The integrin–collagen connection

12 Pages·2016·7.38 MB·English

©2016.PublishedbyTheCompanyofBiologistsLtd|JournalofCellScience(2016)129,1284doi:10.1242/jcs.188672
CORRECTION
– –
The integrin collagen connection a glue for tissue repair?
CédricZeltzandDonaldGullberg
TherewasanerrorpublishedinJ.CellSci.129,653–664.
InFig.2A,thefibroblastswereincorrectlylabelled.Thecorrectannotationshouldhavebeenα11−/−fibroblast(left)andα11+/+fibroblast
(right).ThecorrectFig.2isshownbelow.
A α11–/– fibroblast α11+/+ fibroblast C Mestuemncohry cmealll-like Invasion
7
Impaired RhoC
reomrgaatnriixzation 3α11β1 α2β1 α11β1
2
9
JNXKSmads Smads JNK 4 Cmoaltlraixgen ‘Trailblazer’ cell
remodeling
Cdc42
Invasion
α2β1 8
1
D
Tumor cell
B
CAF
α2β1
α1β1 α11β1
10?
α2β1 EMT
5? 6
α11β1
CXCL5 Myoblast
differentiation ?11
Tumor cell Migration
Mesenchymal-like
tumor cell
E
Key 12 Growth Tumor cell
CAF
Collagen I
Organized Tumor cell α1β1 α2β1
collagen I Endothelial cell
Bmaesmebmraennet Mlikees teunmcohry mcealll- 14
Angiogenesis α-SMA Angiogenesis Intravasation
Integrin α1β1 TGF-β receptor
IInntteeggrriinn αα21β11β 1 TIGnhFi-bβi1tion AngioMstMatPin-913 α1β1
Fig.2.Rolesofcollagen-bindingintegrinsincancer.(A)Integrinα11β1incollagenreorganization.α11β1promotescollagenremodeling,whereasα11
deficiencyleadstoimpairedmatrixreorganization(Schultzetal.,2015).(1)BindingofTGF-βtoitsreceptor,inducesα-SMAexpressionand(2)upregulatesα11
expressionthroughSmadsignaling.(3)α11isnecessarytostabilizeα-SMAproteinexpression.(4)α11β1integrinreorganizescollagenmatricesthroughTGF-β-
inducedJNKsignaling.(B)Collagen-bindingintegrinsintumor–stromainteraction.(5)α1β1andα2β1areexpressedoncancer-associatedfibroblasts(CAF),but
howthisaffectstumorcellsisso-farunclear.However,(6)α11β1onfibroblastscanmodulateautocrinesecretionofCXCL5inlungadenocarcinomacellsto e
promotetumorcellmigration(Luetal.,2014).(C)Collagen-bindingintegrinsintumorinvasion.(7)α2β1promotesprostatecancerinvasionthroughRhoC nc
activation(Halletal.,2008).α11β1isoneofthesevengenesidentifiedasasignatureforthe‘trailblazer’cellphenotype(Westcottetal.,2015).(8)Trailblazercells e
leadcollectiveinvasionandgeneratepathwayswithincollagenmatricesthatalsoallowopportunistfollowercellstoinvade.(9)α11β1andCdc42arebothinvolved ci
S
intheformationofthelongcellprotrusionsneededforinvasion.(D)Collagen-bindingintegrinsinepithelial-to-mesenchymaltransition(EMT).(10)Collagen-
bindingintegrinsdonotappeartohaveamajorroleinEMT.(11)Becauseα11β1isexpressedonmesenchymal-liketumorcells,itmighthavearolein ell
myofibroblastdifferentiationofmesenchymal-liketumorcells.(E)Collagen-bindingintegrinsinangiogenesis.(12)α1β1isexpressedontumorcells,and C
promotestumorgrowthandmetastasis(Chenetal.,2005).(13)α1β1isalsoexpressedonendothelialcells,whereitpromotesangiogenesis(Pozzietal.,2000), f
o
anddownregulateslevelsofactiveMMP-9,whichsuppressestheproductionoftheangiogenesisinhibitorangiostatin.Bycontrast,(14)thepresenceofα2β1on
l
tumorcellsinhibitstumorcellintravasationduringthemetastaticprocess(Ramirezetal.,2011). a
n
r
u
Weapologisetothereadersforanyconfusionthatthiserrormighthavecaused. o
J
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©2016.PublishedbyTheCompanyofBiologistsLtd|JournalofCellScience(2016)129,653-664doi:10.1242/jcs.180992
COMMENTARY
– –
The integrin collagen connection a glue for tissue repair?
CédricZeltzandDonaldGullberg*
ABSTRACT in wounds (Schulz et al., 2015), in fibrotic tissue (Talior-
Theα1β1,α2β1,α10β1andα11β1integrinsconstituteasubsetofthe Volodarsky et al., 2015) and tumor models (Lu et al., 2014;
Navabetal.,2015).Thesefindings,whichestablishimportantroles
integrinfamilywithaffinityforGFOGER-likesequencesincollagens.
Integrins α1β1 and α2β1 were originally identified on a subset of forcollagen-binding integrins in relation to fibroblasts, are timely
and fitwell into therecentawarenessthatwoundhealing,fibrosis
activated T-cells, and have since been found to be expressed on a
numberofcelltypesincludingplatelets(α2β1),vascularcells(α1β1, and tumor–stroma interactions share key mechanisms at the
α2β1), epithelial cells (α1β1, α2β1) and fibroblasts (α1β1, α2β1). molecularlevel(Rybinskietal.,2014).ThisCommentaryfocuses
Integrinα10β1showsadistributionthatisrestrictedtomesenchymal on the collagen-binding integrins and their biological roles,
stem cells and chondrocytes, whereas integrin α11β1 appears summarizing some basic facts and recent findings that might
changeourviewofcollagen-bindingintegrins.
restrictedtomesenchymalstemcellsandsubsetsoffibroblasts.The
bulkofthe current literature suggeststhat collagen-bindingintegrins
Indirectbindingtocollagens:thenectinandCOLINBRI
onlyhavealimitedroleinadultconnectivetissuehomeostasis,partly
concepts
duetoalimitedavailabilityofcell-bindingsitesinthematurefibrillar
Beforetheidentificationoftheintegrinfamily,cellswerethoughtto
collagenmatrices.However,somerecentdatasuggestthat,instead,
beanchoredtocollagensindirectlythroughtissue-specificnectins
theyaremorecrucialfordynamicconnectivetissueremodelingevents
–suchaswoundhealing–wheretheymightactspecificallytoremodel [from nectere (lat.): to bind, join together]. One such nectin is
osteonectin, now known as secreted protein acidic and rich in
and restore the tissuearchitecture.ThisCommentary discussesthe
cysteine (SPARC), which is present in bone and binds Ca2+ and
recentdevelopmentinthefieldofcollagen-bindingintegrins,theirroles
collagen I (Termine et al., 1981). Another example is
in physiological and pathological settings with special emphasis on
woundhealing,fibrosisandtumor–stromainteractions,andincludea chondronectin, which was thought to mediate cell attachment to
discussionofthemostrecentlyidentifiednewcomerstothissubfamily– collagen II in cartilage(Hewitt etal., 1982). When integrins were
integrinsα10β1andα11β1. identifiedandfoundtobealargefamilyofreceptorswithversatile
roles in cell adhesion, this concept went out of fashion (Barczyk
KEYWORDS:Collagen,Fibrosis,Integrins,Tumor,Woundrepair et al., 2010). The identification of collagen-binding integrins
appearedtobethelastnailinthecoffinforthenectinconcept,and
Introduction clearlydemonstratedthatcellscanbinddirectlytomonomericand
Withintheintegrinfamily,theintegrinsthatbindtoRGDsequences fibrillarformsofcertaincollagenswithouttheneedforanindirect
have been extensively studied owing to their demonstrable linkage (Camper et al., 1998; Gullberg et al., 1995; Kramer and
importance for development, angiogenesis and thrombosis, and Marks, 1989; Santoro, 1986). On the basis of our current
also on account of their roles in activating transforming growth understanding, however, it is possible that cells in vivo, in
factorbeta(TGF-β)andfibrosis(Barczyketal.,2010;Hynes,2007, additiontodirectcollagenbinding,alsoindirectlybindtofibrillar
2009; Munger and Sheppard, 2011). The RGD-binding integrins collagens. We have introduced the term COLINBRIs for proteins
have, thus, served in many instances as prototypes in order to thatbridgetheinteractionsofcellswithnativefibrillarcollagens,as
understand the details of integrin activation and function. By discussedmorethoroughlyinapreviousreview(Zeltzetal.,2014).
