak strain events as large as 40 microstrain, occurring at a high frequency. Closer inspection of a 3-second period of the strain recording (bottom panel) illustrates events in the order of 5 microstrain occurring through the entire recording period. when the strain activity of a bone is recorded over a 12-hour period, it is clear that there are very few large strain events (>2,000 microstrain) and tens of thousands of small strain events (<10 microstrain). b | Strain recordings from the tibia of a diverse range of animals over a 12-hour period are remarkably similar. Reprinted from Journal of Biomechanics 33, Fritton, S. P., McLeod, K. J. and Rubin, C. T. Quantifying the strain history of bone: spatial uniformity and self-similarity of low-magnitude strains, 317–325 © (2000), with permission from Elsevier.

Figure 2

Interrelationship between loading cycles and bone adaptation. Using the turkey ulna model to determine the nonlinear interrelationship of cycle number and strain magnitude, bone mass can be maintained through a number of distinct strategies (line); bone is preserved with either four cycles per day of 2,000 microstrain, 100 cycles per day of 1,000 microstrain, or hundreds of thousands of cycles of signals of well below 10 microstrain (each represented as a star). These data indicate that falling below this ‘preferred strain history’ would stimulate bone loss, while exceeding this interrelationship would stimulate bone gain.

Figure 3

Low-magnitude mechanical signals are anabolic to bone. Microcomputed tomography of 1 cm cubes of trabecular bone from the distal femur of adult (8-year-old) sheep, comparing a | a control animal with b | an animal subjected to 20 minutes per day of 30 Hz (cycles per second) of a low-level (0.3 g) mechanical vibration for 1 year. The large increase in trabecular bone density results in enhanced bone strength, achieved via bone strain three orders of magnitude below those that cause tissue damage. These data suggest that mechanical signals need not be large to be anabolic to bone, and might represent a non-drug basis for the prevention or treatment of osteoporosis. Permission obtained from J. Bone Miner. Res. 17, 349–357 © (2002) American Society for Bone and Mineral Research.

Figure 4

Mechanical loading influences MSC differentiation. The ability of mechanical signals to increase bone formation while inhibiting fat formation centers on the mechanical sensitivity of the common progenitor stem cell from which osteoblasts and adipocytes differentiate. Shown in reconstructed microcomputed images, low-magnitude mechanical signals bias the bone marrow stem-cell population towards osteoblastogenesis, resulting in greater bone density in the proximal tibia (upper right) and reduced visceral adiposity across the abdomen (red in the lower right image). These images are compared with those from placebo control animals who ate the same amount of food, yet over the same time period had significantly less trabecular bone (lower left) and more fat (upper left; reproduced at same scale). The phenotypic outcomes are mirrored by transcriptional changes, as reflected by increased Runx2 expression and reduced PPARγ expression in the marrow of the LMMS animals. Abbreviations: LMMS, low- magnitude mechanical signal; MSC, mesenchymal stem cell; PPARγ, peroxisome proliferator-activated receptor. Permission obtained from J. Bone Miner. Res.24, 50–61 © (2009) American Society for Bone and Mineral Research.