The FASEB Journal • Review
Mechanotransduction in bone repair and regeneration
Chenyu Huang*,†,1 and Rei Ogawa*
*Department of Plastic, Reconstructive and Aesthetic Surgery, Nippon Medical School, Tokyo, Japan;
and †Department of Plastic Surgery, Meitan General Hospital, Beijing, China
ABSTRACT Mechanotransduction is the process by
which physical forces are converted into biochemical
signals that are then integrated into cellular responses.
It plays a crucial role in bone repair and regeneration
and thus has attracted a great deal of interest from
researchers in various fields. This report reviews the
current clinical evidence that shows the role mechano-
transduction plays in bone processes such as physical
adaptation, pathological fracture healing, and thera-
peutic distraction osteogenesis. We also outline the
progress that has been made in understanding bone
mechanotransduction from both the macro- and mi-
croperspectives. Specifically, we describe the theories
that postulate how mechanical force exhibits effects on
bone repair and regeneration (i.e., the tensegrity and
mechanosome theories). We also summarize the recent
advances in our understanding of the molecular signal-
ing pathways of mechanotransduction, which include
calcium ion channels, integrins, Wnt/␤-catenin, prosta-
glandin, and nitric oxide. A better understanding of
skeletal mechanotransduction will facilitate research
into this promising field and could lead to the develop-
ment of applications that improve bone structures and
functions.—Huang, C., Ogawa, R. Mechanotransduc-
tion in bone repair and regeneration. FASEB J. 24,
3625–3632 (2010). www.fasebj.org
Key Words: mechanical stimulation 䡠 mechanosensation 䡠 mech-
anotransductive pathways 䡠 skeletal adaptation 䡠 bone repara-
tion and reconstruction
Bones serve in our body as skeletal structures that
support the body’s weight, connect tendons and
muscles, provide mechanical protection, assist move-
ment, store minerals, and produce blood cells. Bone
repair and regeneration are undoubtedly influenced
by intimate interactions between the physiological,
biochemical, and mechanobiological environments.
In particular, the effect of mechanical force on bone
regeneration has been studied widely, and this has
led to an increasing awareness of the importance of
studying mechanotransduction.
Mechanotransduction is the process by which phys-
ical forces are converted into biochemical signals
that are then integrated into cellular responses (1).
Consequently, mechanotransduction in the bone in-
cludes 4 phases: mechanocoupling, biochemical cou-
pling, transmission of the signal from the sensor cell
to the effector cell, and the effector cell response (2).
0892-6638/10/0024-3625 © FASEB
Such complex mechanisms are responsible for main-
taining the dynamic balance between bone forma-
tion and bone absorption. A greater understanding
of these processes may lead to the development of
advanced clinical applications that can lead to pre-
dictable and reproducible improvements in bone
structure. Therefore, in this report the clinical evi-
dence of bone mechanotransduction and the basic
research into the mechanotransduction mechanisms
involved in bone repair and regeneration are re-
viewed. Moreover, future perspectives of bone mech-
anotransduction research are discussed.
CLINICAL EVIDENCE OF
MECHANOTRANSDUCTION IN BONE REPAIR
AND REGENERATION
How mechanical stimuli influence bone regeneration
has been explored by studying processes such as phys-
iological bone adaptation and clinical conditions such
as pathological bone fracture and distraction osteogen-
esis.
Physiological bone adaptation
To meet the functional demands of its mechanical
environment, the mass and geometry of bone is physi-
cally remodeled in a dynamic fashion (Wolff’s law).
Mechanostat theory is a refinement of Wolff’s law and
proposes that bone adapts so that it can function
mechanically as needed by detecting and responding to
mechanical loads (3). Thus, in this dynamic and life-
long biological control system, bone formation in terms
of shape, size, and density can be directed by high
mechanical loads. The other side of the coin is that
immobilization can lead to the loss of bone. For exam-
ple, 120 d of bed rest can induce bone loss by acceler-
ating bone resorption and retarding bone formation
(4). This is also true for spaceflight, where bone loss
can be induced because of increased bone resorption
and decreased calcium absorption (5).
