Mechanotransduction in bone: do bone cells act as sensors of fluid flow?

Abstract

When compact bone is subjected to bending loads, interstitial fluid in the bone matrix flows away from regions of high compressive stress. The amount of interstitial fluid flow is strongly influenced by the loading rate in a dose-dependent fashion. We hypothesize that interstitial fluid flow affects bone formation, and we tested this hypothesis indirectly by measuring the effect of different loading frequencies on bone formation rate in vivo. The right tibiae of adult female rats were subjected to applied bending at frequencies of 0.05, 0.1, 0.2, 0.5, 1.0, and 2.0 Hz for a 2-wk period. The rats were then killed and histomorphometric measurements of bone formation were made of the midshaft of the tibia. Bending of the tibia increased bone formation rate in the higher-frequency (0.5 to 2.0 Hz) loading groups as much as fourfold, yet no increase in bone formation rate was observed for loading frequencies below 0.5 Hz. In a separate experiment, we found stress-generated potentials (SGP) in the rat tibia to increase monotonically with increasing loading frequency. The dose-response relationship between loading frequency and the bone formation response closely resembles the relationship between loading frequency and SGP within bone. The qualitative similarity between these two relationships suggests that increased bone formation is associated with increased SGP, which are caused by interstitial fluid flow. Bone cells are known to be sensitive to electric fields and may respond directly to SGP. Also, fluid shear forces have been shown to stimulate bone cells in culture, so it is possible that increased interstitial fluid flow directly affects bone formation.

In vivo static creep loading of the rat forelimb reduces ulnar structural properties at time-zero and induces damage-dependent woven bone formation

“…Second, the dynamic strain that occurs with fatigue may have an additive effect on top of damage. The latter possibility is consistent with the fact that supraphysiological levels of strain can stimulate woven bone formation in the absence of damage [27], and the likelihood that the dynamic strain in the region of fatigue damage is supraphysiological.…”

“…In growing rats, brief-duration static loading had an inhibitory effect on appositional bone formation while dynamic loading triggered an adaptive formation response [22]. In addition, dynamic loading did not stimulate bone formation at frequencies below 0.5 Hz in the rat tibia [27]. Our findings clearly demonstrate that when static loading produces measurable bone damage, woven bone formation is activated.…”

“…Thus, during creep loading, some forelimbs experienced a small, superimposed sinusoidal variation in strain (less than 1% of the total strain). We do not believe this influenced the creep response, as mouse forelimbs statically loaded with superimposed vibration were not stimulated to form new cortical bone [8], and the frequency of the superimposed variation (0.1 Hz) is less than that required to stimulate an adaptive bone response [27]. Second, the applied force was not equal for all animals.…”

Effects of Mechanical Strain on the Function of Gap Junctions in Osteocytes Are Mediated through the Prostaglandin EP2 Receptor

“…Over the past few years, a number of theoretical and experimental studies support the hypothesis that flow of interstitial fluid is the major stimuli for osteocytes in response to loading (14 -16). It has been found that mechanical forces applied to bone cause fluid to flow through the canaliculi surrounding the osteocyte and that fluid flow is probably responsible for deformation in the extracellular matrix and of the cell membrane (16,17). Primary chicken osteocytes have been shown to be more sensitive than osteoblasts with respect to release of prostaglandins in response to either hydrostatic compression or to fluid flow shear stress, with fluid flow being more effective (18,19).…”

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“…There were also small discrepancies in the distal half of the medial side as indicated in The presented mechanobiological model is proposed as a time-dependent analogy to the trilinear curve referred in subsection 2.3. Trilinear stimulus-adaptation functions are commonly used in bone adaptation studies (Adachi et al, 2001;Beaupré et al, 1990;Carter, 1984;Chennimalai Kumar et al, 2012;Cowin, 1984;Huiskes et al, 1987), based on various of studies showed there is a dosedependent relationship between higher mechanical stimulation and bone formation response (Bacabac et al, 2004;Rubin and Lanyon, 1984;Turner et al, 1994).…”