Abstract
This study presents two novel theoretical models to elucidate frequency sensitive nuclear mechanisms in low-intensity ultrasound enhanced bioeffects. In contrast to the typical 1.5 MHz pulsed ultrasound regime, our group previously experimentally confirmed that ultrasound stimulation of anchored chondrocytes at resonant frequency maximized gene expression of load inducible genes which are regulatory markers for cellular response to external stimuli. However, ERK phosphorylation displayed no frequency dependency, suggesting that the biochemical mechanisms involved in enhanced gene expression is downstream of ERK phosphorylation. To elucidate such underlying mechanisms, this study presents a theoretical model of an anchored cell, representing an in vitro chondrocyte, in an ultrasound field. The model results showed that the mechanical energy storage is maximized at the chondrocyte’s resonant frequency and the energy density in the nucleus is almost twice as high as in the cytoplasm. Next, a mechanochemical model was developed to link the mechanical stimulation of ultrasound and the increased mechanical energy density in the nucleus to the downstream targets of the ERK pathway. This study showed for the first time that ultrasound stimulation induces frequency dependent gene expression as a result of altered rates of transcription factors binding to chromatin.
Highlights
Over the past decades, low-intensity pulsed ultrasound (LIPUS) has been shown to induce bioeffects in tissue and promote bone fracture healing, and therapeutic ultrasound devices are available on the market [1,2,3,4]
The study showed that cells in an ultrasound field act like any other oscillator—the mechanical energy couples most effectively when the stimulation occurs at resonance [11]
The same experiments showed that extracellular regulated kinase (ERK) phosphorylation displayed no frequency dependency [11]. These experimental results coupled with the mathematical model developed by Louw et al [11] suggests that the biochemical mechanisms involved in enhanced gene expression is downstream of ERK phosphorylation and that a particular nuclear mechanism is sensitive to the mechanical stimulation frequency [11]
Summary
Low-intensity pulsed ultrasound (LIPUS) has been shown to induce bioeffects in tissue and promote bone fracture healing, and therapeutic ultrasound devices are available on the market [1,2,3,4] These successes drove researchers to study the effect of LIPUS on cartilage repair and restoration, even though the bioeffects were not completely understood [5]. The same experiments showed that extracellular regulated kinase (ERK) phosphorylation displayed no frequency dependency [11] These experimental results coupled with the mathematical model developed by Louw et al [11] suggests that the biochemical mechanisms involved in enhanced gene expression is downstream of ERK phosphorylation and that a particular nuclear mechanism is sensitive to the mechanical stimulation frequency [11]. Louw et al [11] posited that two possible mechanisms that could be effected are 1) nuclear transport and/or 2) chromatin binding
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
