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

COUPLING CELL MECHANICS AND INTRACELLULAR
SIGNALLING: MECHANOTRANSDUCTION THROUGH ERK
1. ABSTRACT
J. Kerkhofs 1 , L. Geris 2 , B. Bosmans 3 and H. Van Oosterwyck 4
Load-bearing tissues are dependent on mechanical stimuli in their environment to
maintain a stable phenotype. Tissue’s basic unit, the cell, must process these stimuli into
what constitutes an appropriate response on the tissue level. Here, we present a
theoretical model that bridges the gap between mechanical signals and their regulation
of intracellular signalling pathways. The model comprises an Ordinary Differential
Equations (ODE) model of the ERK signalling pathway, coupled to a 1D rheological
model of cell-matrix mechanics. The model predicts markedly different ERK activation
for static versus dynamical loading. Furthermore, the model demonstrates the
importance of substrate stiffness for ERK signalling. These results show the model’s
potential in elucidating mechanotransduction phenomena.
2. INTRODUCTION
Cells have different ways to feel mechanical loading. In cells attached to a solid
substrate, focal adhesions play an important role. Focal adhesions are protein complexes
built around integrin molecules. The integrins are transmembrane proteins which bind to
the extracellular matrix (ECM) and are attached to the cytoskeleton inside the cell. The
integrins transmit the mechanical signal from the outside of the cell to the inside by
initiating signalling pathways that may ultimately signal to the nucleus to regulate gene
transcription. Many signalling pathways are activated by mechanical loading, not only
through integrins but also, for example, via stretch activated Ca 2+ channels. However
many of those pathways are still under investigation and the mechanisms behind the
activation by mechanical stimuli and the effect of the signalling are not yet clear, in
particular because of multiple crosstalks between those pathways.
The phosphorylation of the extracellular regulated kinase (ERK) in the mitogen
activated protein kinase (MAPK) pathway, which is initiated by mechanical loading of
integrin, is well characterized. Phosphorylated ERK is an important signal transducer in
chondrocytes and osteoblasts promoting among others the transcription of activator
protein 1 (AP-1), which in turn is a transcription factor for different important genes in
both cell types [1]. Interestingly, the ERK response in chondrocytes is different for a
1 PhD student, Biomechanics section, KU Leuven, Celestijnenlaan 300C – Mailbox 2419 , 3000 Leuven,
Belgium
2 Professor, Biomechanics Research Unit, Chemin des Chevreuils 1 - BAT 52/3, U.Liège, 4000 Liège,
Belgium
3 MSc student, Biomechanics section, KU Leuven, Celestijnenlaan 300C – Mailbox 2419 , 3000 Leuven,
Belgium
4 Professor, Biomechanics section, KU Leuven, Celestijnenlaan 300C – Mailbox 2419 , 3000 Leuven,
Belgium