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

same and depends on the sum of their stiffness, hence a low substrate stiffness leads to a
larger deformation in the integrin components, thereby increasing the stimulation of the
ERK pathway. Figure 5 depicts the phosphorylation in response to a static load with
varying substrate stiffness.
The sensitivity to an alteration in the substrate stiffness illustrates how the ECM
stiffness influences mechanotransduction and the activation of intracellular pathways
and gives rise to different cell fates. Discher and coworkers demonstrated the
importance of culturing cells on a substrate that resembles their natural mechanical
environment, in this way modulating cell fate [11]. In the model, the nucleus also
appeared to play a significant role, as a change in nucleus stiffness had a large impact
on the model output. Therefore the nucleus should be taken into account when studying
mechanotransduction, confirming the idea of Wang et al. [12] that the nucleus can be
important for mechanotransduction in several ways.
Changes in the actin stiffness, the passive cytoskeleton stiffness and the viscosity had
little effect on the output of the model. In addition the model was very sensitive to a
change in all the interaction parameters except for actin feedback. Hence the actin
component is probably bypassed by the active force generating component, thereby
limiting its influence.
The biological response does not end at ERK, ERK can stimulate the production of AP-
1, a transcription factor whose targets include Sox9, which in turn will stimulate the
production of aggrecan and collagen II and stimulate the proliferation of chondrocytes.
Therefore a sustained ERK activation will probably lead to a production of ECM and
the proliferation of chondrocytes. The activation of ERK can also lead to another
outcome by stimulating the formation of Runx2 and the direct inhibition of Sox9.
Runx2 plays a role in endochondral bone formation and stimulates chondrocyte
maturation and hypertrophy [13]. Which of the two pathways will be followed probably
depends on other factors in the environment.
5. CONCLUSIONS
Due to the constantly enlarging compendium of studies elucidating the control of
differentiation in developmental biology we can now wonder how mechanics impacts
on these elaborate control systems. One missing piece in the puzzle is how integrins
sense and respond to mechanical stimuli. This model is a first attempt to sketch the
mechanisms that may in time close the gap between mechanical cues and the eventual
bearing on cell fate. Regardless of the specifics our model shows that changes in the
mechanical environment can be directly translated by cells through surface-adhesion
receptors, of which integrin is the prime example. Analysis of our model reveals that the
timing, strength and the context of mechanical signals all play an important role in
mechanotransduction by integrins. Specifically, the simulations show that the model is
very sensitive to a change in nucleus stiffness, substrate stiffness and most of the
interaction parameters. The interaction parameters determine the activation of the ERK
pathway, the feedback and the balance between phosphorylation and dephosphorylation
activation, consequently their quantification could greatly increase the model’s
predictive power. In agreement with the results presented here, various in vitro
experiments have shown substrate stiffness to be important in cell fate decisions, for
example in the determination of the differentiation path an MSC will take. The nucleus
putatively has an important role in the mechanical behaviour of the cell as well.
In order to reach a mechanistic and quantitative understanding of mechanotransduction
by integrins we will need to build a more comprehensive view of the plethora of