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Bio-Mechanical Stimulation of Skin Fibroblasts Biomechanical Stimulation and its Clinical Prospects 43
cooperation between the TGF- and -catenin signalling pathways is part of the
pathogenesis of HSs and keloids [77].
Calcium ion Signalling
It is believed that many signalling pathways bridge the Ca
2+
influx that is
associated with reactions to mechanical forces. Indeed, Ca
2+
permeable channels
that are voltage-gated [79] or stretch-activated [80] act together with G protein-
coupled receptors (GPCR) or receptor tyrosine kinases (RTK) [81] to arouse the
intracellular reactions of the PKC, PLC-IP3, or PLCγ-DAG pathways and their
ensuing Ras/Raf/Erk [82] pathways, respectively. Calcium ions are involved in
the mechanoresponses in different cell types. Thus in fibroblasts or keratinocytes
elevations in intracellular calcium can be observed after applications of hydraulic
pressure [83], hypotonic stress [84], or stretching [85]. Ca
2+
influx can be induced
in dermal fibroblasts by uniaxial stretching and membrane deformation, and can
be inhibited by mechanosensitive Ca
2+
channel blockers such as gadolinium(III)
chloride and non-selective Ca
2+
channel blocker such as ruthenium red [85].
It was suggested that in myofibroblasts the calcium ions play an important role in
the intercellular communications by the following mechanism [86]: a contraction
of a particular myofibroblast is transmitted to the adjacent cells via adherence
junctions, this phenomenon leads to an opening of mechanosensitive ion channels
in the adjacent cells with resulting effect of Ca
2+
influx, which in turn induces
cellular traction that feeds back on the cell that initiated this process, etc. In this
way myofibroblasts’ contractile activity is synchronized and facilitates overall
connective tissue contracture and remodelling.
Ca
2+
pathways not only participate intimately in G protein, PKC, IP3 and MAPK
signalling, they also associate with the integrin and cytoskeleton system. It has
been shown that the transduction of mechanical force into Ca
2+
sparks requires a
structural linkage of integrin to the cytoskeleton [87]. Conversely, the induction of
a physical linkage between integrins and the cytoskeleton also depends on
intracellular calcium. This indicates that intracellular calcium is a part of the
integrin-dependent both outside-in and inside-out signalling pathways [88]. In
particular the actin stress fibres are essential for the efficient force transmission
that is needed to open the stretch-activated Ca
2+
channels [89] and conversely,
actin reorganization can also be mediated by intracellular calcium signals that are
initiated by stretch-activated channel activation [80]. Such close coordination of
the cytoskeleton and calcium signalling processes suggests that cells have a
reflexive protective system that maintains their homeostasis, despite their
exposure to potentially damaging physical forces [90].
44 Biomechanical Stimulation and its Clinical Prospects Har-Shai et al.
CONFLICT OF INTEREST
The author confirms that author has no conflict of interest to declare for this
publication.
ACKNOWLEDGEMENTS
Declared None.
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Mesenchymal Cell Activation by Biomechanical Stimulation and its Clinical Prospects, 2016, 49-57 49
Nahum Rosenberg (Ed)
All rights reserved-© 2016 Bentham Science Publishers
CHAPTER 5
Mechanotransduction in Osteoblats
Yaron Berkovich, Jacob Shapira and Nahum Rosenberg
*
Department of Orthopaedic Surgery, Rambam Health Care Campus, POB 9602, Haifa 31096,
Israel
Abstract: Skeletal system is highly capable to adapt and respond to various mechanical
stimuli. The mechanisms for osteoblasts’ differentiation and their cross-talk with
osteocytes and osteoclasts are under extensive investigation but the exact interactions of
cellular pathways are not fully understood. The mechanisms of osteocytes’ response to
the different aspects of a mechanical stimulation remain unclear and so are the
mechanisms by which osteoblasts co-ordinate the different intracellular signaling.
Further investigation of the molecular principles of mechnotransduction is needed in
order to exploit the value of mechanically oriented therapeutics. Therapeutic methods
that utilize the use of cellular mechanical stimulation of osteoblasts might provide a
non-invasive approach for bone regeneration in osteodegenerative conditions and
following traumatic bone damage.
