Mechano Biology

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REVIEW ARTICLE^ ^

Mechanobiology and diseases of

mechanotransductionDonald E Ingber

The current focus of medicine on molecular genetics ignoresThe current focus of medicine on molecular genetics ignores

Introduction

the physical basis of disease even though many of thethe physical basis of disease even though many of the The molecular biology revolution has led to advances

problems that lead to pain and morbidity, and bring patientsproblems that lead to pain and morbidity, and bring patients in knowledge and new technologies that are revolu-to the doctor'

s ofce, result from changes in tissue structureto the doctor's ofce, result from changes in tissue structure tionizing the way in which clinical medicine is

or mechanics. The main goal of this article is therefore toor mechanics. The main goal of this article is therefore to practiced. Completion of the Human Genome Pro-help integrate mechanics into our understanding of

the

help integrate mechanics into our understanding of the ject,massively parallel gene and protein prolingmolecular basis of disease. This article rst reviews the

keymolecular basis of disease. This article rst reviews the key techniques,and powerful bioinformatics tools are justroles that physical forces, extracellular matrix and cellr

oles that physical forces, extracellular matrix and cell a few examples. Yet there is a huge disconnectstructure play in the control of normal development, as w

ellstructure play in the control of normal development, as well between these genome-age' technologies and theas in the maintenance of tissue form and function. Rece

ntas in the maintenance of tissue form and function. Recent reality of how diseases manifest themselves. Frominsights into cellular mechanotransduction the mo

lecularinsights into cellular mechanotransduction the molecular the time the rst human looked,listened and felt formechanism by which cells sense and respond to mechani

calmechanism by which cells sense and respond to mechanical what is wrong with a sick friend,caregivers havestress also are described. Re-evaluation of hum

anstress also are described. Re-evaluation of human recognized the undeniable physical basis of disease.pathophysiology in this context reveals that a wide ra

ngepathophysiology in this context reveals that a wide range The thrill in the chest of a patient with aortic valveof diseases included within virtually all elds of medic

ineof diseases included within virtually all elds of medicine disease,bounding pulse in the hypertensive andand surgery share a common feature:their etiolog

y orand surgery share a common feature:their etiology or wheeze of the patient with emphysema all igniteclinical presentation results from abnormal mechano

trans-clinical presentation results from abnormal mechanotrans- reexive clinical responses in the mind of the skilledduction. This process may b

e altered by changes in cell

duction. This process may be altered by changes in cell physician,and sometimes even lead to immediatemechanics, variations in extracellular matrix structure,

or bymechanics, variations in extracellular matrix structure, or by diagnoses.deregulation of the molecular mechanisms by which cell

sderegulation of the molecular mechanisms by which cells But in the current genome euphoria,there appearssense mechanical signals and convert them into a c

hemicalsense mechanical signals and convert them into a chemical to be no place for `physicality'. This is especiallyor electrical response. Molecules that mediate mechano

-or electrical response. Molecules that mediate mechano- worrisome given that abnormal cell and tissuetransduction, including extracellular matrix molecules,transduction, including extracellular matrix molecules, responses to mechanical stress contribute to thetransmembrane integrin receptors, cytoskeletal struct

urestransmembrane integrin receptors, cytoskeletal structures etiology and clinical presentation of many importantand associated signal transduction components, may t

here-and associated signal transduction components, may there- diseases,including asthma,osteoporosis,athero-fore represent targets for therapeutic intervention in afore represent targets for therapeutic intervention in a sclerosis,diabetes,stroke and heart failure. There isvariety of diseases. Insights into the mechanical basi

s ofvariety of diseases. Insights into the mechanical basis of also a strong mechanical basis for many generalizedtissue regulation also may lead to development of imp

rovedtissue regulation also may lead to development of improved medical disabilities,such as lower back pain andmedical devices, engineered tissues, and biological

ly-medical devices, engineered tissues, and biologically- irritable bowel syndrome,which are responsible for ainspired materials for tissue repair and reconstruction.inspire

d materials for tissue repair and reconstruction. major share of healthcare costs world-wide. In fact,Keywords: c y tos k el eto n; di s eas e; extra c ell u la r matr ix; i n tegri n ; mec ha ni c al surgeons sometimes even use mechanical forces asforc e s; mec h an otra ns du c ti on; s tre ss - ac ti v ated i on c h an nel s ; t is s ue e ngi n eeri ng therapeutics,such as when traction forces are used to

accelerate bone healing. However,what is missing isAnn Med 2003; 35: 114how these physical interventions could inuence cell

and tissue function,or how altered cell or tissue

mechanics may contribute to disease development.From the Vascular Biology Program,Departments of Surgeryand Pathology,Children's Hospital and Harvard Medical School, In this article,I rst review the fundamental roleBoston,MA 02115,USA. that physical forces and changes in tissue mechanics

Correspondence: Donald E Ingber,MD,PhD,Children'splay in normal development and physiology. I then

Hospital,Enders 1007,300 Longwood Avenue,Boston,MAdescribe recent advances in our understanding of02115,USA. Fax: 617-232-7914. E-mail: [email protected] mechanotransduction,the molecular mech-harvard.edu

