Table Of ContentStructure and Function
of the Extracellular Matrix
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Structure and Function
of the Extracellular Matrix
A Multiscale Quantitative Approach
Be(cid:1)la Suki
Professor of Biomedical Engineering, Department of Biomedical Engineering,
Boston University, Boston, MA, United States
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Contents
Preface ix Effectsofmutationsonmolecularstructure
Definition ofsymbols xi andfunction 49
References 52
4. Collagen supramolecular
1. Introduction to structure-function
structures:Evolution,organization,
relationships
and biogenesis
Whatisstructure? 1
Evolutionofthefibrilandthediversification
Whatisfunction? 1
Whatarestructure-functionrelations? 2 ofthecollagenfamily 56
Themultiscalenatureofstructure-function Multiscalenatureoffibrilstructure 59
relations 3 NetworkstructureoftypeIVcollagen 62
Evolutionaryaspects 4 Fibrilformation 64
Implicationsforscienceandmedicine 5 Modelingfibrilgrowth 67
References 6 References 73
5. Collagen suprastructures: The data
2. Extracellular matrix background
and the models
material: Building blocks, general
structure, mechanics, relation to StructureandfunctionoftypeIVcollagen
cells, and evolutionary aspects networks 78
Quantitativeanalysisofstructure-function
Thebuildingblocksandthestructureof relationsintheglomerularbasement
proteins 9 membraneofthekidney 80
Generalpropertiesandorganizationofthe Structure-functionofelasticnetworksfrom
ECM 11 thepointofviewofpercolation:
Mechanicalforces,stresses,andstiffness 14 Implicationsfortissueengineering 85
RelationoftheECMtocells 19 Microscopicstructure-functionrelations
ECMandevolution 21 ofthecollagenfibril 88
References 25 Multiscalemechanicalpropertiesofthe
collagenfibril:Thedata 91
3. The collagen molecule Modelingfibrilfunction:Fromsimpleto
complex 96
Collagenclassification 29 Isfibrilviscoelasticityasignatureofhidden
Abriefevolutionaryhistoryofthecollagen
complexity? 100
family 31 References 108
Structureofthecollagenmolecule 33
Biosynthesis 35 6. Selected examples of tissue-level
Collagenfunctions 36 collagen suprastructures: Tendon,
Collagenbindingproperties 38 bone, and skin
Collagenelasticity 39
Polymer-basedmodeling:Themechanical Basicstructureandfunctionofthetendon 113
propertiesofthemolecule 44 Modelingtherecruitmentofwavyfibrils
Structuralmodelsofthecollagenmolecule 45 duringtendonstretching 114
vii
viii Contents
Modelingtendonrupture 119 9. Elastic fibers: The near ideal
Abriefintroductiontotheevolutionarily linear springs of the extracellular
shapedstructureandfunctionofthebone 120 matrix
Examplesofmultiscalestructure-function
relationinbones 123 Evolutionofelastin 194
Theevolutionandbasicfunctionoftheskin 128 Thetropoelastingenestructure 196
Multiscalemechanicsandtearresistanceof Structure,disorder,andaggregation 197
theskin 130 Mechanicalpropertiesof
Anoteonthebiologicalsignificanceof tropoelastin 201
recruitment 136 Microfibrils 204
References 139 Elastogenesis:Howtobuildanetwork
ofelasticfibers 206
7. Small leucine-rich proteoglycans: Elasticfibers:Aretheyideallinear
The tiny controllers of the springs? 208
extracellular matrix Abriefsummaryonorgan-levelfunction
anditsbreakdown 217
BasicstructureandevolutionofSLRPs 143 Finalnotesonthenearidealspring 219
BiologicalfunctionsofSLRPs 146 References 223
ThePGinteractionnetwork 149
PhysiologicalfunctionsofSLRPs 151 10. Modeling maintenance and
InfluenceofGAGsonlungparenchymal repair: The matrix loaded
mechanics 155
Summary 159 Evolutionofhomeostasisandrepair 230
AcontinuumapproachtoECMgrowth
References 159
andremodeling 235
8. Hyaluronan and hyalectans: Dynamicsofhomeostasisandstructural
The good, the bad, and the ugly remodeling 237
Fluctuation-drivenhomeostasis 240
Evolutionaryhistory 166 Atoymodelofself-healing 243
ThestructureoftheHA-hyalectan Agent-basedmodeling:Thenetwork
aggregate 167 paradigm 245
Bindingandmoleculartocellularfunctions 171 Theuninvitedaging:Maintenance
Microscalephysiologicalfunctions 173 andrepairslippingoutofcontrol 249
Structureandfunctionoftheendothelial Whathavewelearned? 250
glycocalyx 176 References 251
Physiologicalfunctions 179
Thebadandtheugly 184 11. Outlook
Summary 187
References 188 Index 259
Preface
LifeonEarthstartednearly4billionyearsagowiththeemergenceofprokaryoticcells.Theseearlycellswererelatively
simpleandlikelydidnotinteractsignificantlywitheachother.Approximatelytwobillionyearslater,theeukaryoticcell
enteredthestageofbiologicalevolution.Comparedtoprokaryoticcells,theywerelargewithcomplexgeneticandmor-
phologicalcharacteristics.Additionally,therewasamajorchangeinhowthesecellsoperatedbecausetheywerecapableof
touching and probing their physical environment. The next step in the increase in biological complexity occurred when
eukaryotic cells about 1 billion years ago began to form multicellular organisms, and this marks the time of the birth
of the extracellular matrix, commonly abbreviated as ECM and loosely defined as the organic material produced by
andfoundbetweencellsofallmulticellularorganisms,includingplantsandanimals.WiththearrivaloftheECM,limitless
newpossibilitiesopenedthepathforfurtherbiologicalevolutionthathaseventuallyledtotheemergenceofhumans.The
impact the ECM has had on shaping biological function, complexity, anddiversity cannot be understated.