It is also currently clear that the skeleton needs “time
1
Correspondence: Department of Plastic, Reconstructive
and Aesthetic Surgery, Nippon Medical School, 1-1-5 Sendagi
Bunkyo-ku, Tokyo 113-8603, Japan. E-mail: huangchenyu2000@
gmail.com
doi: 10.1096/fj.10-157370
3625
off” from mechanical loading. Mechanical loading pre-
sents a potent osteogenic stimulus, but bone cells
desensitize rapidly to mechanical stimulation. Resensi-
tization must occur before the cells can transduce
future mechanical signals effectively (6). Consequently,
it has been suggested that cyclical or intermittent
loading, which provides the skeleton with regular “time
off” periods, may be more effective than continuous
loading in inducing the bone formation needed to
promote the growth and repair of the skeleton (7).
Supporting this is that the osteogenic response to
simulated high-impact exercise over a long period can
be enhanced by dividing the exercise into brief sessions
of loading that are separated by recovery periods (8).
Factors such as age and gender also affect the mech-
anotransduction process in bone. Aging can inhibit
mechanotransduction, as shown by the fact that 19-mo-
old rats exhibit over 16-fold less mechanically induced
bone formation than 9-mo-old rats (9). There also
appears to be a “window of opportunity” during the
development of peak bone mass in which the bone is
especially responsive to weight-bearing physical activity
(10). Furthermore, during advancing age increased
remodeling rate and worsening of basic multicellular
unit (BMU) imbalance increase bone loss and struc-
tural damage, resulting in a predisposition to bone
fracture following mechanical stimulation such as min-
imal trauma (11). In fact, according to Seeman, 4 of the
age-related changes in bone modeling and remodeling
that compromise bone’s material properties and struc-
tural design are a reduction in bone formation at tissue
level, reduction in bone formation at cellular level
within each BMU, continued resorption in the BMU,
and increase in the rate of bone remodeling accompa-
nied by worsening of negative bone balance in each
BMU (12, 13). In addition, gender affects bone mech-
anotransduction because males rather than females
exhibit significantly reduced mechanoresponsiveness
compared with controls (14). Conversely, males suffer
larger bone mass reductions in both the cortical and
cancellous compartments than females when they are
subjected to hind limb unloading (15). In fact, the
position of the cortex in relationship to the long axis of
the long bone differs in males and females (16).
Estrogen reduces the osteogenic response induced by
exercise on the periosteal surface of the bone, whereas
it enhances bone formation on the endocortical surface
of 8-wk-old male Sprague-Dawley rats (17). Such age-
and gender-specific variations may be due to differ-
ences in the efficiency of mechanical sensors and sex
hormone production and/or signaling, respectively.
However, additional research is needed to clarify this.
Fracture healing and distraction osteogenesis
The clinical bone regeneration that occurs in fracture
healing and distraction osteogenesis is also evidence of
bone mechanotransduction. The healing of a bone
fracture is a unique process whose result is not scarring
but regeneration (18), while distraction osteogenesis is
3626 Vol. 24 October 2010 The FASEB Journal 䡠 www.fasebj.org
a special form of bone healing in which gradual trac-
tion on the bone leads to osteogenesis and the tandem
lengthening of the skin, muscles, and nerves (19, 20).
It is well known that bone cells consist mainly of
osteoblasts (active osteoblasts and inactive bone-lining
cells), osteoclasts, and osteocytes. Clinical osteogenesis
in fracture healing and distraction osteogenesis aims to
facilitate bone formation by osteoblast and bone re-
modeling together with osteoclast. From the perspec-
tive of mechanotransduction, bone tissue is described
as an extensively connected cellular network where the
osteocytes serve as sensory cells and the osteoblasts and
osteoclasts are the effector cells (21). Loads applied to
a whole bone are related to the flow past the osteocytic
processes in their canaliculi (22). The osteocytes can
sense the flow of fluid and then produce signaling
molecules that regulate osteoclast-mediated bone re-
sorption and osteoblast-mediated bone formation. This
results in adequate bone remodeling (23). That this
process occurs has been supported by the finding that
the targeted ablation of osteocytes in mice results in
defective mechanotransduction and fragile bone with
osteoblastic dysfunction (24).
The mechanical modulation of bone fracture healing
varies depending on the type of fracture, the therapeu-
tic fixation, and the loading that follows. A series of
hypotheses have been proposed to explain mechanical
influence on tissue differentiation in fracture: in these
hypotheses, hydrostatic pressure and tensile strain (25,
26), or shear strain and fluid flow, have been identified
as the key stimulating mechanical forces (27, 28).
