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64 Biomechanical Stimulation and its Clinical Prospects Haddad et al.
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Mesenchymal Cell Activation by Biomechanical Stimulation and its Clinical Prospects, 2016, 65-72 65
Nahum Rosenberg (Ed)
All rights reserved-© 2016 Bentham Science Publishers
CHAPTER 7
Cellular Molecular Pathways in Distraction
Osteogenesis
Yoav Leiser and Adi Rachmiel
*
Department of Oral and Maxillofacial Surgery, Rambam Health Care Campus, POB 9602, Haifa
31096, Israel
Abstract: The process of in vivo bone generation following mechanical stimulation of
cells by external distraction force is defined as “distraction osteogenesis”. The events in
bone formation and neovascularization in membranous craniofacial bones during the
distraction osteogenesis are presented in this chapter.
When distraction force is applied, cellular differentiation in pluripotent tissue, via
specific biochemical pathways, is activated with subsequential osteogenesis.
Multifactorial interrelations between osteoblasts and other bone cells occur at the bone
forming boundaries. There are several cytokines and growth factors that regulate bone
generation and resorption while distraction osteogenesis.
External distraction induces formation of a pool of progenitor cells that dedicated to
osteoblastogenesis and local vascularisation.
Recognition of the molecular cellular pathways of membranous distraction osteogenesis
is important for the further design of efficient clinical methods for therapeutic bone
regeneration.
Keywords: Bone regeneration, distraction osteogenesis, osteoblast.
INTRODUCTION
The membranous bone tissue of skull is an important model for investigation of
bone formation by distraction osteogenesis. In this anatomical site bone is
generated by distracting of bone callus, which is generated following osteotomy.
This process is often investigated in the mid-facial bone (Fig. 1).
The distraction osteogenesis acts according to the “tension-stress principle”
popularized by Ilizarov G. [1, 2]. This method of the in vivo bone regeneration is
*Corresponding author Adi Rachmiel: Department of Oral and Maxillofacial Surgery, Rambam Health
Care Campus, POB 9602, Haifa 31096, Israel; E-mail: a_rachmiel@rambam.health.gov.il
66 Biomechanical Stimulation and its Clinical Prospects Leiser and Rachmiel
based on a gradual application of external distraction force upon fracture callus
following osteotomy or corticotomy of bone. Preservation of the overlying soft
tissue at the site of the osteotomy is essential due to the importance of local blood
supply (Fig. 1).
Mechanical stimulation by distraction causes bone regeneration via secondary
cellular pathways in osteoblasts which maturate from the MSCs with parallel
essential local vascularization causing mineralization and remodelling [3, 4].
Extensive molecular interactions between the osteoblasts and osteoclasts in the
local osteogenic microenvironment occur during this process. Additionally
vascular endothelial cells, which are responsible for vascularization of the newly
generated bone tissue, are also play a part in bone regeneration process. These cell
types maturate from MSCs behave in “orchestrated” interrelations in the process
of osteogenesis.
Figure 1: Illustration of osteotomy line in a sheep mandible (thick arrow) and a distraction device.
The thin arrow demonstrates the direction of distraction. The molecular events are in the distracted
area after the osteotomy.
The molecular events occur in the distracted area after the osteotomy. There is
evidence that the growth factors and cytokines have a crucial role in the process
of bone matrix elaboration and resorption. The genetic expression of these
Cellular Molecular Pathways in Distraction Osteogenesis Biomechanical Stimulation and its Clinical Prospects 67
cytokines (including TGF-, bone morphogenetic protein, IGF1, FGF2) and ECM
components (osteonectin, osteopontin) while distraction osteogenesis was
investigated extensively. The mechanical distraction process creates a pool of
MSCs and initiates local capillary formation. The newly generated woven bone
starts to generate after five to ten days following the commencing of the
distraction (Fig. 2). The bone trabecula are formed and align along the vector of
the distraction force (Fig. 2). The vascularization of generated bone tissue is
interrelated and associated with osteogenesis during the distraction osteogenesis
[4].
Figure 2: Histological micrograph demonstrating bone generation by distraction. The new delicate
bone trabecula (T), which appear during the active distraction, are oriented in the direction of the
elongation from the original bone tissue (B).(calibration bar - 100μ)
The recognition and understanding of the bimolecular cellular pathways that are
involved in the process of membranous distraction osteogenesis should enable the
improvement and facilitation of the distraction osteogenesis method for bone
regeneration in clinical use.
Distraction Osteogenesis Pathways in Bone Cells
Following mechanical stimulation modulation of gene expression occurs in the
osteoblasts (see chapter 5). The mechanical stimulation of the newly generated
68 Biomechanical Stimulation and its Clinical Prospects Leiser and Rachmiel
bone by gradual controlled distraction induces the expression of early-response
genes of the AP -1 family of transcription factors [5]. Following the initial time
period of distraction (around two weeks), the young woven bone is generated by
the pre-osteoblasts and osteoblasts that retain c-Fos and c-Jun immunoreactivity.
In these cells an increased expression of c-Jun and c-Fos genes was observed and
thought to be related to the mechanical stimulation by the distraction forces [5].