comparison,thecollagen-bindingintegrinsα1β1,α2β1,α10β1and
α11β1 have been living in the shadow of these prototypes, partly Directbindingtocollagens:thenon-integrincollagen-
becauseoftheirrelativelylimitedrolesinembryonicdevelopment bindingreceptors
andalsobecauseoftherelativelymildphenotypesobservedinmice Inadditiontothecollagen-bindingintegrinsα1β1,α2β1,α10β1and
that lack individual collagen-binding integrins (Popova et al., α11β1 (Leitinger, 2011; Zeltz et al., 2014), the collagen-binding
2007b; Zeltz et al., 2014). In addition, there are also technical receptors include a number of other proteins with affinities for
limitations,forinstancethecomplexityofauthenticsynthetictriple varioustypesandformsofcollagen,suchasplateletglycoproteinVI
helicalpeptidesforthecollagen-bindingintegrinsascomparedwith (GPVI) (Clemetson et al., 1999; Kehrel et al., 1998; Zahid et al.,
e
thefarsimplerlinearRGD-containingpeptides. 2012),discoidindomainreceptortyrosinekinases1and2(DDR1 c
n
The picture of collagen-binding integrins playing a relatively and DDR2) (Leitinger, 2014; Vogel et al., 1997), leukocyte- e
i
minor role in normal physiology contrasts with the severe associated immunoglobulin-like receptor 1 (LAIR-1) (Meyaard, c
S
phenotypes that have been documented when the ligands of 2008, 2010), osteoclast-associated immunoglobulin-like receptor
l
these integrins – members of the collagen family – are defective (OSCAR)(Barrowetal.,2011)andG-protein-coupledreceptor56 el
C
(Zeltz et al., 2014). Recent data, however, have highlighted the (GPR56,genenameADGRG1)(Luoetal.,2012)(Fig.1).
f
contributionofthecollagen-bindingintegrinstofibroblastfunction Whereas the direct and indirect binding to collagen through o
integrins serve as mechanolinks, the other collagen-binding al
DepartmentofBiomedicineandCentreforCancerBiomarkers,Universityof receptorshavemoreheterogeneousfunctionsand,ingeneral,tend n
r
Bergen,JonasLiesvei91,BergenN-5009,Norway. to affect cellular signaling rather than serving as mechanolinks u
o
*Authorforcorrespondence([email protected]) betweenfibrillarcollagenmatricesandthecytoskeleton. J
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COMMENTARY JournalofCellScience(2016)129,653-664doi:10.1242/jcs.180992
Collagen-binding integrins Key Fig.1.Collagenreceptors.Schematicofstructures
α1β1, α2β1, α10β1 and α11β1 forthecollagenreceptorsdiscussedinthis
Collagen Commentary.GPVIandOSCARarecomposedof
β-propeller αI domain twoimmunoglobulin-like(Ig)ectodomains,andare
associatedwithadimericFcreceptorγchainatthe
βI-like domain
cytoplasmictail.CollageninteractswiththeIg1
domainand,inthecaseofOSCAR,withboththeIg1
DDRs andIg2domain.GPVIformsadimer,whereas
GPVI OSCAR
dimerizationofOSCARhasnotbeenobserved.
LAIR-1 LAIR-1interactswithcollagenthroughitsIg
Ig1 Ig1 DS GPR56 ectodomain.Integrinscompriseoneαandoneβ
subunit.Collagen-bindingintegrinsdisplayanαI
Ig2
Ig2 Ig domainontheαsubunit,towhichcollagenbinds.
Discoidindomainreceptortyrosinekinases(DDRs)
arehomodimericcollagenreceptors;collagenbinds
α β throughthediscoidin(DS)ectodomain.GPR56isa
FcRγ FcRγ G-protein-coupledreceptorcomposedofseven
Kinase transmembranedomains.Collageninteractswiththe
longextracellularN-terminalregionofGPR56.
GPVI is an important collagen-binding immune receptor on (Hemleretal.,1985a,b)and,later,showntobecollagenreceptors
platelets,withanactivatingrolethatisindependentofintegrinα2β1 present on multiple cell types (Ignatius et al., 1990; Staatz et al.,
(Marjorametal.,2014;Zahidetal.,2012).Recentdatasuggestthat 1989).Thelastmemberoftheintegrinfamily,integrinα11β1,was
itcanalsobindlamininisoformsandfibrin(Alshehrietal.,2015; clonedin1999(Vellingetal.,1999),justafterthecharacterization
Inoue et al., 2006). Significantly, its binding to human placenta ofα10in1998(Camperetal.,1998).Thus,considerablylessdata
laminin (a mixture of laminins-211, -411 and -511) is of lower havebeen accumulatedfor these twolast additionsto the integrin
affinitythanthattocollagenIandreliesonα6β1integrin-mediated family. As collagen-binding integrins have been extensively
activationofGPVI(Inoueetal.,2006;Wondimuetal.,2006). reviewed in the past few years (Leitinger, 2011; Zeltz et al.,
LAIR-1 is present on immune cells (Meyaard, 2010) where it 2014),wehereemphasizetheirbiologicalroleswithaspecialfocus
generates inhibition signals because binding to collagens inhibits onintegrinsα10andα11.