However, to date, far less is understood about the signal
mechanotransductive pathways that lead to fracture
repair (29). One study has shown that receptor activa-
tor of nuclear factor ␬B (RANK) signaling is not
required for the early phase of fracture healing, as
evidenced by the repair (callus formation) observed in
RANK⫺/⫺ mice with bone fractures; this is supported
by the fact that administration of RANK signaling
inhibitors sufficient to reduce bone resorption is not
detrimental to fracture healing (30). Another study has
shown that proinflammatory cytokines such as TNF-␣
and IL-1, which are known to regulate immune func-
tion and inflammation, participate in fracture healing
because they are expressed at both the very early and
late phases of the repair process. It then suggests that
these cytokines are important in the initiation of the
repair process and play important functional roles in
intramembraneous bone formation and remodeling
(31).
Distraction osteogenesis is specifically character-
ized by osseous regeneration that occurs primarily
via intramembranous ossification, which is stimu-
lated by several mechanotransductive pathways. In
the integrin-mediated, extracellular signal-related ki-
nase (ERK 1/2) -dependent mechanotransduction
pathway, ERK 1/2 is a potential central mediator that
acts as a signaling convergence point and regulates
the osteogenic differentiation of mesenchymal stem
cells during distraction (32, 33). In addition, in-
HUANG AND OGAWA
creased expression of osteogenic proteins, including
BMP 2/4, can be induced via the c-Src-dependent
mechanotransduction pathway (34). Mechanical
forces can also stimulate the expression of the early-
response genes of the activator protein-1 (AP-1)
family of transcription factors (35), up-regulate the
expression of Runx2, and initiate the differentiation
of periosteal cells into osteogenic cells (36), thus
promoting osseous regeneration.
These observations show the central role mechano-
transduction plays in bone regeneration, physical me-
chanical loading, pathological bone fracture, and the
surgical intervention of distraction osteogenesis. Stud-
ies that elucidate the fundamental signaling processes
that are involved are needed.
BASIC RESEARCH INTO THE
MECHANOTRANSDUCTION MECHANISMS
INVOLVED IN BONE REPAIR AND
REGENERATION
Mechanotransduction, particularly in bone, has been a
focus of interest in fields ranging from molecular
biophysics to clinical medicine. Research into mech-
anotransduction has been approached from 2 direc-
tions. Some researchers have sought to understand it
from the macro/system perspective, where it is seen as
a control system that requires feedback and stability.
Others have viewed it from a micro/molecular perspec-
tive and have sought to understand how it works by
characterizing the specialized molecular signaling path-
ways that are involved.
Tensegrity theory
Drawing on control theory and architecture, tenseg-
rity theory proposes a mechanism that explains how
mechanical stresses applied at the macroscopic level
can influence the molecular structure and function
of living cells (37). In this theory, the whole cell, not
just the single specialized mechanotransduction mol-
ecules in isolation, is believed to serve as a mechano-
transducer as it integrates the local signals with other
environmental inputs before eliciting a specific be-
havioral response (38).
The key determinants in tensegrity are architecture
(the 3-dimensional arrangement of the elements) and
the level of prestress (isometric tension) in the cytoskel-
eton (37). Thus, on the one hand, an even distribution
of load protects individual cells from damage, while on
the other hand, a small mechanical stimulus is allowed
to have an effect on a large number of cells (39, 40).
Integrins and focal adhesions are recognized as
being the ubiquitous mediators of mechanosensation.
Integrins are a family of ubiquitous, heterodimeric
glycoproteins that mediate cell attachment to the ex-
tracellular matrix. They act as mechanoreceptors of the
cell by spanning the cell membrane and being con-
nected at one end to the cytoskeleton and at the other
MECHANOTRANSDUCTION IN BONE REPAIR AND REGENERATION
end to the extracellular matrix (ECM) (38). Focal
adhesions are multimolecular complexes that connect
the ECM to the actin cytoskeleton and link integrins to
the ends of contractile microfilament bundles. They
are thought of as mechanosensory organelles (41, 42),
where mechanochemical signal conversion is carried
out in the cell.
The forces that are channeled as described above
over the ECM and to the integrins are converted into
biochemical changes by producing changes in defor-
mation of other load-bearing mechantransducer mole-
cules, such as stress-sensitive ion channels, protein
kinases, G proteins, and other signaling molecules,
inside the cell (42).