Mineralized bone matrix is synthetized by osteoblasts. This process is essential
for skeletal growth, bone remodelling and for bone healing and repair. Several
humoral factors (hormones, cytokines and growth factors) physiologically
regulate the live bone tissue maintenance. This process also involves the
expression of proteins of the AP-1 complex [6-10]. The activation of genetic
expression of bone-associated proteins is associated with AP-1 activity. This
genetic expression is characteristic to the synthesis of several bone specific
molecules, such as collagen type I, alkaline phosphatase, osteocalcin, collagenase
3, parathyroid hormone (PTH) and PTH - related peptide receptor [11-13]. As it
has been mentioned above one of the proteins promoted by the AP-1, c-Fos, was
found to be involved in the mechanotransduction pathways in bone cells [14, 15].
The Role of Pro-Inflammatory Cytokines in the Distraction Osteogenesis
The expression of pro-inflammatory cytokines IL-1 and IL-6 is increased in
osteoblasts following commencement of external distraction of the fracture callus.
This high expression of IL-6 that follows the mechanical force application induces
intramembranous ossification via enhanced osteoblasts’ maturation with
subsequential enhanced osteogenesis [16].
During distraction osteogenesis TNF-α mRNA cellular content raises at the end of
the consolidation process [10]. Additionally the RANKL/OPG expression ratio
which is increased when the distraction phase starts, gradually decreases at the
consolidation phase [16, 17].
In the latency phase of the distraction osteogenesis the resorption of calcified
cartilage of the generated callus in the bone gap periphery is dependent primarily
on the RANKL and OPG cellular contents [18].
The Role of Bone Morphogenetic Proteins
The levels of BMP-2 and -4 in osteoblasts is increased during the distraction
osteogenesis process especially at the primary mineralizing front. This process is
Cellular Molecular Pathways in Distraction Osteogenesis Biomechanical Stimulation and its Clinical Prospects 69
clearly enhanced by the mechanical stimulation because after the distraction
cessation the expression of BMP-2 and BMP-4 can’t be detected [19-21].
The BMPs are involved in the cellular proliferation and in bone matrix
elaboration, which is essential for bone regeneration [21-23]. Since BMP-2 is
osteoinductive, its exogenous administration has been used successfully in the
clinical setup in order to reduce the lengths of distraction osteogenesis time period
due to the local acceleration of bone generation at the consolidation phase [23,
24]. The BMP-7 has similar to the BMP-2 and BMP-4 activities during distraction
osteogenesis [20]. Interestingly, in most reports only very low levels of BMP-7
were detected locally at the site of the distraction osteogenesis [19, 22, 25].
TGF β Role in Distraction Osteogenesis
Transforming Growth Factor (TGF-) expression was found to increase during
the distraction phase. TGF- was shown to have a diffuse expression in the
distraction area [26]. In the in vivo experiments on a canine model the
implementation of destruction force caused elevation in TGF- levels with
parallel decrease in the levels of osteocalcin [27]. These findings indicate that
TGF- suppress the osteoblast differentiation, presumably during the
mineralization stage of distraction osteogenesis.
Additional Growth Factors’ Role in Distraction Osteogenesis
Additional cytokines and growth factors, e.g. insulin-like growth factor 1 (IGF-1)
and basic fibroblast growth factor (bFGF), play roles in cellular pathways, which
are activated by a mechanical distraction. These phenomena are supported by the
findings of the expression of the bFGF in MSCs and more mature osteoblasts in
the generated trabecular bone [28]. Furthermore, the IGF-1 is also extensively
expressed in cells in the distraction area [26].
Angiogenic Factors in the Distraction Osteogenesis
Application of distraction force on regenerating bone causes elevation in blood
flow and induction of new bony formation [29, 30]. Local vascularization at the
distraction osteogenesis site was found to be induced by the VEGF-A and
neuropilin, an alternative receptor for VEGF. The expression of VEGF- A is
mainly observed in both, in the metabolically active osteoblasts and osteoclasts
[31]. The localization of VEGF-A to the primary mineralizing front of
regenerating bone indicates on the coordinated activities of neovascularization
and osteogenesis [32].
70 Biomechanical Stimulation and its Clinical Prospects Leiser and Rachmiel
Additional group of angiogenic factors, the angiopoietins, was found to be
expressed in cells while distraction process, i.e. initially the angiopoietin-1 is
expressed, then the angiopoietin-2 and finally the VEGF-A was observed in its
highest expression.
Angiopoietin-2 has antagonistic to angiopoietin-1 properties. But there are
indications that the combination of angiopoietin-2 and VEGF-A stimulates
angiogenesis, elevate the vascular plasticity and contributes to neovascularization
[32]. Furthermore the elevation in VEGF-A and angiopoietin-1 expression is
associated with an upregulation in the expression of hypoxia-induced factor 1 α
(HIF1α),which has a pivotal role in the regulation of the genetic expression of
transcription factors, such as VEGF-A and angiopoietin-1, which are associated
with angiogenesis [30, 32]. The optimal rate of mechanical distraction is
associated with effective angiogenesis. Several authors argue that this is a specific
drive for intramembranous bone formation [33, 34].