LAIR-1function.Thecollagen-likeproteinsurfactantD(SFTPD)has
recentlybeenshowntobeanotherligandforthisimmuneinhibitory Integrinα1β1
receptor(Abbonanteetal.,2013;OldeNordkampetal.,2014). Integrinα1β1(theα1subunitisalsoknownasverylateantigen-1,
OSCAR is present on osteoclasts, where it co-stimulates VLA-1,CD49a;genenameITGA1)iswidelyexpressedbothoncells
osteoclastogenesis with receptor activator of NF-κB (RANK) thatareincontactwithbasementmembranes(e.g.vascular,visceral
(Barrowetal.,2011),anditsabsenceonbonemarrowmacrophages and smooth muscle cells, pericytes and endothelial cells) and on
leadstoosteoclastdifferentiationdefects.Thisreceptorhasalsobeen connective tissue cells, such as fibroblasts, chondrocytes and
showntohavearoleinthematurationofhumanmonocyte-derived mesenchymalstemcells,aswellasalsooncirculatingwhiteblood
dendritic cells (Schultz et al., 2015). The protein surfactant D has cells(Gardner,2014;Gardneretal.,1996).Insomecelltypes,suchas
recentlybeenshowntobeanOSCARligand(Barrowetal.,2015). hepatocytes, α1β1 constitutes the only collagen-binding integrin
DDRsaretyrosinekinasesthatareactivatedbycollagens(Vogel receptorpresent(Gullbergetal.,1990).
et al., 1997); they have been found to be important in bone Ligandsforα1β1includecollagensI,III,IV,IX,XIII,XVIand
(Labrador et al., 2001) and mammary gland development (Vogel the collagen IV chain-derived peptide arresten (Gardner, 2014;
etal.,2001).DDRshaverecentlybeenshowntobeabletoactivate Hamaiaetal.,2012;Nykvistetal.,2000)butthisintegrinprefersthe
collagen-binding integrins (Abbonante et al., 2013; Staudinger non-fibrillarcollagen IV to collagen I (Eble et al., 1993). In vitro
etal.,2013;Xuetal.,2012). studies have, furthermore, suggested that α1β1 prefers the
GPR56 is present on meningeal fibroblasts, oligodendrocytes, monomeric form of collagen I to the fibrillar forms that are
melanoma cells and cytotoxic NK and T lymphocytes (Chiang present in mature connective tissues (Jokinen et al., 2004). It is
etal.,2011;Pengetal.,2011;YangandXu,2012).HumanGPR56 possible that contacts with mature fibrillarcollagen I matrices are
mutationscauseabrainmalformationcalledbilateralfrontoparietal enabled through binding to fibril associated collagens with
polymicrogyria (Chiang et al., 2011). Interestingly, the observed interrupted triple helices (FACIT) collagens, such as collagen
brain phenotype of GPR56-deficient mice appears to be XVI(Ebleetal.,2006).Variouslamininisoformsalsoserveasgood
phenocopied in the brains of collagen-III-deficient mice and is ligandsforα1β1(Barczyketal.,2010).
e
further enhanced by integrin α3β1 deficiency (Jeong et al., 2013; Ithasbeensuggestedthatα1β1activatestheadaptorproteinShc c
n
Luoetal.,2012).Morerecently,ablationofGPR56haspointedtoa independentlyoffocaladhesionkinase(FAK)(Waryetal.,1996) e
cell-autonomous function in oligodendrocyte development (Giera butlaterdata,includingsignalingdatain3Denvironments,didnot ci
S
et al., 2015). GPR56 also binds to other ligands, including tissue includeanyroleforShcbindinginα1β1-mediatedERKsignaling.
l
transglutaminase2(Yangetal.,2014). Thebindingofα1β1toligandresultsinreducedcollagensynthesis el
C
andreducedsynthesisofmatrixmetalloprotease(MMP)(Jablonski
f
Directbindingtocollagens:thecollagen-bindingintegrin etal.,2014;Ronzier̀eetal.,2005).Thecytoplasmictailofα1isthe o
receptors shortest of all integrin tails and it is interesting to note that this al
Thecollagen-bindingintegrinsaremembersoftheβ1integrin(also integrinuseselaborateinteractionswithgrowthfactorreceptorsto n
r
knownasCD29)subfamily.Thecollagenreceptorsα1β1andα2β1 mediatesomeofitseffects(Chenetal.,2007;Mattilaetal.,2008, u
o
werefirstidentifiedinthemid-1980sonsubsetsofactivatedT-cells 2005)(discussedbelow). J
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COMMENTARY JournalofCellScience(2016)129,653-664doi:10.1242/jcs.180992
Despite the prominent expression of integrin α1 in multiple to exacerbate glomerulosclerosis after glomerular injury by a
tissues, the phenotype of α1-deficient mice is relatively subtle mechanism that involves increased production of reactive oxygen
(Gardneretal.,1996;Zemmyoetal.,2003).Invitrostudiessuggest species (Chen et al., 2004) (Table 1). Integrin α1β1 reduces the
that this integrin can negatively regulate collagen synthesis but, production of reactive oxygen species by downregulating the
because it also regulates collagen-degrading MMPs, a fibrotic activation state of the profibrotic epidermal growth factor (EGF)
phenotypeintheskinofα1−/−miceisonlymanifestedwhenthese receptor. This is achieved by controlling the level and
are crossed with mice that express collagen I with a mutated phosphorylationstateofcaveolin-1,ascaffoldingproteininvolved
collagenase cleavage site (Gardner et al., 1999). Although α1- in receptor signaling and localization (Borza et al., 2010; Chen
deficient mice are normal in appearance, careful studies of this et al., 2007, 2010). In a mouse model for Alport syndrome
knockout strain by using a variety of challenging protocols have (COL4A3−/− mice), α1β1-mediated transmigration of monocytes
suggested amodulatory function for α1β1 in a numberof tissues, oncollagenXIIIthatisproducedbyvascularendothelialcellshas
includingthekidney,theimmuneandmusculoskeletalsystemand, been described (Dennis et al., 2010). It has recently been
mostrecently,theliver(seebelow). demonstrated that integrin α1β1 negatively regulates unilateral
At the molecular level, a role for α1β1 in maintaining kidney ureteral obstruction-mediated tubulointerstitial fibrosis through a
homeostasishasbeendemonstrated(Cosgroveetal.,2008;Moeckel mechanism that involves the T-cell protein tyrosine phosphatase
etal.,2006;Zentetal.,2006)andtheabsenceofα1hasbeenfound (TCPTP)-mediated downregulation of tyrosine phosphorylation
Table1.Summaryoftherolesofcollagen-bindingintegrinsinfibrosis,inflammationandcancer
Woundhealingin Fibrosisinknockout Inflammationinknockout Cancerinknockout
Integrin Knockoutphenotype knockoutmodels models models models
α1β1 Hypocellularskin Normal(Gardner Increased Reducedsizeof Reduced
(Gardneretal.,1996; etal.,1999). experimental atheroscleroticplaques experimentaltumor
Pozzietal.,1998). kidneyfibrosis ofmorefibrotic angiogenesisin
Age-related (Chenetal.,2004). composition(Schapira breastcancer
osteoarthritis(Parekh etal.,2005). (Pozzietal.,2000).
etal.,2014;Zemmyo Reducedexperimental Reduced
etal.,2003). arthritis,reduced experimental
contacthypersensitivity tumorigenesisin
(deFougerollesetal., lungcancermodels
2000;Ianaroetal., (Chenetal.,2005;
2000),reducedDSS Macias-Perezetal.,
colitis(Krieglsteinetal., 2008).
2002).
α2β1 Transientmammary Increased Reduced Reducedexperimental Increasedbreast
glanddevelopmental neoangiogenesis experimental arthritis(Petersetal., cancermetastasis
defect(Chenetal., (Grenacheetal., kidneyfibrosis 2012),reducedDSS intheMMTV-neu
2002;Holtkotteretal., 2007;Zweers (Borzaetal.,2012; colitis(Gillbergetal., model(Ramirez
2002) etal.,2007). Rubeletal.,2014). 2013;Lundbergetal., etal.,2011).