# 2003 Taylor & Francis. ISSN 0785-3890DOI 10.1080/07853890310016333 Annals of Medicine 35

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Key messagesAbbreviations and acronyms

Mechanical forces are critical regulators of.ECM extracellular matrix

cellular biochemistry and gene expression asICAM intercellualr adhesion moleculewell as tissue development.PDGF platelet-derived growth factor

RGD argine-glycine-aspartate Mechanotransduction the process by which.3D three-dimensional

cells sense and respond to mechanical signals

is mediated by extracellular matrix, transmem-

brane integrin receptors, cytoskeletal structuresanism by which cells sense and respond to mechanical and associated signaling molecules.signals. Finally,I explain how the clinical manifesta-

Many ostensibly unrelated diseases share the.tions of many ostensibly unrelated diseases similarly

common feature that their etiology or clinicalresult from abnormal mechanotransduction,and how

presentation results from abnormal mechano-this insight may lead to new avenues for therapeutic

transduction. Mechanotransduction may beintervention.altered through changes in cell mechanics,

extracellular matrix structure or by deregulation

of the molecular mechanisms by which cellsMechanobiology sense mechanical signals or convert them into a

chemical response.In biology and medicine,we tend to focus on the

Molecules that mediate mechanotransduction.importance of genes and chemical factors for controlmay represent future targets for therapeutic

of tissue physiology and the development of disease,intervention in a variety of diseases. Insights

whereas we commonly ignore physical factors. This isinto the mechanical basis of tissue regulationinteresting because it was common knowledge at thealso may lead to development of improvedturn of the last century that mechanical forces aremedical devices, engineered tissues, and biomi-critical regulators in biology (1). Wolff's law describ-metic materials for tissue repair and reconstruc-ing that bone remodels along lines of stress was

published in 1892 (2). However,the advent of more tion.

reductionist approaches in the basic sciences,and the

demonstration of their power to advance under-

standing of the molecular basis of disease,led to a

loss of interest in mechanics. example,are composed of several organs (e.g.,bone,

Although it has received much less attention than muscle) that are constructed by combining variousthe genomics revolution,there has been a renaissance tissues (e.g.,bone,muscle,connective tissue,vascular

in the eld of mechanobiology over the past two endothelium,nerve). These tissues,in turn,are

decades. Physiologists and clinicians now recognize composed of groups of living cells held together by

the importance of mechanical forces for the develop- an extracellular matrix (ECM) comprised of a net-work of collagens,glycoproteins,and proteoglycans.ment and function of the heart and lung,the growthEach cell contains a surface membrane,intracellularof skin and muscle,the maintenance of cartilage and

bone,and the etiology of many debilitating diseases. organelles,a nucleus,and a lamentous cytoskeleton

Exploration of basic mechanisms of sensation and that connects all these elements and is permeated by a

autonomic control,including hearing,balance,touch, viscous cytosol. Each of these subcellular components

and peristalsis,also has demanded explanation in is,in turn,composed of clusters of different mol-

mechanical terms. At the same time,biologists have ecules. In other words,our bodies are complex

come to recognize that mechanical forces serve as hierarchical structures,and hence mechanical defor-important regulators at the cell and molecular levels, mation of whole tissues results in coordinated

and that they are equally potent as chemical cues. For structural rearrangements on many different size

example,cell-generated tensional forces have been scales.

shown to regulate diverse functions,ranging from To understand how individual cells experience

chromosome movements and cell proliferation to mechanical forces,we therefore must rst identify

tissue morphogenesis,in addition to cell contractility the path by which these stresses are transmitted

and motility (35). through tissues and across the cell surface. As in any

To explain mechanoregulation,we must take into three-dimensional (3D) structure,mechanical loads

account that living organisms,such as man,are will be transmitted across structural elements that are

constructed from tiers of systems within systems physically interconnected. Thus,forces that are

within systems (4,6,7). Our arms and legs, for applied to the entire organism (e.g.,due to gravity

# 2003 Taylor & Francis. ISSN 0785-3890 Annals of Medicine 35





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D 3ISEASES OF MECHANOTRANSDUCTION

or movement) or to individual tissues would be integrins that link to the internal cytoskeleton provide

distributed to individual cells via their adhesions to a much greater degree of mechanical coupling across

the ECM support scaffolds (basement membranes, the cell surface as measured by an increased strength-

interstitial matrix,cartilage,bone) that link cells and ening (stiffening) response when compared with

tissues throughout the body. This can be seen in transmembrane growth factor receptors,histocom-

specialized mechanosensory organs that recognize patibility antigens,or metabolic receptors.

and respond to physical stimuli. In the vestibular Thus,integrins appear to function as cell surface

apparatus,for example,the otoliths (dense calcareous `mechanoreceptors' in that they are among the rst

crystals) mediate sensation of linear acceleration due molecules to sense a mechanical stress applied at theto gravity by deforming a specialized bilaminar ECM. cell surface,and they transmit this signal across the

Local distortion of this ECM activates sensory plasma membrane and to the cytoskeleton over a

neurons within adjacent hair cells by transferring specic molecular pathway. Cell-cell adhesion mol-

mechanical forces across the cell surface and thereby ecules,such as cadherins and selectins,may provide a

inducing bending of cytoskeletal stereocilia that similar mechanical coupling function between the

extend from the cell surface (8). ECM similarly cytoskeletons of neighboring cells (1821). Interest-

mediates mechanical energy transfer to sensory cells ingly,even forces that produce generalized celldistortion,such as apical uid shear stresses inwithin muscle stretch receptors (9).