There is experimental evidence that the regulation of angiogenesis by distraction
is associated with increase of HIF1α [10]. The observed transient upregulation of
HIF1α in response to mechanical distraction indicates on subsequential activation
of additional genes’ expression. These genes express specific osteogenic and
angiogenic factors, such as VEGF-A, in the response to the effect of HIF1α.
Therefore both angiogenesis and osteogenesis in distraction osteogenesis are
dependent on the activity of VEGF receptors 1 and 2.
In conclusion, the distraction force induces osteogenesis by directing
undifferentiated MSCs toward osteogenic differentiation with parallel
vascularization of the generated bone tissue. The generated bone trabeculae can be
detected between the fifth and tenth days after the distraction commencement.
During the distraction process the osteoblasts become aligned according to the
vectors of the distraction force. The process of bone matrix elaboration by the
osteoblasts is parallel in time to the distraction force application. Furthermore the
new bone generation is dependent on the vascularization process which is also
induced by the bone distraction. Therefore interruption in the vascularization
process might lead to the undesirable cessation of the osteogenesis and
subsequentially to the clinical failure of the treatment by the distraction
osteogenesis.
The distraction osteogenesis process is regulated by the humoral inflammatory
factors, the TGF-β superfamily of morphogens (BMP's) and by the mediators of
angiogenesis. Understanding of the biomechanical mechanisms of membranous
Cellular Molecular Pathways in Distraction Osteogenesis Biomechanical Stimulation and its Clinical Prospects 71
distraction osteogenesis should facilitate the development of clinical methods that
utilize the distraction osteogenesis for induction of bone regeneration.
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, 73-75 73
Nahum Rosenberg (Ed)
All rights reserved-© 2016 Bentham Science Publishers
Subject Index
A
Actin crosslinker (AC) 7
Activated growth factors 51, 54
Active osteoblasts 69
Adherent cells 15
Adherent osteoblasts 18
Adhering cells 5
Adhesion domains 5, 6
Adhesion molecules 3, 4, 39
Adhesion process 5, 6
Adipogenesis 28, 29
Adjacent cells 43
Anabolic effect 52, 54
Angiogenesis 40, 70
Angiogenic factors 69, 70
Angiopoietin-1 70
Angiopoietin-2 70
AP-1 52, 68
Apoptosis 55, 61, 62
Autocrine 54
B
Basic fibroblast growth factor 54, 69
Biochemical signals 26, 39, 40
Blood vessels 9, 24, 37, 38, 39
Bone cells metabolism 51
Bone formation 49, 50, 65
Bone generation 65, 67, 69, 70
Bone matrix 8, 13, 17, 51
Bone matrix elaboration 8, 66, 69, 70
Bone morphogenetic proteins 67, 68
Bone multicellular unit (BMU) 49, 50
Bone regeneration 49, 65, 66, 67, 69, 71
Bone remodelling 50, 68
Bone resorbing cells 49
Bone resorption 49, 50
Bone surface 50, 51
Bone tissue 24, 67
C
Ca
2+
influx 43
Calcium ions 43
Calponin 30
Cartilage cells 60, 61
Catenin 40, 42
Cell adhesion 5, 26, 55
Cell adhesion molecules (CAMs) 4, 6, 39
Cell differentiation 23, 27, 28
Cell migration 3, 7, 8
Cells activation 19
Cells adherent 17, 52
Cells detachment 55
Cells origin parameters 21
Cellular adhesion 6, 8
Cellular contents 68
Cellular maturation 25, 28, 30, 31
Cellular mechanical stimulation 49
Cellular mechanosensing 6, 7
Cellular mechanotransduction 13, 35
Cellular membrane 5, 6, 15
Cellular microenvironment 25, 26
Cellular pathways 5, 25, 28, 29, 41, 49, 67, 69
Chondroblat 59
Chondrocytes gene expression 62
Chondrocytes phenotypic expression 62
Collagen 26, 35, 36, 38, 51
Collagen fibres 36, 37, 38
Connective tissue 9, 23, 24, 30, 35
Consolidation phase 68, 69
Controlled mechanical stimulation 13, 14
Core proteins 61
Cultured cells 17, 18, 19
Cultured cells adherent 13
Cultured osteoblasts 17, 19, 21
Cultured osteoblasts adherent 16
Cyclic strain 41, 42
Cytokines 26, 49, 51, 52, 65-68
Cytoskeletal components 7, 13, 14, 18
Cytoskeleton 3, 4, 5, 7, 8, 9, 14, 15, 26, 39, 41, 43
Cytoskeleton dynamics 3
D
Deformations modulate gene expression 30
Dermal fibroblasts 40, 41, 43
Dermis 36-39
Differentiation of MSCs 9, 30, 31
Dimensional cultures 14, 27, 28, 62
Diseased cells 24
Disordered square array 29
Distraction force 65, 67-70
Distraction force application 69, 70
Distraction osteogenesis 65, 67-71
Distraction osteogenesis process 68, 70
E
Elastic fibres 36, 38, 39
Elastic membranes 13, 16, 18
Elastic properties 26
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