Delayedage-induced 2006),reducedbone
osteoporosis(Stange loss(ElAzreqetal.,
etal.,2013). 2015),reduced
Mildthrombusstability inflammatoryresponse
defect(Heetal.,2003; ofmastcells(Edelson
Kuijpersetal.,2007). etal.,2004),increased
vascularizationand
reducedinsulin
resistanceindiabetes
model(Kangetal.,
2011).
α10β1 Mildcartilagephenotype ND ND ND ND
inmice(Bengtsson
etal.,2005);
chondrodysplasiain e
c
dogs(Kyöstiläetal., n
2013). e
i
c
S
l
α11β1 Defectiveincisortooth Reducedgranulation Reducedfibrosisina ND Reduced el
eruption,dwarfed tissue,reduced diabetes-induced experimental C
mice(Popovaetal., woundstrength cardiacfibrosis NSCLCgrowthand f
o
2007a).Human (Schulzetal., model(C.A. metastasis(Navab
l
patientscanliveinto 2015). McCulloch*, etal.,2015;Zhu a
n
theireighties(Sulem personal etal.,2007).
r
etal.,2015). communication). u
o
ND,notdetermined. *,ChristopherA.McCulloch,MatrixDynamicsGroup,UniversityofToronto,Toronto,Ontario,Canada. J
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COMMENTARY JournalofCellScience(2016)129,653-664doi:10.1242/jcs.180992
levelswithinthecytoplasmictailofTβRII,avariantofthetypeII platelets (Madamanchi et al., 2014b). Ligands for α2β1 include
TGF-βreceptor,andresultsin dampening oftheSmad-dependent collagensI,III,IV,VandXI,aswellascollagensXVIandXXIII
profibrotic signaling in collecting-duct-derived cells (Chen et al., (Jokinen et al., 2004; Kapyla et al., 2004; Kern et al., 1993). In
2014). This phosphatase-dependent mechanism builds on a additiontoitscollagenligands,italsobindsproteoglycans,suchas
principle that is similar to the one first observed in the elegant lumican(Zeltzetal.,2010)anddecorin(Fiedleretal.,2008)atsites
original work by Mattila and colleagues, who described an α1β1- distinct from the collagen-binding site present in the integrin αI
dependenteffect on EGF receptor signaling (Mattila etal., 2005). domain.Aproteolyticfragmentderivedfromperlecan(alsoknownas
As mentioned above, integrin α1β1 is expressed in chondrocytes HSPG2), called endorepellin, also binds α2β1 (Bix et al., 2004;
and osteogenic cells. Reduced callus size and reduced cartilage Woodall et al., 2008). Although α2β1 is abundantly expressed on
production have been observed in bone fracture healing cells that are in contact with basement membranes, its affinity for
experiments, and it has been suggested that these effects correlate collagenIVislowerthanthatobservedforcollagenI(Heino,2000;
withaproliferationdefectwithinmesenchymalprecursorcellsthat Käpylä et al., 2000). The ligand-binding I-domain of α2 has been
occursintheabsenceofα1β1(Ekholmetal.,2002).Independent crystalized together with a triple-helical peptide containing the
experiments have later demonstrated that osteoarthritis is GFOGERsequence(Emsleyetal.,2000).Unlikewhatisthecasefor
acceleratedintheabsenceofα1(Zemmyoetal.,2003).α1β1was fibronectin matrices where the cell-binding site is exposed when
firstdetectedonT-cells(asVLA-1),andexperimentswithintegrin fibronectiniscoatedtoastiffsurface,thecell-bindingsiteappearsto
α1−/−micesuggestedthatlackofα1attenuatesinflammatorybowel beavailabletocellswithoutanyneedforconformationalchangeof
disease (Krieglstein et al., 2002) and contact hypersensitivity thecollagen(Seongetal.,2013).Itisinterestingtonoteinthiscontext
(Suzukietal.,2007).Pharmacologicalprogressinblockingintegrin thatbindingofα2β1toGFOGER-likemotifsofcollagenIcanoccur
α1 on human immune cells to reduce inflammation has, without the need for inside-out signaling (Nissinen et al., 2012;
nevertheless, been slow, although anti-VLA-1 antibody treatment Siljanderetal.,2004)(Box1).Analysesofsignalingpathwaysthatare
has been suggested to be beneficial to treat inflammatory activated in fibroblasts within 3D collagen matrices have
conditions,suchasrheumatoidarthritisandpsoriasis,thatinvolve demonstrated α2β1-dependent activation of p38α MAP kinase
localizedpathologicalmemoryT-cells,(Gardner,2014).Arolefor (MAPK14) signaling and stimulatory effects on collagen synthesis
α1β1inliverhasrecentlybeendiscovered,almost20yearsafterthe (Ivaskaetal.,1999;Ravantietal.,1999).
original integrin α1−/− mouse strain was created, and recent data Integrinα2β1isalsowidelyandabundantlyexpressedonspecific
show that severity of obesity-induced fatty liver disease is celltypessuchaskeratinocytes,andisthoughttobethemaincollagen
attenuated in integrin α1−/− mice (Williams et al., 2015). receptoronseveralepitheliaandplateletcells.Unchallengedintegrin
Although α1β1 is the only collagen receptor on hepatocytes α2−/− mice appear to be largely normal but display a mild and
(Gullberg et al., 1990), it does not seem to be involved in liver transientdefectinmammaryglandbranching(Grenacheetal.,2007;
fibrosis. Instead, αvβ1 appears to play a role in liver through Zweersetal.,2007).Despitealargebodyofdatafromα2β1antibody-
mechanismsthatinvolveactivationofTGF-β;ahypothesisderived blocking experiments in various platelet assays and the reduced
from experiments conditionally deleting integrins from liver platelet response to collagen I observed in vitro, only a limited
myofibroblasts (differentiated from the pericyte-like stellate cells) hemostaticdefecthasbeenobservedinvivothatislargelyrestrictedto
(Hendersonetal.,2013;Reedet al.,2015). anaccessoryroleinthrombusstabilization(Heetal.,2003;Kuijpers
Inatumorcontext,ablationofintegrinα1hasbeen reportedto etal.,2007).Interestingly,inrecentstudiestheselectiveα2deletionin
attenuatetumorgrowthinabreastcancermodelowingtotheMMP- megakaryocyteshasbeenfoundtoresultinreducedmegakaryocyte
9-dependentgenerationofangiostatin(Pozzietal.,2000),resulting differentiationandreducedplateletvolume(Habartetal.,2013).It,
inreducedangiogenesis(Fig.2).Furthermore,theabsenceofα1has thus,appearsthatwearefarfromunderstandingthefullrepertoireof
beenfoundtoameliorateorreducetumorgrowthandmetastasisina α2β1functionsonplatelets;thesemightonlyemergeintheyearsto
number of lung cancer models (Chen et al., 2005; Macias-Perez come,asnewandrefinedcell-specificgenetictoolsbecomeavailable.
