ARUP; ISBN: 978-0-9562121-5-3 - CMBBE 2012 - Cardiff University

positive effect of the number of activated integrins on the total amount of available
integrin molecules. The activation of integrins will hence influence the mechanical
model since stretching of the integrins is not only dependent on the external load but
also on the number of integrins. Furthermore, the ERK pathway also has an influence on
the mechanics of the cell, generating an additional feedback mechanism within the
model. More specifically, ERK can stimulate the Rho/ROCK pathway and Rhoassociated
protein kinase (ROCK) promotes the polymerisation of actin proteins into
actin filaments and the assembly of actin filaments into stress fibers [10]. This feedback
is modelled through the stimulation of the formation of actin components in the
mechanical model by the ERK pathway. The more springs in parallel the stiffer they are
combined, reducing their stretch. An overview of the model with its feedback
mechanisms is shown in figure 3.
4. RESULTS & DISCUSSION
We compared the response of ERK signaling in static and dynamic loads, since this has
been shown to differ in cartilage explants. In addition, different parameter settings were
applied in order to examine the sensitivity of the model to the parameters describing the
interaction between the biological and mechanical part of the model, and to get an idea
of the influence of the mechanical parameters on the ERK response.
The modelled ERK response to a
static load, a dynamic load with a
high frequency and a dynamic
load with a low frequency are
depicted in figure 4. The
modelled response qualitatively
resembles the response described
in the literature [2]. The
oscillation is the result of the
interplay between repeated
activation of the ERK
phosphorylation path and the
deactivation and recovery of the
dephosphorylation path in
synchrony with the force. At
higher frequencies the
dephosphorylation does not get
the time to recover.
The influence of the mechanical
parameters as well as the
influence of the interaction
parameters on the model were
tested for static and dynamic
loading. Variations in integrin
stiffness, nucleus stiffness and
substrate stiffness have a large
effect on the ERK response. The
substrate component and the
integrin-actin-nucleus part are in
Fig. 4 Modelled ERK phosphorylation in response to a static and two
dynamic loads: one with a frequency of 0.053 Hz and one with a
frequency of 0.00053 Hz.
Fig. 5 The response of ERK to a static force with the influence of a
variation in the substrate stiffness [Pa].
parallel in the mechanical model. Therefore the deformation in those branches is the