Keywords: Bone, growth factors, osteogenesis, remodelling, Wnt.
BACKGROUND
Bone is a dynamic tissue, constantly remodelling under the stimuli of hormones,
cytokines and mechanical triggers. Among other components, bone consists of an
extracellular fluid compartment that communicates with the vascular system.
External mechanical stimuli increase the fluid exchange between these two
compartments, which in turn increases bone formation and decreases bone
resorption [1]. Cellular strains, which are induced by interstitial fluid flow, are an
important part of mechanotransduction chain that starts by the external
mechanical stimuli and then transferred into biochemical pathways in bone cells.
Bone multicellular unit (BMU) is the basic regulatory cellular unit of the bone as
a whole live organ. BMU consists of bone forming cells (lining cells, osteocytes
and osteoblasts), bone resorbing cells (osteoclasts) and associated supporting
cells, i.e., precursors, endothelial and nerve cells [2].
*Corresponding author Rosenberg Nahum: Department of Orthopaedic Surgery, Rambam Health Care
Campus, POB 9602, Haifa 31096, Israel; E-mail: nahumrosenberg@hotmail.com
50 Biomechanical Stimulation and its Clinical Prospects Berkovich et al.
Bone 3D structure is maintained by osteogenesis and bone resorption, i.e. by
modelling and remodelling. Osteogenesis is the initial step of bone formation.
Bone formation occurs either by intramembranous ossification or by
endochondral ossification. After bone formation has taken place, modelling
commences, changing the shape and the structure through the activity of
osteoblasts and osteoclasts. Lastly, remodelling acts through localized bone
renewal.
Mechanical loading is one of the fundamental triggers that initiates bone
remodelling and matrix deposition and enhances bone formation [3]. Osteoclasts
and osteoblasts are coupled together in forming and resorbing bone at the same
small area on the bone surface. Remodelling is crucial in maintaining the optimal
mechanical characteristics and metabolic capacity of the body skeleton. The BMU
works in coordination and regulated through interconnected hormones, growth
factors and mechanical signals. Those signals result in a cascade by activating
certain transcription factors and eventually their downstream genes (Fig. 1).
Figure 1: Interactions between BMU components. + indicates induction. - indicates suppression.
Hematopoetic progenitor cells
Mesenchymal stem cells
(+)M-CSF,RANKL
(-)OPG
BMU
(+)
Osteoclasts
Osteoblasts
(+)
(+)
(-)
(-)
(-)
(Hormones)
PTH, 1,25 Vit D
(
Local agents)
IL1, IL6, IL11, TNF
BMP, IGF, TGFb, PDGF
(Hormones)
Estrogens
BMP-bone morphogenic protein
BMU- basic multicellular unit
IGF - insulin-like growth factor
IL - interleukin
M-CSF- macrophage colony stimulating
factor
OPG- osteoprotegerin
PTH - parathyroid hormone
PDGF - platelet-derived growth factor
RANKL-receptor activator of nuclear
factor (NF)-kappaB ligand
TGFb - transforming growth factor b
TNF - tumor necrosis factor
Vit D - vitamin D
Mechanotransduction in Osteoblats Biomechanical Stimulation and its Clinical Prospects 51
Mechanotransduction and Signaling Pathways
Mechanotransduction is generated by three interconnected mechanisms;
mechanosensing via biochemical coupling, signal propagation and metabolic
activation on the cellular level (Fig. 2).
Osteocytes are the most abundant cells in the bone matrix. These cells are
considered as the mechanoreceptors, and as such, direct the osteoblats to activate
osteogenic genes including collagen type I and osteocalcin. Osteoblasts and
osteocytes share similarities due to common cell lineage origin. Nevertheless,
each cell possesses distinct features, such as different responses to mechanical
stimuli and exploiting different signalling pathways in order to execute their
function. Wnt signalling for example, is utilized by osteoblasts for differentiation,
proliferation and mineralization, whereas osteocytes utilize it to relay signals of
mechanical stimuli to osteoblasts on the bone surface [4]. In the absence of
osteocytes, it has been shown that osteoblasts have the ability to sense mechanical
cues via mechanosensors, such as the integrins and mechanosensitive calcium
channels.
