Small oscillatory accelerations, independent of matrix deformations, increase osteoblast activity and enhance bone morphology

Abstract

A range of tissues have the capacity to adapt to mechanical challenges, an attribute presumed to be regulated through deformation of the cell and/or surrounding matrix. In contrast, it is shown here that extremely small oscillatory accelerations, applied as unconstrained motion and inducing negligible deformation, serve as an anabolic stimulus to osteoblasts in vivo. Habitual background loading was removed from the tibiae of 18 female adult mice by hindlimb-unloading. For 20 min/d, 5 d/wk, the left tibia of each mouse was subjected to oscillatory 0.6 g accelerations at 45 Hz while the right tibia served as control. Sham-loaded (n = 9) and normal age-matched control (n = 18) mice provided additional comparisons. Oscillatory accelerations, applied in the absence of weight bearing, resulted in 70% greater bone formation rates in the trabeculae of the metaphysis, but similar levels of bone resorption, when compared to contralateral controls. Quantity and quality of trabecular bone also improved as a result of the acceleration stimulus, as evidenced by a significantly greater bone volume fraction (17%) and connectivity density (33%), and significantly smaller trabecular spacing (-6%) and structural model index (-11%). These in vivo data indicate that mechanosensory elements of resident bone cell populations can perceive and respond to acceleratory signals, and point to an efficient means of introducing intense physical signals into a biologic system without putting the matrix at risk of overloading. In retrospect, acceleration, as opposed to direct mechanical distortion, represents a more generic and safe, and perhaps more fundamental means of transducing physical challenges to the cells and tissues of an organism.

Figure 1. Mean (+SE) mineralizing surfaces (MS/BS), mineral apposition rates (MAR), and bone formation rates (BFR/BS) measured in trabecular bone of the tibial metaphysis of control (CTR) and accelerated tibiae (ACC).

Figure 2. 3D reconstructed images of metaphyseal trabecular bone from a tibia that was subjected to short durations of sinusoidal accelerations (ACC, right panel) and its contralateral control (CTR, left panel) at baseline (top row) and at completion of the 3 wk protocol (bottom row).

The greater tissue quantity and quality in the accelerated tibia resulted from an enhanced preservation of tissue, as emphasized in the circled regions, during the 3 wk unloading period.

Figure 3. Mean (+SE) bone volume fraction (BV/TV), connectivity density (Conn.D), structural model index (SMI), trabecular number (Tb.N), trabecular thickness (Tb.Th), and trabecular separation (Tb.Sp) of control (CTR) and accelerated tibiae (ACC).

Values are expressed as a percentage of their normal weight-bearing age-matched controls. *: p<0.05 between CTR and ACC.

Figure 4. Osteocyte sitting in a lacuna within the matrix (left panel).

The nucleus is coupled to the membrane by the cytoskeleton. Upon the application of large loads, the matrix strains and distorts the osteocyte (central panel). These large distortions result in the cytoskeleton pulling on the nucleus, and stimulating transcriptional activity. While this can stimulate a biologic response, it does so at risk of damaging the matrix. Upon the application of sinusoidal accelerations, the bone matrix moves forward and back (or up and down). The cell within the lacunae will oscillate out of phase with the matrix and the nucleus will oscillate out of phase with the cell body, causing the cytoskeleton to pull on the nucleus in the absence of matrix distortion (right panel). In this scenario, accelerations can alter biologic activity in the absence of direct loading, with the potential to distort the cell much greater than with direct loading of the calcified matrix.