Mechanosomes theory
Mechanosomes theory is an appealing hypothesis that
was proposed by Pavalko (43). The key aspect of this
model is the load-induced formation of mechano-
somes, which are multiprotein complexes comprised of
focal adhesion-associated or adherens junction-associ-
ated proteins. In terms of cellular structure, the load-
induced deformation of bone is converted into the
deformation of the sensor cell membrane, which drives
conformational changes in membrane proteins. Some
of these membrane proteins are linked to a solid-state
signaling scaffold that releases protein complexes
called mechanosomes that are capable of carrying
mechanical information into the nucleus. In this way,
“bending bone ultimately bends genes” (43). In terms
of signal conversion, the solid-state and diffusion-con-
trolled signaling pathways integrate with the tissue
matrix-mediated transfer of mechanical energy to pro-
teins of the adhesion complexes and selected proteins
associated with the cyto- and nucleoskeleton. This
conversion of mechanical energy into chemical energy
drives changes in protein conformation, phosphoryla-
tion, and alterations in DNA geometry and mediates
the formation and/or mobilization of nascent signaling
complexes to the bone cell cytoplasm (43).
Role of osteocyte in mechanosignal transduction
Osteocytes orchestrate different cell populations in
bone in response to mechanical loading (44). They can
be activated by strain amplification through canaliculi.
The electrically coupled 3-dimensional network of os-
teocytes and lining cells is a communications system for
the control of bone homeostasis and for structural
strain adaptation, and the effector cells are osteoblasts
and osteoclasts (45).
Osteocytes are the most abundant cells in bone cells
and are spaced throughout the mineralized matrix.
They appear to be the most mechanosensitive cells in
bone and are involved in the transduction of mechan-
ical stress into a biological response. Osteocytes, but not
osteoblasts, react to a 1-h pulsating fluid flow, resulting
in the sustained release of prostaglandin E2. By con-
trast, intermittent hydrostatic compression stimulates
3627
prostaglandin production after 6 and 24 h in osteocytes
and after 6 h in osteoblasts (46). Osteocytes are more
responsive to pulsating fluid flow than osteoblasts with
respect to the production of soluble factors of nitric
oxide, which affect both osteoblast proliferation and
differentiation (44), as well as osteoclast formation and
bone resorption (47). Pulsating fluid flow for 15 min
stimulates by 3-fold prostaglandin G/H synthase-2
(PGHS-2, COX-2) mRNA expression in osteocytes but
does not have the same effect in osteoblasts (48).
Besides, targeted ablation of osteocytes in mice induces
osteoporosis with defective mechanotransduction (24).
In fact, the main source of signaling induced by oscil-
latory fluid flow in osteoblasts occurs through the focal
adhesion complex and the focal adhesion kinase (49).
Formation of focal adhesions on fibronectin promotes
fluid shear stress induction of cyclooxygenase (COX)-2
and PGE2 release in osteoblasts (50). The linkage of
actin stress fibers to integrins in focal adhesions via
␣-actinin is a critical link in osteoblasts, because block-
ing this linkage prevents fluid shear-induced COX-2
and c-Fos expression (51). Excitation of osteocytes may
also be related to interaction of pericellular matrix and
cell process cytoskeleton (52).
Compared to the bone lining cells that cover the
bone surface, osteocytes located within the bone matrix
would be more efficient sensors. With osteocytes as
sensors, remodeling would be more sensitive to exter-
nal loads; such remodeling would lead to adaptation of
the architecture rather than that of strut thickness, and
the remodeling process drifts more easily and effec-
tively toward a significantly different morphology. As
for changes in load magnitudes only, surface bone
lining cells should be equally capable of regulating
adaptation as osteocytes. However, adding surface cells
to the osteocyte model makes no difference to the
output of the model (53).
Molecular skeletal mechanotransducers
Bone, as a mechanosensitive organ, reacts to mechani-
cal stimuli through a series of molecules and crosstalk
between them. Research into mechanotransduction
has shown that gaps between physical forces and bio-
chemical signals are bridged by intracellular ion chan-
nels such as K⫹ (54) and Ca2⫹ (55) channels, intracel-
lular signaling, such as that of Wingless-type/␤-catenin
and inositol 1,4,5-triphosphate, mechanically induced
signaling molecules such as that of prostaglandin and
nitric oxide (56), transmembrane molecules such as
integrin (57), growth factors such as insulin-like growth
factor and bone morphogenetic protein, and systemic
hormones such as parathyroid and estrogen.
Calcium ion signaling
Several studies have revealed that calcium ion signaling
plays an important role in osseous mechanobiology. In
vitro studies have shown that the intracellular calcium
in osteoblastic cells can be increased within minutes in
3628 Vol. 24 October 2010 The FASEB Journal 䡠 www.fasebj.org
response to fluid flow and that this can be suppressed
by gadolinium, a stretch-activated channel blocker
(58). In vivo studies have shown that mechanically
induced bone formation in rats is substantially sup-
pressed by verapamil and nifedipine, 2 blockers of
L-type calcium channels (59). Furthermore, inositol
1,4,5-triphosphate (IP3) can mediate intracellular Ca2⫹
release, which is required for modulating flow-induced
responses (60).