The mechanical properties of the ECM also endothelium,eventually distribute the stress through

contribute signicantly to the cellular mechanotrans- the cytoskeleton and to integrins within the cell's

duction response. For instance,the high exibility of basal focal adhesions,and to cell-cell adhesion mol-

the ECM of Pacinian corpuscle mechanoreceptor cells ecules at the lateral cell borders (22,23).

in skin ensures that rapid deformations will be sensed,

whereas sustained stresses will dissipate before they

reach the cell (10). This mechanism is used to lter out Force-induced changes in cell structure andsustained signals due to continuous pressure or touch mechanics(e.g.,when we sit and write on the computer for

extend periods of time) a common form of To understand the physiological mechanism by which

receptor adaptation. If the ECM is less exible,then cells respond to mechanical stress,we must rst

stresses will be transmitted to and through the cell, consider how forces impact the cell once they are

only to be dissipated through movements in the transmitted across transmembrane adhesion recep-

cytoskeleton,as observed in stereocilia in hair cells. tors. When most of the readers of this article went to

ECM plays a similar role in mechanoregulation in medical school,they learned that cells are composed

all solid tissues. These molecular scaffolds distribute of a viscous cytosol surrounded by a membrane,with

stresses throughout tissues and focus these forces on a nucleus in its center. With this view of cellsites of cell-ECM adhesion. Cells adhere to ECM architecture,it is difcult to understand how mech-

through binding of specic cell surface receptors. The anical forces could modulate intracellular structure or

most ubiquitous and well characterized class of ECM biochemistry. Over the past quarter century,how-

receptors are known as integrins'. Over 20 different ever,our view of cell structure has changed comple-types of these dimeric protein receptors exist; their tely. We now recognize that living cells contain abinding specicity (e.g.,for collagen versus bronec- cytoskeleton. This is an internal molecular frame-tin) depends on the specic pairing combination of work or lattice composed of three different types of

interacting a and b subunits (11,12). The external molecular laments (microlaments,microtubules

portion of these transmembrane receptors binds to and intermediate laments) that provides shape

specic peptide sequences (e.g.,RGD) in ECM mol- stability to the cell (24). However,the cytoskeleton

ecules,while their intracellular domains physically is not simply a passive gel. All cells generate tensional

associate with actin-associated proteins and thereby, forces through actomyosin lament sliding in theirform a molecular bridge between the ECM and the cytoskeleton. These tensional forces are resisted and

cytoskeleton. Integrins are not evenly distributed in balanced by external adhesions to ECM and neigh-

the membrane,rather they cluster together within boring cells,and by other molecular laments (e.g.,

specialized anchoring complexes known as focal microtubules) that locally resist inward-directed

adhesions' (13). tensional forces inside the cytoskeleton.

Importantly,integrins provide a preferred site for This type of force balance is a hallmark of an

mechanical signal transfer across the cell surface, architectural system known as tensegrity',and

when compared with other types of transmembrane computational models based on tensegrity theory

receptors. This has been demonstrated directly by can predict complex mechanical behaviors of mam-

applying mechanical forces to surface membrane malian cells (7,2426). Thus, the cell does not

receptors of cultured cells (1417). Cell surface respond to mechanical stress like a balloon lled






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with molasses or jello'. Instead,the viscoelastic Starling curve exhibited by the whole heart. Cell

behavior of living cells results from collective mech- shape-dependent changes in the sensitivity of the

anical interactions within the tensed molecular contractile machinery may ensure compliance match-

cytoskeleton. Cytoskeletal forces are also harnessed ing' in muscle cells of the gastrointestinal tract,

to transport organelles (e.g.,mitochondria,synaptic genitourinary system,pulmonary airways,blood

vesicles) in the cytoplasm,to move chromosomes vessels and heart,as well as in epithelial and

during mitosis,and as long recognized in muscle,to connective tissues,so that the level of tension exerted

generate tensional forces that are important for cell by the cell precisely balances the mechanical stress

contractility as well as movement. The effects of transmitted through the surrounding ECM inapplied stresses on cell shape and mechanics will response to tissue distortion.

therefore depend on the material properties of the In summary,these studies have revealed that the

cytoskeletal laments,their organization (architec- physicality of the ECM substrate and degree of cell

ture),and the level of isometric tension or prestress' distortion govern cell behavior regardless of the

in the cell,much like the mechanical responsiveness of presence of hormones,cytokines or other soluble

whole muscle is governed by its structural organiza- regulatory factors. Local alterations in ECM structure

tion and by its contractile tone. Because individual that inuence cell shape and mechanics,such asthinning of basement membrane produced bycells (both muscle and non-muscle) apply tractional

forces on their adhesions,cultured cells spread and increased ECM turnover (e.g.,metalloproteinase

atten on rigid ECM substrates,whereas they retract activities),also appear to drive regional changes in

and round on exible ECMs. cell growth and motility during tissue development

(25,42). Lung branching morphogenesis in the

embryo can be selectively inhibited or accelerated by

decreasing or increasing cytoskeletal tension,respec-Mechanical determinants of cell andtively,using pharmacological agents (43). Regionaldevelopmental controlchanges in ECM structure and associated changes in