Various studies demonstrate that fluid flow, both over osteocytes and osteoblasts,
results in intracellular calcium mobilization, production of nitric oxide (NO) and
prostaglandins E2 and increased genes expression for osteopontin (Opn) and
cyclo-oxygenase-2 (Cox2). Other mechanosensors include the cell-cell adhesion
elements (cadherins, gap junctions), surface processes (primary cilia, stereocilia),
various membrane elements (caveola, surface receptors), cytoskeleton elements
(microfilaments, microtubules, and intermediate filaments), ECM constituents
(collagen, fibronectin, proteoglycans, and basement membrane) and other cell-
ECM adhesions (focal adhesions) [5]. Those components act in independent and
interactive manner. Mechanosensors transduce their signal to a number of cardinal
intracellular enzymes. According to the duration and the type of force applied,
MAPKs, Cox-2, NO, TNFα and Wntβ-catenin are triggered [6]. In addition,
mechanical stimulation of osteoblasts causes secretion of various growth factors,
e.g. IGF, VEGF, PDGF, bFGF, TGF-β and BMPs. Those are considered to be the
key regulators of osteogenesis, despite of their non-specificity to the osteoblasts.
The effects on bone are mediated by interactions of these growth factors with
humoral factors and with distinctive intracellular mediators. Glucocorticoids, sex
steroids, PTH and PGE2 have a roll in bone cells metabolism and function as a
link between cytokines or growth factors with nuclear proteins. The activated
growth factors and intracellular signals are converged to activate transcription
factors, such as Runx2, the key transcriptional regulator of osteoblast
52 Biomechanical Stimulation and its Clinical Prospects Berkovich et al.
differentiation. Additional transcription factors were also found to be part of the
process: osterix, beta-catenin and ATF4 act downstream to Runx2, activator
protein-1 (AP-1), C/enhancer binding proteins (EBPs), PPAR gamma and
homeodomain, helix- lop -helix proteins [7]. Therefore it is apparent that
mechanical stimulation induces secretion of humoral factors (hormones, growth
factors and cytokines) and triggers the differentiation and proliferation of
osteoblasts.
Osteocytes, the mechanotransducers, promote osteoblastogenic events by
orchestrating the combined action of hormones and growth factors, following
mechanical stimuli. The mechanical stimuli might be generated by fluid flow,
surface strain, membrane deformation via integrin stimulation, vibration, altered
gravity and compressive loading (increased hydrostatic pressure). Response to
external mechanical cues may be induced by either of the two proposed
mechanisms. First, by deformation of the cell structure as a result of mechanical
strain, following external mechanical force. Second, indirect mechanical loading
that generates fluid flow and strain by induction of extracellular flow through the
bone lacuno-canalicular system.
Research results provide evidence that indirect stimulation of the cell body,
resulting from load induced fluid flow, might be the primary mechanism by which
bone cells sense their mechanical environment [8]. But if the stimulatory
mechanical strains exceed the strain that is obligatory for bone structural integrity
(~0.4%) fracture of bone occurs.
Fluid flow drives electrolytes by pressure gradient through channels and porous
plugs, causing streaming potentials, which activate bone cells, in addition to
activation by wall shear stress. Substrate strain can be induced by mechanical load
on cells adherent to elastic platform. This occurs, either following single trigger,
such as static strain, or following application of controlled cyclic strain. Following
the generation of physiological or excessive mechanical strains the osteoblasts
secrete various growth factors (in particular PGE2), hormones, trauma or
inflammatory cytokines. Then PGE2 induces the cAMP dependent IGF-I
expression. IGF-I, in turn, promotes osteoblasts proliferation differentiation,
increases bone collagen synthesis and decreases collagen degradation.
In vitro studies showed that in osteoblasts IGF-I and IGF-II trigger osterix
(transcriptional factor) expression and promote cellular metabolism with
subsequential increase in bone matrix synthesis. The anabolic effect of PGE2 is
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