etal.,2008).Carefulinvestigationoftheroleofα1inthecolonhas Asinthecaseofα1integrin,extensivestudiesofintegrinα2−/−mice
revealedthatitisexpressedonbothepithelialcellsandsubmucosal invariouschallengeexperimentsordiseasemodelshaverevealeda
myofibroblasts (Boudjadi et al., 2013, 2015). Interestingly, numberofphenotypes(Table1). Inviewofitshighexpression on
increased levels of α1 in tumors can be found in the majority of keratinocytesanditsidentificationondermalfibroblasts,thefinding
colon cancer patients (Boudjadi et al., 2013), and it has recently that α2β1 was not involved in keratinocyte migration or dermal
been demonstrated that α1 expression is mediated by the fibroblastwoundclosureinvivowassurprising(Parks,2007),even
transcription factor Myc, raising the possibility that α1 integrin is though increased neoangiogenesis was observed during wound
importantinmediatingtheeffectsofMycincoloncancerandother healing(Grenacheetal.,2007;Zweersetal.,2007).Inamorerecent
tumors(Boudjadietal.,2015).Onlylimitedinformationexistswith study,reducedpathologicalneovascularizationinintegrinα2−/−mice
regard to theexpressionof α1in the tumor stroma,except for the wasobservedinamodelforretinopathy(Madamanchietal.,2014a).
e
above-mentionedroleintumorangiogenesis(Pozzietal.,2000)and Theabsenceofα2isknowntodelayfibrosisandglomerulardamage c
n
the expression of cancer-associated fibroblasts (CAFs) in colon in experimental kidney disease models, including the Alport e
i
cancer(Boudjadietal.,2013;Rodriguezetal.,2009). syndrome mouse model (Borza et al., 2012; Rubel et al., 2014). c
S
Moreover,anothermorerecentstudyhasdemonstratedaroleforα2β1 l
l
Integrinα2β1 in inflammation during rheumatoid arthritis, with reduced disease e
C
Theα2β1integrin(theα2subunitisalsoknownasVLA-2,CD49b; severity in integrin α2−/− mice (El Azreq et al., 2015). Somewhat
f
genenameITGA2)iswidelyexpressedbothoncellsincontactwith surprisingly,thisprotectiveeffectwasnotduetotheabsenceofα2on o
basement membranes (keratinocytes, epithelial cells, endothelial immunecellsasreportedinapreviousstudy(Gillbergetal.,2013). al
cells) and on cells that contact interstitial collagen-I-rich matrices, Thefindingofreducedlevelsofα2β1insynoviocytesintwomouse n
r
suchasfibroblasts,T-cells,myeloidcellsandmegakaryocytesand/or models of arthritis, which results in decreased ERK activation and u
o
platelets.Itis,infact,theonlycollagen-bindingintegrinexpressedon MMP-3 production, was thought to have caused the reduction of J
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A α–/– fibroblast α+/+ fibroblast C Mesenchymal-like
tumor cell Invasion
7
Impaired RhoC
3
matrix
reorganization α11β1 α2β1 α11β1
2
9
JNXK Smads Smads JNK 4 Cmoaltlraixgen ‘Trailblazer’ cell
remodeling
Cdc42
Invasion
α2β1 8
1
D
Tumor cell
B
CAF
α2β1
α1β1 α11β1
10?
α2β1 EMT
5 ? 6
α11β1
CXCL5 Myoblast
differentiation ? 11
Tumor cell Migration
Mesenchymal-like
tumor cell
E
Growth
12 Tumor cell
Key
CAF
Collagen I
Organized Tumor cell α1β1 α2β1
collagen I Endothelial cell
Basement
Mesenchymal-
membrane 14
like tumor cell
Angiogenesis α-SMA Angiogenesis Intravasation
Integrin α1β1 TGF-β receptor
Integrin α2β1 TGF-β1 AngioMstMatPin-913 α1β1
Integrin α11β1 Inhibition
Fig.2.Rolesofcollagen-bindingintegrinsincancer.(A)Integrinα11β1incollagenreorganization.α11β1promotescollagenremodeling,whereasα11
deficiencyleadstoimpairedmatrixreorganization(Schultzetal.,2015).(1)BindingofTGF-βtoitsreceptor,inducesα-SMAexpressionand(2)upregulatesα11
expressionthroughSmadsignaling.(3)α11isnecessarytostabilizeα-SMAproteinexpression.(4)α11β1integrinreorganizescollagenmatricesthroughTGF-β-
inducedJNKsignaling.(B)Collagen-bindingintegrinsintumor–stromainteraction.(5)α1β1andα2β1areexpressedoncancer-associatedfibroblasts(CAF),but
howthisaffectstumorcellsisso-farunclear.However,(6)α11β1onfibroblastscanmodulateautocrinesecretionofCXCL5inlungadenocarcinomacellsto
promotetumorcellmigration(Luetal.,2014).(C)Collagen-bindingintegrinsintumorinvasion.(7)α2β1promotesprostatecancerinvasionthroughRhoC
activation(Halletal.,2008).α11β1isoneofthesevengenesidentifiedasasignatureforthe‘trailblazer’cellphenotype(Westcottetal.,2015).(8)Trailblazercells
leadcollectiveinvasionandgeneratepathwayswithincollagenmatricesthatalsoallowopportunistfollowercellstoinvade.(9)α11β1andCdc42arebothinvolved
intheformationofthelongcellprotrusionsneededforinvasion.(D)Collagen-bindingintegrinsinepithelial-to-mesenchymaltransition(EMT).(10)Collagen-
bindingintegrinsdonotappeartohaveamajorroleinEMT.(11)Becauseα11β1isexpressedonmesenchymal-liketumorcells,itmighthavearolein e
c
myofibroblastdifferentiationofmesenchymal-liketumorcells.(E)Collagen-bindingintegrinsinangiogenesis.(12)α1β1isexpressedontumorcells,and n
promotestumorgrowthandmetastasis(Chenetal.,2005).(13)α1β1isalsoexpressedonendothelialcells,whereitpromotesangiogenesis(Pozzietal.,2000), e
i
anddownregulateslevelsofactiveMMP-9,whichsuppressestheproductionoftheangiogenesisinhibitorangiostatin.Bycontrast,(14)thepresenceofα2β1on c
S
tumorcellsinhibitstumorcellintravasationduringthemetastaticprocess(Ramirezetal.,2011).