What may be most surprising is that changes in cytoskeletal mechanics similarly contribute to control

microscale forces that alter the cytoskeletal force of angiogenesis that is required for wound healing as

balance and modulate cell shape also control complex well as tumor progression (44). In fact,cell-generated

cell behaviors that are critical for development and tensional forces appear to play a central role in the

tissue homeostasis. Cell growth,differentiation, development of virtually all living tissues and organs

polarity,motility,contractility and programmed cell (24,25,42),even in neural tissues,such as retina (45)

death,all can be inuenced by physical distortion of and brain (46).

cells through their ECM adhesions. For instance, Various in vitro and in vivo studies conrm that

chondrocytes,hepatocytes,mammary epithelium, mechanical forces directly regulate the shape andretinal epithelium,capillary endothelium,and bro- function of essentially all cell types (5). Individual

blasts can be switched from growth to differentiation bone cells increase deposition of bone ECM when

in the presence of soluble mitogens by decreasing the exposed to mechanical stresses with high frequency

stiffness or adhesivity of the ECM,and thereby and low strain in vitro,just as they do within wholebone (47),and differences in mechanical loadingpromoting cell retraction and rounding (2734).conditions can direct bone versus cartilage formationAdherent endothelial cells can be switched from

growth to apoptosis by more fully restricting cell (48). Chondrocytes respond to compressive loading

spreading (35). Varying the mechanical compliance by altering production of proteoglycans that comprise

(exibility) of the ECM also inuences the rate of cell cartilage matrix (49). Skeletal muscle cells increase

migration (36) and the direction of motility can be their mass,upregulate expression of muscle-specic

affected by geometric cues from the ECM (37). Direct proteins and even organize into muscle fascicles in

application of tensional forces to cultured endothelial vitro when stretched with physiologically relevantcells similarly promotes capillary outgrowth in 3D load cycles (50,51); heart cells increase secretion of

collagen gels (38) and nerve cells respond to tensional atrial natriuretic factor (52). Skin epithelium,bone

forces exerted on their surfaces by extending nerve cells,broblasts,and embryonic heart muscle cells all

processes in the direction of the applied stress (39). increase their growth rates when they experience

Changing vascular smooth muscle cell shape through mechanical strain (5356),whereas stretch induces

modulation of cell-ECM adhesion or alteration of differentiation in periodontal ligament cells (57).

ECM compliance also regulates its contractile Endothelium sense uid shear stresses and respond

response to vasoagonists,such as endothelin-1 (40, by altering their expression of proteins that are

41). In fact,individual cultured vascular smooth involved in lymphocyte binding (e.g.,ICAM),tissue

muscle cells display a bell-shaped,force-length remodeling (e.g.,PDGF) and handling oxidant stress,

relationship (40) that is highly reminiscent of the and some of these effects are mediated through






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activation of specic shear stress-response elements' cultured cells are mechanically stressed,the cell

in certain gene promoters (58,59). Kidney epithelial responds by increasing recruitment of focal adhesion

cells respond to levels of uid shear similar to those (cytoskeletal linker) proteins and mechanically

produced by urine ow in collecting ducts by strengthening itself against additional stress (14

increasing calcium inux (60,61). Changes in gene 17,6870). When the same stress is applied to other

expression and growth of bladder smooth muscle cells transmembrane receptors that do not mediate cell

that are triggered by outlet obstruction appear to adhesion,there is very little response. Because

result from mechanical stretch secondary to over- integrins preferentially mediate mechanical signal

lling of the bladder (62). Glomerular ltration rate is transfer across the cell surface,the molecular compo-similarly controlled by alterations in vasomotor tone nents of the cytoskeletal scaffolds that connect to

of preglomerular,glomerular,and postglomerular integrins within the focal adhesion will experience

microvessels,as well as associated changes in mesan- increased mechanical stress whereas soluble compo-

gial cell contractility (63). During pregnancy,the nents in the nearby cytosol will not. For example,

onset of labor is triggered by distention of the uterus when large-scale deforming forces are applied to

imposed by the growing fetus (64),and pulmonary integrins,cytoskeletal laments and linked intra-

epithelial cells increase secretion of surfactant when nuclear structures can be seen to realign along theapplied tension eld lines (71,72). Application of uidstretched in vitro (65),just as they do in a newborn

when it takes its rst breath. shear stress to the apical membrane of vascular

endothelium similarly results in distortion of cyto-

skeletal laments throughout the cell (73) as well as

funneling of stress along this load-bearing network inCellular mechanotransductionthe cytoplasm all the way to the cell's basal ECM

But how do mechanical forces in uence cellular adhesions (22,23). Kidney epithelium senses shear

biochemistry and gene expression so as to produce stress through deformation of the primary cilium (60,

these varied effects on cell and tissue behavior? This 61). This is a single,specialized,cytoskeletal process

mechanism is difcult to envision because it does not that extends vertically from the apical cell surface and

involve a classic stimulus-response' coupling as used functions like a long lever arm for the whole

by soluble hormones or secretagogues. In the case of cytoskeleton,much like stereocilia in hair cells of

hormonal stimulation,no molecular signal is present the inner ear.