Today,theprimaryroleoftheECMistoprovidethestructuralsupportforlife.WithouttheECM,plantscouldnotgrow
andtherewouldbenocartilage,tendon,andboneswithwhichanimalscanmove,swim,orfly.Itisinfactlikelythatthere
wouldbenocomplexmulticellularlifeeither.AstheECMevolvedtogetherwithcells,ithasbecomemuchmorethanjusta
simplesupportstructureatthemacroscopiclevel.Byprovidingstructureatthescaleofcells,theECMallows,forexample,
cellmigration,acriticalcomponentofdevelopmentandwoundhealing.Itisnowwellestablishedthatthecompositionand
thestiffnessoftheECMinfluencecellularsignalingandhencecontinuouslyregulatethemaintenanceoftissues,including
theECMitself.ThespecificcompositionandstructureoftheECMhavethereforeevolvedtosupportvariousfunctional
roles at different length scales throughout the body. These interdependencies, shaped by evolution, are called structure-
functionrelations.Therelationshipsbetweenstructureandfunctionatdifferentlengthscalesofteninfluenceeachother,
leading tothe popular notionof multiscale behavior.
Characterizationofmultiscalestructure-functionrelationscanhelpunderstandbasicphysiologicalandbiologicalpro-
cessesaswellasthepathologicalchangesthatareassociatedwithdisease.Forexample,infibrosis,thepropertiesofcol-
lagen,oneofthemostimportantload-bearingcomponentsoftheECM,undergochanges,calledcellularremodeling,by
excessivecollagendeposition,reorganization,andcross-linking.Thesepathologicalchangesinstructureresultinanabnor-
mallyhightissuestiffnessandsubsequentlossoffunctionality,suchasthesoftelasticnatureofhealthyskin.Structure-
functionrelationsarealsokeytosuccessfuldrugdesign.Whenadrugisusedtotreatfibrosis,thestiffcollagenneedstobe
brokendownsothatthecollagennetworkregainsitsstructurethatallowsnormalfunction.Additionally,theevaluationof
drugefficacycanalsobeenhancedbyquantitativestructure-functionstudies.Itisinterestingtonotethatmedicinehasbeen
practiced for centuries utilizing empirical and more recently experimental structure-function relations. Indeed, doctors
often attempt to draw conclusions about pathological alterations in structure from observed abnormalities in function.
Beyonddescriptivecharacterization,aquantitativedescriptionoftheECMispreferredbecauseitallowsadeeperunder-
standing of function and hence biology, and pathology that are crucial for rational drug design. Proper computational
modeling ofthe multiscale structure-functionrelations can also allow the prediction ofdisease progressionor aging.
Thisbookisanattempttosummarizethestate-of-the-artofECMstructureandlinkitspropertiesandorganizationto
physiologicalandbiologicalfunctionsfromamultiscaleevolutionaryperspective.TheECMisgenerallydiscussedinterms
ofpurebiology,structure,orfunction,andoftenthetreatmentislimitedtophenomenology.Atpresent,thereisapaucityof
studieswithacoherentandoverarchinggoaltoquantitativelytreattheECMasamultiscalesystem.Mostimportantly,few
studies have examined the evolutionary origins and consequences of ECM structure and function. This book therefore
intendstointegrateevolutionarybiologywithmultiscalestructuretoquantitativelyunderstandfunction.Withoutthecom-
bination of these factors, the ECM cannot be fully appreciated. This approach will, in turn, allow a fresh look into the
normal functioning as well as the pathological alterations of the ECM. This book starts with an introduction to what
structure,function,andtheirrelationreallymeansintermsofmultiscalebehaviorandevolution.Thefundamentalcom-
ponentsoftheECM,includingcollagens,proteoglycans,andelastin,arediscussedusingbasicprinciplesofbiophysicsand
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