l
l
e
C
pannus formation and cartilage erosion observed in α2−/− mice thatα2β1cooperateswiththeinterleukin7(IL-7)receptoronTh17
f
(Peters et al., 2012). Studies of aging bone and cartilage further cellstomediateboneloss(ElAzreqetal.,2015).Polymorphismsin o
revealeddefectsinbonecollagendynamicsanddelayedage-induced the coding region of the α2 gene ITGA2 have been observed to al
osteoporosisinα2-deficientmice(Petersetal.,2012;Stangeetal., regulate α2 levels on human platelets (Kuncki and Nugent, 2010); n
r
2013). Three decades after identification of the cell surface protein andallelesencodingthesevariantswerefoundinaseparatestudyto u
o
VLA-2onT-cells(Hemleretal.,1985b),arecentstudy demonstrated be associated with an increased risk of thrombosis and myocardial J
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COMMENTARY JournalofCellScience(2016)129,653-664doi:10.1242/jcs.180992
theendosteumandperiosteum(Camperetal.,2001;Gullbergand
Box1.Modesofbi-directionalintegrinsignaling Lundgren-Åkerlund,2002;Lundgren-ÅkerlundandAszòdi,2014;
Outside-insignaling.Bindingofintegrintoligandleadingtoachemical Popovetal.,2011).Interestingly,theareaaroundformingboneis
signal being transmitted into the cell. This occurs by association of rich in mesenchymal stem cells, and the treatment of these with
integrins with adapter proteins and soluble kinases and connect fibroblastgrowthfactor2(FGF2)concomitantlyinducesexpression
integrins, which themselves lack enzymatic activity, to signaling ofintegrinα10andthatofachondrogenicphenotype(Varasetal.,
patwhays(Hynes,2002). 2007).Furthermore,ITGA10mRNAexpressionisinducedinbone-
Inside-outsignaling.Conformationchangeinextracellulardomainof
marrow-derived mesenchymal stem cells because these cells
integrin,regulatingaffinityforextracellularligand.Thisoccursasaresult
ofseparationofcytoplasmicintegrintailswhichinturntakesplaceasa form the chondrogenic niches that are needed to establish a bone
response to intracellularevents leading to binding of the cytoskeletal marrow microenvironment (Reinisch et al., 2015). Thus, several
proteins talin and kindlin to cytoplasmic tail of integrin β subunit independentstudiessupportaroleforα10integrinasabiomarkerof
(HarburgerandCalderwood,2009). chondrogenicstemcells(Lundgren-ÅkerlundandAszòdi,2014).
Micethataredeficientinintegrinα10haveamildcartilagedefect
(Bengtssonetal.,2005)and,morerecently,theanalysisofinbred
infarction (Santoso et al., 1999). The meaning of these findings is dog strains that present a truncating mutation in ITGA10 has
unclearbuttheyindicatethattherelativeimportanceofintegrinα2in demonstrated full-blown canine chondrodysplasia (Kyöstilä et al.,
humansisdifferentfromthatinmice.Asα2β1iswidelyexpressed,it 2013)(Table1).Itisinterestingtonotethatmutationsingenesthat
could be argued that it will never constitute a feasible therapeutic encodecomponentsofthemusculoskeletalsystemsometimesyield
target, on account of potential side effects. However, studies mildphenotypesinmice–whichareshort-livedandsmall,whereas,
of integrin α2−/− mice suggest that α2 can be a target without inlargeranimals,withalongerlife-span,thesamemutationsmay
significant side effects. Indeed, clinical trials in which antibodies havemoresevereconsequences.
against α2 were used to treat Crohn’s disease and chronic Chondrosarcomacellsexpressα10β1,butitspossibleroleinthis
autoimmune disorders are underway (http://newdrugapprovals.org/ formoftumorhasnotbeenassessed(Kapylaetal.,2004).Ligand-
category/glenmark). bindingstudieshavesuggestedthatα10β1onchondrosarcomacells
Theroleofα2intumorigenesisisdifficulttodissectbecauseof can bind collagen IX as well as collagen II (Kapyla et al., 2004).
its wide expression. Comparing the experimental tumor datawith Meanwhile, based on observations of fluctuating ITGA10 RNA
humanclinicaldata,highexpressionofα2inbothbreastcancerand levelsandfollowingmeasurementsofITGA10promoteractivity,it
prostate cancer appears to correlate with a favorable prognosis has been suggested that retinoblastoma protein (pRB) drives
(Ramirez et al., 2011); this is supported by MMTV-neu mice ITGA10 expression and that the reduced levels of integrin α10
deficientinintegrinα2,inwhichincreasedtumorcellintravasation proteinincasesofosteosarcomadependonthepresenceofmutant
wasobserved,suggestingthatα2servesasametastasissuppressor pRB(Engeletal.,2013).
(Ramirez et al., 2011) (Fig. 2). Intriguingly, α2 expression in Perhapsmoresurprisingisthefindingthatthelargelycartilage-
xenograftmodelswithprostatetumorcellscandrivemetastasesto specificintegrinα10isexpressedinmelanomacells.Furthermore,
the bone, suggesting that the expression and functioning of α2 in vitro analyses have suggested a role for α10 in melanoma
integrin on tumor cells is dynamic (Hall et al., 2006). High cell migration (Wenke et al., 2007). Since collagen II is not
expression of α2 in a well-differentiated tumor may well prevent expressed in the dermis, this points to the existence of another
metastasis,whereaslowexpressionatcertainstagescouldpromote collagen ligand for α10β1 in melanoma cells. One interesting
dedifferentiation and metastasis. At other stages, however, high candidateiscollagenVI,whichhasrecently beenshowntoaffect
expression on metastasizing cells could direct these cells to hairgrowthinwoundedskin(Chenetal.,2015).Singlenucleotide
collagen-rich tissues, such as bone (Hall et al., 2006). α2β1 is polymorphism (SNP) analysis has revealed an ITGA10 SNP
knowntoaffecttumorgrowthandmetastasisinamousemodelof signature associated with favorable outcome for melanoma
squamouscarcinoma(Tranetal.,2011),andhighα2β1expression disease(Lencietal.,2012).
has been reported to accelerate experimental metastasis in
melanoma and gastric and colon cancer (Baronas-Lowell et al., Integrinα11β1
2004;Bartoloméetal.,2014;Matsuokaetal.,2000).Clinicaltrials Expression of integrin α11β1 (gene name ITGA11) is primarily
areinprogressfortreatingmetastaticcoloncancerbyusingasmall- restrictedinvivotosubsetsoffibroblastsandtomesenchymalstem
moleculeinhibitorofα2β1,thesulphonamideE7820,(Mitaetal., cells(MSCs).Transientexpressionofα11inodontoblastshasalso
2011). been observed (Popova et al., 2007a, 2004; Tiger et al., 2001;
In summary, the role of α2 in tumorigenesis and metastasis Velling et al., 1999); whereas, in bone marrow-derived non-
appearstovarydependingonintegrinα2expressionlevelsandtype haematopoeticMSCs,α11wasreportedtobeexpressedonasmall
oftumor.Itsroleinthetumorstromahasnotbeenexploredindetail sub-fraction of cells able to undergo osteogenic differentiation
e
butα2β1onfibroblastscouldpotentiallyactinordertoreorganize (Kaltzetal.,2010).Morenotably,however,thesub-fractionofstem c
n