Integrin signaling
Integrins, as mentioned above, are transmembrane
molecules connected at one end to the ECM and at the
other end to the intracellular cytoskeleton. They also
play an important role in osseous mechanobiology.
When focal adhesion kinase, an intracellular compo-
nent of the integrin signaling pathway, was condition-
ally inactivated, the mechanically induced osteogenic
response was abolished (61). Moreover, an integrin-
mediated, extracellular signal-related kinase ERK 1/2-
dependent mechanotransduction pathway was found to
play a significant role in distraction osteogenesis (33).
Prostaglandin (PG) and nitric oxide (NO) signaling
PG is an important biochemical mediator of mechani-
cal loading in bone. Fluid flow shear stress can promote
the release of intracellular PGE2 from osteocytes (62).
It induces the translocation of Cx43 to the membrane
surface, and the unapposed hemichannels formed by
Cx43 serve as a novel portal for the release of PGE2 in
response to mechanical strain (63). Moreover, the
bone formation that follows brief bouts of mechanical
loading involves the release of PG from cells at the time
mechanical loading is applied, rather than new PG
synthesis associated with mechanically induced COX-2
expression (64). Since PGs are synthesized through the
conversion of arachidonic acid by the rate-limiting
COX enzymes, the role of COX in PG signaling re-
mains unclear. One study has shown that a functional
COX-2 gene is not required for skeletal mechanotrans-
duction because mice with a null mutation in the
COX-2 gene respond to loading by inducing skeletal
COX-1 expression (65). In contrast, another study has
shown by administering the COX-2 inhibitors NSAIDs
or NS-398 that COX-2 does play an important role in
the bone formation elicited by mechanical strain (66).
NO signaling is also involved, as shown by the fact that
application of mechanical strain onto bone stromal cells
regulates NO synthase in synergy with RANK ligand to
promote positive bone remodeling; this process involves
mitogen-activated protein kinase (67). Moreover,
mechanically induced bone formation can be sup-
pressed by L-NAME, a NO synthesis inhibitor (68).
Wingless-type (Wnt)/␤-catenin signaling
Wnt signaling through LDL receptor-related protein-5
(LRP5) receptor plays an important and complex role
HUANG AND OGAWA
in skeletal mechanotransduction. One study has shown
that Wnt/␤-catenin signaling is stimulated in calvarial
cells in vitro after they have been subjected to mechan-
ical loading such as stretching (69). Wnt signaling was
also observed in vivo in mice after mechanical loading
of the tibia; indeed, Wnt signaling enhanced the sensi-
tivity of osteoblasts to mechanical loading (70). In
Lrp5⫺/⫺ mice, the osteogenic responses to mechanical
loading of the ulna are dramatically impaired (88 and
99% reductions were observed in males and females,
respectively) (71). Notably, however, the inhibition of
Wnt signaling can also stimulate osteoblast differentia-
tion and mineral formation. One study has shown that
to enable the formation of a mineralized bone matrix,
Wnt signaling in maturing osteoblasts needs to be
down-regulated (72). Another study revealed Wnt sig-
naling inhibits the osteogenic differentiation of human
mesenchymal stem cells (73). Moreover, in human
osteoblastic cells subjected to 15 min of stretching,
although there is an initial early increase in ␤-catenin
levels, Wnt signaling is ultimately down-regulated. This
biphasic Wnt signaling level is likely to play an impor-
tant role in end-stage osteoblasts in that the reduced
Wnt signaling may induce terminal differentiation and
matrix mineralization (74).
Other signaling pathways, such as those that em-
ploy ATP (75), insulin-like growth factor, bone mor-
phogenetic protein (76), and receptors of hormones
such as parathyroid hormone (77) or estrogen (78),
are also of increasing interest in skeletal mechano-
transduction research.
The observations above show that, regardless of
whether mechanotransduction in bone regeneration
is approached from the macro- or microperspective,
this biological process is highly diverse and complex
and involves multiple overlapping and coordinated
molecular signaling pathways. Further research elu-
cidating this process is greatly warranted.