prior to stimulation and the relevant receptor binding If the cytoskeletal laments and associated regula-

sites are unoccupied. Then when the hormone tory molecules distort without breaking when integ-

stimulus is provided,it binds to its receptor and rins or specialized cytoskeletal extensions (e.g.,

initiates an intracellular signaling response. In con- stereocilia,primary cilia) are stressed,then some or

trast,because cell shape is determined through a all of the molecules that comprise these structuresbalance of mechanical forces (2426),any external must similarly change shape. When the shape of a

mechanical stimulus that impinges on an adherent cell molecule is altered,its biophysical properties (ther-

is imposed on a pre-existing force balance,much like modynamics,kinetics) change,and hence biochem-

pulling an arrow back against a tensed bow-string. istry (e.g.,chemical reaction rates) will be altered(4,74). This is important because many of theThis is important because the pre-existing tensileenzymes and substrates that mediate cellular metab-stress (prestress) or tone in the cell can at times govern

the response' to the mechanical stimulus' (66,67). olism (e.g.,protein synthesis,glycolysis,RNA pro-

In the case of adherent cells,forces applied at the cessing,DNA replication) are physically immobilized

macroscale also will result in changes in ECM and on the cytoskeleton and nuclear matrix (nucleoskele-

cytoskeletal mechanics on the microscale. For exam- ton) (75,76). In particular,many signal transduction

ple,the vessel wall decreases its mechanical compli- molecules are oriented on the cytoskeletal backbone

ance (i.e.,becomes more rigid) when it is physically of the focal adhesion complex at the site of integrindistended due to increased blood pressure. Osmotic binding; these include mechanically-gated ion chan-

forces similarly tense and stiffen interstitial matrix, nels,protein kinases (e.g.,FAK,src),small GTPases,

for example,in cerebral edema or following injury to heterotrimeric G proteins,inositol lipid kinases,and

the liver; pressure overload has a similar effect in the certain growth factor receptors (77,78).

heart. These changes in ECM mechanics will not Experiments conrm that local changes in bio-

transfer force equally to all points on the surface of chemical signal transduction are produced when

neighboring adherent cells. Rather,a tug on the ECM external forces are applied to integrins. The increased

will be felt by the cell through its focal adhesions and recruitment of focal adhesion proteins and associated

hence,through its transmembrane integrin receptors cytoskeletal strengthening response that result when

that link to the cytoskeleton. integrins are stressed (1417,79) are mediated by

When integrins on the surface membrane of local activation of the small GTPase Rho and the






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protein tyrosine kinase,c-src (69,70,79). Mechanical ously activated by subtle variations in ECM structure

stress application to integrins also stimulates rapid within living tissues that are constantly exposed to

(within 10 msec) calcium inux in the neuromuscular physiological stresses. Because forces applied locally

synapse (due to rapid muscle twitching) (80),recruits through integrins also produce coordinated deforma-

the protein synthetic machinery to the site of force tion of molecular structures throughout the cyto-

application (81),and activates cAMP signaling within skeleton and nucleus (71,72), mechanochemical

the focal adhesion which eventually leads to stress- transduction could occur at distant or multiple sites

induced changes in gene transcription (82). Stress in the cell. In fact,application of mechanical stress to

application through integrins induces endothelin-1 integrins can produce the same focal adhesiongene expression in endothelial cells and this response signaling response (e.g.,production of cAMP) in

can be prevented by dissipating cytoskeletal tension round versus spread cells (82),however,the cells that

(prestress) and hence,altering cell mechanics (66,67). are globally distorted proliferate whereas the round

Again,application of similar mechanical stresses to cells undergo apoptosis (35). As described above,the

other transmembrane receptors that are not adhesion global shape of the cell dictates its behavior (e.g.,

receptors fails to produce these responses. Other growth versus differentiation or apoptosis),and these

signaling molecules that have been shown to be effects are mediated through tension-dependentchanges in cytoskeletal structure and mechanicsactivated by mechanical stress in an integrin-depen-

dent manner in various cell types include protein (37,100,101). Thus, cells appear to think globally'

tyrosine kinases (FAK,src),Shc,ERK1/2,protein in that large-scale mechanical distortion of cell shape

kinase C,PI-3-kinase,Akt,small GTPases (Rho, and the cytoskeleton govern how the cell processes

Rac),heterotrimeric G proteins,paxillin,SREBP1, and integrates locally-elicited signals (mechanical as

hsp 27 and b-catenin (70,79,8291). well as chemical) to produce a concerted behavioral

Importantly,all cells also contain stress-sensitive' response (74).