thecollagenmatrixandalteritsstiffness–ashasbeenobservedfor cellsthatundergoadipogenicdifferentiationdonotexpressα11.In e
lysyloxidase(LOX)(Leventaletal.,2009)andα11β1(Navabetal., aseparatestudy,ithasbeenreportedthatMSCsdependonbothα2 ci
S
2015)inexperimentaltumormodels.Toclarifytheroleofα2inthe andα11forosteogenicdifferentiation(Popovetal.,2011),andthat l
tumormicroenvironmentitwillbenecessarytoconditionallydelete knockdown of ITGA2 and ITGA11 in human mesenchymal stem el
C
α2onvariouscellpopulationswithinthetumorstroma. cellsreducesERKandAktsignaling,andresultsindecreasedcell
f
proliferation and increased apoptosis (Popov et al., 2011). Mice o
Integrinα10β1 deficientinα11aredwarfedduetoanincisortootheruptiondefect al
Integrin α10β1 (gene name ITGA10) appears to be primarily (Popova et al., 2007a), and an analysis of periodontal ligament n
r
expressed in vivo on chondrocytes but also on some junctional fibroblasts isolated from their incisors demonstrated that reduced u
o
fibroblasts,chondrogenicmesenchymalstemcellsandcellslining levels of MMP-13 and cathepsin K contributed to their reduced J
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COMMENTARY JournalofCellScience(2016)129,653-664doi:10.1242/jcs.180992
capacityofcollagenremodeling(Barczyketal.,2013).Theroleof et al., 2002). Using representational difference analysis, they
α11 in inflammatory conditions has not been tested directly but, showed that its gene ITGA11 is overexpressed in lung
recent findings that citrullination of the cell-adhesive GFOGER adenocarcinoma as compared with healthy lung tissue. Later, it
sequence within collagen selectively affects collagen binding becameclearthatα11β1isessentiallyoverexpressedinthestroma
mediated by α10β1 and, even more efficiently, α11β1 integrin of NSCLC, especially in CAFs (Navab et al., 2011; Zhu et al.,
(Sipiläetal.,2014),havespurredspeculationsthatdefectiveα11β1- 2007). A role for α11β1 in tumorigenesis has been indicated in
mediatedinteractionofsynovialcellswithcollagenmightinfluence xenograft experiments where the mixing of tumorcells with α11-
thepathologicalprocessinvolvedinrheumatoidarthritis(Zeltzand expressing fibroblasts was shown to stimulate tumor growth. In a
Gullberg,2014).Thisisaninterestingpossibilitythatremainstobe differentmodel,involving3DheterospheroidscomposedofMEFs
tested. and lung carcinoma cells, a downregulation of the chemokine
The first indication that α11β1 is involved in dermal wound CXCL5 within the tumor cells in the absence of α11 has been
healingwastheobservationthatα11integrinisstronglyinduced observed,suggestingthatα11-expressingfibroblastsstimulatesthe
in mice 7 days after inflicting excisional wounds (Zweers et al., autocrine secretion of CXCL5 in NSCLC cells (Lu et al., 2014)
2007). Thecontribution of α11β1 towound healing has recently (Fig. 2). However, this is not the only role of α11β1 in
beendeterminedbyusingα11-deficientmice(Schulzetal.,2015) tumorigenesis – as indicated by our recent study that emphasizes
inwhichdermalwoundsdisplayreducedgranulationtissue7days the ability of α11β1 to remodel collagen matrices during wound
after excision due to a defect in myofibroblast differentiation healing (Schulz et al., 2015). In the heterospheroid model,
(Table 1). This finding is in agreement with a previous study in fibroblasts synthesize collagen I independently of α11 but, only
which α11β1 was shown to contribute to TGF-β-induced α11-expressing fibroblasts are able to induce contraction of the
myofibroblast differentiation in vitro (Carracedo et al., 2010). collagen matrix. This reorganization of the matrix resulted in an
Integrinα11β1isalsoimportantforthequalityofthescartissue increase in interstitial fluid pressure (Lu et al., 2014), forming a
because α11−/− wounds display less tensile strength. This is barriertodrugdelivery.Inanotherrecentstudy,aNSCLCxenograft
indicativeofanimportantroleforα11β1incollagenremodeling model has been described, in which α11β1-promoted collagen
within granulation tissue. Despite the already described role of remodeling, and a correlation between tumor tissue stiffness and
α2β1incollagenreorganizationinvitro(Zhangetal.,2006)and α11expressionwasobserved(Navabetal.,2015).Here,areduced
its expression on mouse dermal fibroblasts, α11β1 appearsto be activationofFAKandERKintumorsgrownwithinα11-deficient
the main collagen receptoron dermal fibroblasts and contributes mice was also noted. An analysis of possible genes involved in
to early collagen remodeling in a TGF-β-dependent manner regulatingtissuestiffnessdirectlyorindirectlyrevealedacorrelation
(Schulz et al., 2015) (Fig. 2). It is interesting, in this context, to between stromal α11 expression and LOXL1, an elastin and
note that, although TGF-β1 is known to regulate α11 integrin collagen cross-linking enzyme (Navab et al., 2015). As α11 is
through Smad signaling (Lu et al., 2010), the involvement of selectively expressed on fibroblasts, it is not surprising that its
non-canonical Jun N-terminal kinase (JNK)-dependent TGF-β mRNAisup-regulatedbyEMT-likeeventsinvarioustumormodels
signalingwasshowntobecrucialforα11β1-dependentcollagen (Fernandoetal.,2010;Keetal.,2008).Sofar,thisinductionofα11
remodeling. Further studies are needed to determine the link mRNAhasnotbeenconfirmedtotranslatetotheproteinlevel,and
between α11β1 and JNK activation. In this respect, TGF-β- it is thus not yet known whether α11β1 affects the EMT process
activated kinase 1 (TAK1) is an interesting candidate, as it is (Fig.2).Recently,however,ITGA11wasidentifiedasaninvasion-
requiredforJNKsignalingandcanbeactivatedbytumornecrosis promoting gene within a seven-gene signature that had been
factor(TNF)receptor-associatedfactor6(TRAF6)atthelevelof establishedfortheleadinginvasive‘trailblazer’cellsinaspheroid-
TGF-βreceptortypeI(Muetal.,2012).Furthermore,TRAF6has basedmodelforcollectiveinvasionofbreastcancercells(Westcott
recently been shown to interact with the β1 subunit of α3β1 etal.,2015).Thesedataindicatethattheroleofα11intumorsisnot
integrin(Yazlovitskayaetal.,2015). restrictedtoCAFsbutcouldalsoextendtotumorcellsthatassumea
Theroleofα11β1inskinfibrosisiscurrentlyunknownbutithas mesenchymal invasive phenotype (Fig. 2). The roles of the
beenshowntohaveapro-fibroticroleindiabeticcardiomyopathy, individual collagen-binding integrins in wound healing, fibrosis
aconditioninwhichhighlevelsofglucoseleadtotheglycationof andtumorsaresummarizedinTable1.
collagen,resultinginheartfibrosis.Inanexperimentalratmodelof
diabeticcardiomyopathy,theinteractionofcardiacfibroblastswith Thereceptor-ligandparadox:collagen-bindingintegrins–
glycated collagen through α11β1 increased TGF-β2 expression, receptorsinsearchofafunction?
