Mechanical modulation of molecular signals which regulate anabolic and catabolic activity in bone tissue

Abstract

Identifying the molecular mechanisms that regulate bone's adaptive response to alterations in load bearing may potentiate the discovery of interventions to curb osteoporosis. Adult female mice (BALB/cByJ) were subjected to catabolic (disuse) and anabolic (45 Hz, 0.3g vibration for 10 min/day) signals, and changes in the mRNA levels of thirteen genes were compared to altered indices of bone formation. Age-matched mice served as controls. Following 4 days of disuse, significant (P = 0.05) decreases in mRNA levels were measured for several genes, including collagen type I (-55%), osteonectin (-44%), osterix (-36%), and MMP-2 (-36%) all of which, after 21 days, had normalized to control levels. In contrast, expression of several genes in the vibrated group, which failed to show significant changes at 4 days, demonstrated significant increases after 21 days, including inducible nitric oxide synthase (iNOS) (39%, P = 0.07), MMP-2 (54%), and receptor activator of the nuclear factor kB ligand (RANKL) (32%). Correlations of gene expression patterns across experimental conditions and time points allowed the functional clustering of responsive genes into two distinct groups. Each cluster's specific regulatory role (formation vs. resorption) was reinforced by the 60% suppression of formation rates caused by disuse, and the 55% increase in formation rates stimulated by mechanical signals (P < 0.05). These data confirm the complexity of the bone remodeling process, both in terms of the number of genes involved, their interaction and coordination of resorptive and formative activity, and the temporal sensitivity of the processes. More detailed spatial and temporal correlations between altered mRNA levels and tissue plasticity may further delineate the molecules responsible for the control of bone mass and morphology.

Osteogenic Effect of High-frequency Acceleration on Alveolar Bone

“…This new bone matrix had increased collagen crosslinking, which suggested an acceleration of bone deposition and maturation by resident osteoblasts. Studies in long bones did not produce similar results, which can be related to differences in mechanical stimulation regimen, time-points and genes studied, and different types of bones (Judex et al, 2005;Kotiya et al, 2011). Our results also support an important role for vibration during the mineralization process.…”

Molecular pathways mediating mechanical signaling in bone

“…We have seen that the resident bone cell populations possess mechanoreceptors which sense the mechanical environment and that virtually every type of signaling cascade is subject to activation (or in the case of osteoclast recruitment, suppression) by mechanical forces. Certainly, it is clear that new mechanical signals in bone alter the transcriptional activity of bone (Judex et al, 2005), and that the resultant adaptation is an effective strategy for a "smart" material to accommodate new loading challenges. The growing amount of information in this area highlights critical questions that need to be addressed by investigators in mechanotransduction and the signaling world in general.…”

Osteocytes as mechanosensors in the inhibition of bone resorption due to mechanical loading

“…Osteoclastogenesis has been shown to be regulated by mechanical loading both in vitro and in vivo (17,19,21,(40)(41)(42)(43). Rubin and colleagues (40)(41)(42)(43) have shown that dynamic mechanical strain can decrease osteoclast formation by about 50% in primary marrow cultures, and this is mediated through a decrease in RANKL and an increase in eNOS-generated NO in bone marrow stromal cells.…”