(mechanically-gated) ion channels that either increase

or decrease ion ux when their membranes are

mechanically stressed (92,93). For example, specia- Implications for clinical medicinelized mechanosensory `hair' cells of the inner ear

detect sound through de ections of their stereocilia These new insights into mechanobiology suggest that

that result in the opening of mechanosensitive cation many ostensibly unrelated diseases may share a

channels. Direction- and amplitude-dependent depo- common dependence on abnormal mechanotransduc-

larizations caused by these de ections result in tion for their development or clinical presentation.

induced currents that are relayed to nerve bers Mechanotransduction may be altered through

(94). The vestibular system relies on similar hair cells changes in cell mechanics,ECM structure or by

at the base of the semicircular canals to sense three- deregulation of the molecular mechanisms by whichdimensional rotation through uid ow; linear accel- cells sense mechanical signals or convert them into a

erations are sensed in the utricle and saccuole through chemical response. In fact,physicians in almost every

deection of mineral deposits (otoconia) within a branch of medicine and surgery care for patients who

specialized ECM (otolithic membrane) that again tugs have ailments that may be viewed as diseases ofon stereocilia within adjacent hair cells (95). Stretch- mechanotransduction,as discussed below and sum-sensitive channels at the sensory neuron terminals marized in Table 1.located under the epidermis and hair follicles also Although the question of how cells determine their

mediate touch sensation,and related mechanisms are shape and mechanics may seem esoteric,the reality is

used for pressure and stretch sensation as well as that it has important clinical implications. For

proprioception (96,97). However,even the function example,leukocytes physically deform when they

of these specialized mechano-electrical transducers pass through pulmonary capillary beds (102) and

appears to depend on their linkage to the cytoskeleton inammatory agents that increase cytoskeletal stiff-and hence,indirectly on integrin coupling to the ECM ness in circulating neutrophils induce leukocyte

(93,98) which stabilizes the entire cytoskeleton sequestration in the lung (103). The ability of tumor

against shape distortion (24). For readers interested cells to resist traumatic destruction in the vasculature,

in molecular mechanisms of mechanotransduction, and hence their ability to metastasize and survive in

more detailed discussions can be found in various distant capillary beds,depends on their exibility

recent reviews (4,5,47,85,95,98,99). (104). The effectiveness of delivery of therapeutic

In biology,we emphasize linear thinking and focus cytotoxic lymphocytes into tumor tissues similarly

on local molecular binding and assembly events. But if can vary with their stiffness (105). Mechanical

all mechanosensing was carried out locally at the site stretching of kidney mesangial cells through integrins

where stresses impinge on the surface membrane (e.g., due to glomerular hypertension represents a common

in the focal adhesion),then cells would be continu- nal pathway for glomerulosclerosis (106107),and






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Table 1. Diseases of mechanotransduction

Cardiology Angina (vasospasm) C T

Atherosclerosis T M

Atrial brillation M

Heart failure C T M?

Hypertension C T M?

Intimal hyperplasia C T M?

Valve disease T

Dermatology Scleroderma T

Gastroenterology Achalasia C

Irritable bowel syndrome C M?

Volvulus C T

Nephrology Diabetic nephropathyC T M?

Glomerulosclerosis C T M?

Neurology Cerebral edema T

Facial tics C

Hydrocephalus T C?

Migraine C M?

Stroke C T

Stuttering C

Oncology Cancer C T M?

Metastasis C

Opthalmology Glaucoma C T M?

Orthopedics Ankylosing spondylitis C T

Carpal tunnel syndrome C T

Chronic back pain C T

Dupytren's contracture C T

Osteoporosis T M

Osteoarthritis T

Rheumatoid arthritis T

Pediatrics Collagenopathies T

Congenital deafness C T M

Mucopolysaccharidoses T

Musculodystrophies C T M

Osteochondroplasias C T

Polycystic kidney disease T M

Pulmonaryhypertension of newborn C T M?

Pulmonary medicine ARDS C T M

Asthma C T M?

Emphysema T

Pulmonarybrosis T

Pulmonaryhypertension C T M?

Ventilator InjuryC M

Reproductive medicine Pre-eclampsia C T M?

Sexual dysfunction (male & female) C M?

Urology Urinaryfrequency/incontinence C M?

A partial list of diseases that share the feature that their etiologyor clinical presentation results from abnormal mechanotransduction.

The right column indicates whether the mechanical basis of the disease or condition is likelydue to changes in cell mechanics (C),

alterations in tissue structure (T), or deregulation of mechanochemical conversion (M); ?' indicates situations where deregulation of

mechanochemical conversion is likelybut remains to be demonstrated.

altered cell mechanics contributes to the clinical pulmonary hypertension of the newborn,broncho-presentation of asthma and other pulmonary diseases pulmonary dysplasia,asthma,achalasia,preeclamp-

(108). Even some of the genetic causes of deafness sia,urinary frequency,irritable bowel syndrome,and

involve mutations in cytoskeletal proteins,such many causes of chronic back pain,are all based on

myosin,espin and mDia,that alter hair cell mechanics muscle cell hypercontractility. Dupytren's contracture

(109111),and certain patients with autoimmune ear is characterized by hypercontractility of ligamental

disease have antibodies directed against b-actin (112). broblasts (114),whereas glaucoma (115) and hydro-

Mutations in specialized ECM proteins and deletion cephalus (116) result from physical constrictions that

of integrin a8b1,which is found in hair cells,also obstruct uid ow in the eye and cerebrospinal space,

hinders stereocilia maturation and hair cell differ- respectively. Recent studies suggest that genetic

entiation (113). mutations or malfunction of cytoskeletal proteins,

Systemic and pulmonary hypertension,persistent ECM molecules or integrins that alter cell and tissue