FUTURE PERSPECTIVES OF BONE
MECHANOTRANSDUCTION RESEARCH
Mechanical loading activates mechanotransducers
that in turn stimulate bone formation, thereby main-
taining the dynamic skeletal balance between osteo-
genesis and bone absorption. This process is regu-
lated by local cytokines and growth factors and
systemic hormones. Further, mechanical forces are
even believed to be potent regulators of cell and
tissue development as soluble hormones and insolu-
ble ECM proteins (42). Should this be the case, there
are many different avenues future studies in skeletal
mechanotransduction can take.
Most current studies have focused on how mechan-
ical stimuli from the environment can lead to molec-
ular effects in bone cells. In other words, they have
studied the “on switch.” In contrast, there is compar-
atively little research into bone cell desensitization
(“off switch”) and the possibility that increased me-
MECHANOTRANSDUCTION IN BONE REPAIR AND REGENERATION
chanical strain might lead to cellular toxicity. At
present, the desensitization process is believed to
involve multiple mechanisms in bone cells, most
notably G-protein coupled receptor desensitization
(79). Moreover, increasing strain to increase cellular
toxicity is found in mouse osteoblast, which may
result in decreases in cell number (80). Thus, re-
search that identifies desensitization pathways and
consequently uses specific inhibitors to remove an
“off switch” would be of great interest. It aims to
improve osteogenesis by keeping the switch on,
meanwhile avoiding potential cellular toxicity by
subsequently increased mechanical stimulation.
Mechanical stimuli simultaneously affect other tis-
sues through mechanotransduction, and this could
be manipulated to improve bone regeneration. In-
deed, it is feasible to use mechanical stimuli to
promote bone regeneration, although this will occur
only if there is a timely nutrient supply and waste
cleaning. This suggests that angiogenesis is needed to
facilitate the bone regeneration induced by mechan-
ical stimuli. Notably, a study of the chorioallantoic
membrane revealed mechanical strain could elicit
angiogenic features (81). Moreover, osteoblasts re-
sponded in vitro to mechanical strain by increasing
matrix production and regulating angiogenesis (82).
Current research hypothesized that induction of
matrix metalloproteinases after mechanical strain
enhances attraction and penetration of blood vessels
through which osteoblasts could reach the chondro-
osseous junction and promote ossification (83). Fu-
ture research examining whether mechanical stimu-
lus-induced bone regeneration can be improved by
simultaneously activating mechanotransduction
pathways that promote angiogenesis would be of
considerable clinical interest.
Much remains to be elucidated in mechanotransduc-
tive signaling. Some questions of interest are the follow-
ing: 1) Since various signaling cascades can be simulta-
neously up- and down-regulated by mechanical stimuli,
what are correlations and relationship between different
pathways? 2) How do different cell types participate in
skeletal mechanotransduction? 3) How do different types
of mechanical stimuli such as hydrostatic pressure and
microgravity affect bone regeneration? 4) Genetics prob-
ably plays a major role in determining the degree of
skeletal adaptability to the same mechanical stimulus
(84), but which set of genes is responsible for this differ-
ence in mechanosensitivity? A deeper understanding of
the skeletal mechanotransductive mechanisms will greatly
facilitate the development of innovative interventions,
either pharmaceutical or clinical, that mimic or hamper
responses to loading and thereby improve bone structures
and functions.
CONCLUSIONS
Mechanotransduction in bone regeneration is at-
tracting increasing interest from a variety of fields.
3629
Clinical evidence has shown that it plays a fundamen-
tal role in dynamically modulating and maintaining
the balance between osteogenesis and bone resorp-
tion, thereby leading to physical adaptation, patho-
logical fracture healing, and therapeutic distraction
osteogenesis. Meanwhile, current research has provided
both macro- and microperspectives in understanding the
mechanotransduction signaling pathways that are in-
volved in bone repair and regeneration. According to
tensegrity theory, the whole cells, rather than single
specialized mechanotransducer molecules, are seen as
the mechanotransducers. The mechanosome theory
and other signaling pathways such as calcium ion
channels, integrins, and autocrine and paracrine
messengers such as prostaglandin and nitric oxide
provide a microview of the mechanotransductive
signaling in which molecules play overlapping and
coordinated roles. The study of bone mechanotrans-
duction is a highly promising field, and it is likely that
a greater understanding of the fundamental molec-
ular signal pathways that are involved and collabora-
tion with other fields of research such as investiga-
tion of angiogenesis may facilitate the development
of pharmaceutical and clinical applications that can
improve bone structures and functions.
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Received for publication February 21, 2010.
Accepted for publication May 20, 2010.
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