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mechanics can lead to impaired vascular smooth appears to be controlled by metalloproteinases that

muscle and cardiac muscle contractility,as well as structurally remodel ECM (139).

various forms of heart disease (119121). In fact,most Other diseases result directly from deregulation of

of the molecular causes of heart failure appear to transmembrane mechanical signaling. Atrial brilla-

disrupt the biomechanical balance between the tion may be caused by abnormal conversion of

cytoskeleton,membrane,and ECM (122). In contrast, mechanical stress gradients (e.g.,secondary to volume

decreased smooth muscle cell contractility results in overload) into intracellular gradients of electrical

urinary stress incontinence (123),as well as defects in activity as a specic peptide inhibitor of stress-

male and female sexual function (124,125). Abnormal activated ion channels can prevent the heartbeat frommuscle tone also can lead to destabilization of the losing its rhythm (140). Dystrophin,the gene product

skeleton (126) and contribute to skeletal and joint that is mutated in Duchenne's muscular dystrophy is

diseases. For example,axial muscular dysfunction has part of the specialized focal adhesion (dystroglycan)

been implicated in the development of joint pathology complex that mechanically couples the cytoskeleton

in ankylosing spondylitis (127). to ECM in skeletal muscle (141). Mutations in various

In other conditions,mechanotransduction may be load-bearing molecules in muscle,including other

compromised as a result of changes in ECM forma- adhesion complex proteins,integrins,or ECM pro-

tion or remodeling. Many genetic diseases and teins,lead to development of similar musculardevelopmental disabilities,including various osteo- dystrophies (130,141143). Moreover, cells with

chondrodysplasias,mucopolysaccharidoses and col- these mutations exhibit abnormal responses to mech-

lagenopathies are essentially disorders of connective anical stress,as well as altered cell and cytoskeletal

tissue structure and mechanics (128,129). In one mechanics (143145). Kidney duct epithelial cells

form of muscular dystrophy,a mutation in an ECM from transgenic mice that lack functional polycystin

protein (laminin a2) leads to both the muscular 1,and hence develop autosomal dominant polycystic

degeneration and sensineural hearing loss that are kidney disease,fail to increase calcium inux in

observed in many patients with this disease (130). A response to uid shear stresses when applied at levels

mutation in a brillar collagen gene (COL11A1) similar to those that occur in vivo (60,61). If

produces chondrodyplasia when homozygous,and collecting ducts utilize a mechanical control mechan-

both osteoarthritis and hearing loss when hetero- ism similar to that of blood vessels which increase

zygous. Patients with Stickler syndrome and Mar- their diameter when hemodynamic shear stresses rise

shall syndrome are also heterozygous for mutations (58),then loss of this normal homeostatic mechanism

in this gene (131). Abnormal brillin deposition in could lead to unregulated duct expansion and hence

patients with Marfan's syndrome alters the vascular cyst formation. Osteoporosis also may be caused by

endothelial cell response to hemodynamic stresses aberrant mechanotransduction since similar bone loss

and results in aortic dissection due to local weakness can result from mechanical unloading,for example,of the vascular wall (132). Accumulation of abnormal due to extended bed rest or exposure to microgravity

ECM also contributes to development of abnormal (146). Interestingly,certain osteoporosis drugs speci-

tissue mechanics and clinical compromise of function cally target integrin receptors that mediate mechan-

in patients with scleroderma,pulmonary brosis, otransduction (147). Other conditions that may resultvascular hypertension,and diabetic nephropathy, from stretch-activated signaling cascades include

whereas emphysema is characterized by enhanced development of intimal hyperplasia induced by stent

ECM breakdown. Although rheumatoid arthritis has placement in coronary arteries or by replacement of

an inammatory basis,joint pain and reduced constricted vessels with arteriovenous grafts (148),

movement are also due to the breakdown of the and ventilation-induced lung injury (e.g.,ARDS)

cartilage matrix. In fact,angiogenesis inhibitors that (149).

prevent cartilage matrix dissolution by inhibiting Recognition of the importance of mechanics and

capillary invasion can signicantly suppress the cellular mechanotransduction for tissue developmentclinical and histological symptoms of rheumatoid also may help to explain the focal incidence of disease.

arthritis in an animal model without evidence of Although high cholesterol and LDL promote athero-

immunosuppression (133). Changes in ECM struc- sclerotic plaque formation,these plaques preferen-

ture that alter tissue mechanics and provide a tially form in regions of disturbed blood ow (e.g.,

constitutive stimulus for cell growth may even near vessel branches) (58). Thus,if one could under-

contribute to cancer initiation and progression stand how cells sense ow,it might be possible to

(134136). For example,overexpression of an prevent plaque formation in the future. Local changes

ECM-degrading enzyme in transgenic mice results in tissue structure also may explain why genetic

in formation of malignant tumors (136,137). The diseases,including cancer,often present focally (e.g.,

`angiogenic switch' that initiates tumor angiogenesis retinoblastoma usually only occurs in one eye). In

and is required for cancer formation (138) also other words,changes in tissue mechanics may






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common feature in many diseases may explain why aTable 2. Mechanical therapies

toxin that modulates cell tension Botulinum AAcupuncture

(Botox) is being tested as a treatment for a wideAnti-arrhythmic drugs

range of ailments,including stroke paralysis,Anti-spasmodic drugsmigraine headaches,facial tics,stuttering,lower backBone fracture healing

pain,incontinence,carpal tunnel syndrome and tennisBotoxCardiac perfusion elbow,in addition to being a high priced cosmeticDistraction osteogenesis

(156). Another chemical inhibitor of cell tension thatInotropic drugs

targets Rho-associated kinase,a molecule that bothLung ventilationmediates mechanosignaling through integrins andMassage therapy

regulates cytoskeletal contractility (69,70), also hasMuscle relaxantsOrthodontics been found to prevent disease progression in experi-Physical therapy

mental models of glaucoma (157) and intimalRho-kinase inhibitor (fasudil)hyperplasia (158). Importantly,one form of thisStentscompound,fasudil,appears to be useful for treatmentSurfactant

Tissue engineering (manufacturing process) of systemic hypertension (159) as well as angina dueTissue expansion (e.g., breast) to myocardial ischemia in humans (160). Conven-Vasodilators

tional vasodilators,muscle relaxants,inotropic agentsVentilator therapy

and anti-spasmodic drugs similarly prevent clinicalWound closure (e.g., vacuum-assisted)symptoms based on their ability to modulate cell

A partial list of clinical therapies that are currentlyin use or inmechanics,and anti-arrythmics directly modulate

development whose action is largelybased on altering cell and mechano-electrical conversion in heart cells. Thetissue mechanics, or directlyaltering cellularfunction of cardiac perfusion devices is also purelymechanotransduction (see text for details).mechanical. However,even complex developmental

processes,such as angiogenesis,can be controlled by

contribute signicantly to the epigenetic basis of altering cell and tissue mechanics,for example,using

disease. drugs that target the cytoskeleton (161,162),integrins

Understanding of the relation between structure (163) or the ECM (164166). Some of these drugs have

and function in living tissues and of fundamental entered human clinical trials for angiogenesis-depen-

mechanisms of cellular mechanotransduction may dent diseases,such as cancer and macular degenera-

therefore lead to entirely new modes of therapeutic tion. Thus,someday it may be possible to treat a huge

intervention (Table 2). In fact,surgeons already use range of diseases using drugs that specically target

mechanical therapies to promote tissue growth and molecules that contribute to mechanoregulation. In

remodeling. Examples include the use of surfactant to the eld of tissue engineering,mechanical forcepromote lung development in premature infants regimens also have been integrated into device

(150),mechanical ventilation with low tidal volume fabrication protocols. Engineered tissues,including

to decrease morbidity and death in patients with acute articial blood vessels,skeletal muscle,cardiac

lung injury and acute respiratory distress syndrome muscle and heart valve,greatly increase their mech-anical strength and clinical efcacy if preconditioned(ARDS)(151),expandable stents to physically prevent

coronary artery constriction (152),tissue expanders to using force regimens prior to implantation (167171).

increase the skin area available for reconstruction of Design and fabrication of synthetic `biomimetic'

large surface defects,and devices for tension applica- biomaterials and nanotechnologies that mimic the

tion for distraction osteogenesis,orthodontics,bone mechanical as well as chemical properties of natural

fracture healing,craniofacial surgery,cosmetic breast tissue structures may revolutionize the medical device

expansion and closure of non-healing wounds (153, industry in the future.

154). These devices are believed to act throughalterations in microscale forces (e.g.,cell stretching)

that activate cellular signal transduction (153,154). ConclusionThe therapeutic value of physical therapy,massage,

and muscle stimulation is also well known. But even The current focus in medicine is on the genetic basis

the effects of acupuncture therapy on pain control and of disease. However,it is not necessary to correct the

other clinical symptoms appear to result from underlying genetic defect in order to treat clinically

physical manipulation (twisting) of the needles that relevant symptoms or relieve the pain and morbidity

produces ECM distortion and associated integrin- of disease. Moreover,most of the clinical problems

dependent changes in cellular mechanotransduction that bring a patient to the doctor's ofce result from

(155). changes in tissue structure and mechanics. Although

The nding that abnormal cell contractility is a these physical alterations have been commonly






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viewed as the end-result of the disease process,recent The value of macroscale forces as therapeutics has

advances in mechanobiology suggest that abnormal already been demonstrated by surgeons,however,the

cell and tissue responses to mechanical stress may potential clinical value of developing approaches to

actively contribute to the development of many selectively control microscale forces may be even

diseases and ailments. Thus,it might be wise to greater. Pursuit of the relation between structure and

search for a physical cause when chemical or mol- function at the molecular scale in living cells and

ecular forms of investigation do not sufce. tissues also may lead to the development of entirely

These observations also raise the possibility that new biomaterials and microdevices for repair and

the molecules that mediate mechanotransduction, replacement of injured tissues. Thus,if we are toincluding ECM molecules,cell surface adhesion advance patient care in the twenty rst century,we

receptors,cytoskeletal components,and related signal need to do more than delineate the genetic causes of

transduction molecules may represent future targets disease; we also must reintegrate mechanics into our

for therapeutic intervention in a variety of diseases. understanding of the molecular basis of disease.

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