whichinturninducedtheexpressionofalpha-smoothmuscleactin We now have substantial detailed and data on the structure and
(α-SMA)(Talior-Volodarskyetal.,2012).Interestingly,glycation functionofintegrins,theirmechanismofactivationandtheirroles
appears to interfere with α11β1-mediated adhesion to collagen, indifferentbiologicalprocessesbut–asoutlinedabove–inthefield
while still stimulating myofibroblast differentiation (Talior- of cell-collagen adhesion, one paradox remains: why are
e
Volodarsky et al., 2015). The increased level of α11 under these phenotypesofindividualorganismsthatlackcertaincollagensnot c
n
conditions has been interpreted as an attempt by the cells to phenocopied when the corresponding collagen receptors are e
compensateforreducedadhesion.Inthediabetesmodels,TGF-β2 defective(Zeltzetal.,2014)? ci
S
isresponsiblefortheincreasedexpressionofα11β1thatisinduced Thetraitthatdistinguishescollagensfromothermatrixligandsis, l
bythebindingofSmad3toasitewithintheITGA11promoterthatis of course, that collagens are the most abundant proteins in the el
C
distinctfromthesitethathaspreviouslybeendescribedtomediate vertebrate body and that they assume a central structural role in
f
TGF-β1-stimulatedgeneexpressionofα11(Luetal.,2010;Talior- forming the framework for connective tissues. This poses an o
Volodarskyetal.,2015). enormouschallengewhentryingtoanalysethefunctionsofthe28 al
One important role for α11β1 in tumorigenesis was first members of the collagen family that depend on collagen-binding n
r
suggested in 2002, when Wang et al. identified this integrin as a cell-surfacereceptors.Someoftherelevantissueswhenconsidering u
o
new biomarker for non-small-cell lung cancer (NSCLC) (Wang why mice deficient in collagen-binding integrins show only mild J
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COMMENTARY JournalofCellScience(2016)129,653-664doi:10.1242/jcs.180992
phenotypes include redundancy, compensation, alternative In view of the restricted distribution of α10β1 in cartilage, it is
attachmentmechanismsandtypeofanimalmodel(seeBox2). possible that reagentsthat stimulate α10β1 have beneficial effects
Taken together, our current knowledge of collagen receptors on cartilage physiology. It should, thus, be possible to conduct
suggests that they have limited roles during static tissue experimentsfocusingonregenerativemedicinethattakeadvantage
homeostasis events but appear to be more important for of the fact that α10β1 identifies chondrogenic mesenchymal stem
dynamic events that occur during tissue damage, regeneration cells to achieve the best result of tissue replacement for relevant
andinflammation. Thisidentifiescollagenreceptors asinteresting groups of patients suffering from osteoarthritis and rheumatoid
biomarkers and prognostic and/or therapeutic disease targets as arthritis.
discussed below.
Collagen-bindingintegrinsinthetumorstroma
Collagen-bindingintegrinsinwoundhealingandtissue The collagen matrices laid down during embryogenesis are, in
regeneration general,thoughttobeaccessibletocells.Asthesematricesmaturein
Therecentfindingthatα11β1 mediatescollagen remodeling inthe theadulttheyarecrosslinkedandmanyoftheinteractionsitesinthe
healing wound has raised a number of questions. Lineage tracing monomeric molecules become occupied by interacting proteins.
studieshaveclearlydemonstratedtheexistenceofdistinctsubsetsof Turnover rates of fibrillar collagens are generally low, with the
cellsinthedermis,suchaspapillary,reticularandadipocyteprecursor periodontal ligament representing an exception (Sodek and Ferrier,
cells(Driskelletal.,2013).Otherexperimentshaveshownthatthe 1988),butthecell–collageninteractionsshowadynamicrelationship
deletionoffibroblaststhatexpressengrailed-1leadstoscarlesswound during tissue regeneration events, such as wound healing, when
healing(Rinkevichetal.,2015).Thus, itisimportantto determine fibroblasts of various origins are recruited and produce a wound
whichsubsetofdermalfibroblastsexpressesα11. matrixthatisrichinfibrillarcollagens(SchäferandWerner,2008).
A fundamental problem in diabetes is ulcer formation and TheseincludecollagentypeIIIwithasmallerfibrildiameterthat,as
delayedwoundhealing(Schultzetal.,2011).Inthiscontext,with the granulation tissue matures, is replaced with collagen I (Merkel
the aim to improve the healing of chronic wounds, it would be etal.,1988).Infibrosis,overproductionoffibrillarcollagencauses
interestingtomodulatecollagen-bindingintegrinactivity. tissue dysfunction, but the role of the fibrillar collagen-rich tumor
stromaisstillamatterfordebate.Experimentaltumormodelssuggest
that fibrillar collagens contribute to tumor growth and metastasis
(Provenzano et al., 2009, 2008; Xiong et al., 2014). Furthermore,
Box2.Hypothesestoexplainweakknockoutphenotypes artificial crosslinking of collagens by overexpression of LOX has
ofcollagen-bindingintegrin beenshowntostimulatetumorgrowthinanartificialbreastcancer
Redundancy within the subfamily of collagen-binding integrins. model (Levental et al., 2009). In numerous models, the rearranged
Thereiscurrentlynogeneticmodelthatallowstoanalyzethedeletionof linearizedcollagenthatisobservedinsometumorsappearstooffer
theentiresubfamilyofcollagen-bindingintegrins.However,thereisno tracksformetastasizingtumorcells,butthepossibleroleofcollagen-
striking overlap of the expression patterns of the collagen-binding
bindingandCOLINBRI-bindingintegrinsintheseprocessesisnot
integrinsas,forexample,inplatelets.Althoughfibroblastsexpressα1β1,
sufficiently well understood to therapeutically target them
α2β1 and α11β1, mice that lack both α2 and α11 show a minimal
(Provenzanoetal.,2006,2009).
additional phenotype when compared with individual knockouts
(Blumbachetal.,2012;Schulzetal.,2015).Thus,thehypothesisthat
collagen-binding integrins have redundant functions is a less likely Concludingremarks
explanationfortheweakphenotypesobserved. On the basis of our current understanding, collagen-binding
Compensation mechanisms. Multiple examples demonstrate that integrins have a modest function with respect to normal tissue
the acute block of protein function by using antibodies (without any homeostasis:α2β1affectsthrombusformation,α10β1appearstobe
opportunityforthecellstocompensate)canhaveeffectsthatdifferfrom important for cartilage formation and α11 for tooth eruption.
thoseseeningeneticknockouts,inwhichthecellororganismhashada
However,underdiseaseconditions,suchasininflammation,tissue
chancetoactivatecompensatorymechanisms.To,morethoroughly,test
the combined roles of α2 and α11 under conditions of minimal regeneration events and tumors, collagen-binding integrins play a
compensation, it would be interesting to conditionally delete α2 and more-prominentrole.
α11inafibroblast-specificmanner.Thecompensationmechanismis, Integrinsα1β1andα2β1mightbeneededforacorrectandinnate
thus, a possible scenario, but one that might be difficult to prove immuneresponseinvariouspopulationsofimmunecells,whereas
experimentally. α10β1andα11β1appeartobecentraltohowconnectivetissuecells
Alternative attachment mechanisms during development.
perform in the musculoskeletal system. Recent data suggest that
Alternative mechanisms of attachment of integrin to collagen exist
α11β1 is a main collagen receptor for collagen remodeling on
duringdevelopment,andreceptorsinvolvedinthisprocesshaveother
rolesthan just the organization of tissue structure. Some of the non- activated fibroblasts in wounds, fibrotic tissues and the tumor
integrinreceptorsmaytakeoverthisfunctionintheabsenceofcollagen- stroma. With the growing realization that fibroblasts and
e
bindingintegrins,althoughourunderstandingoftherolesnon-integrin mesenchymal stem cells are important modulators of tissue c
collagen receptors have as mechanolinks is limited. An attractive regeneration events, integrins α10β1 and α11β1 are promising n
e
hypothesisisthatthefibrilsinmaturecollagenmatricesaresotightly
packedthatthereisonlyalimitedavailabilityofintegrin-bindingsites. molecular targets for modulating regenerative events (wound Sci
healing, cartilage repair), as well as for pathological processes
Thiswouldenabletheanchoringofcellstothecollagenmatricesthrough l
COLINBRI-mediated adhesion (Zeltz et al., 2014) and is a likely (osteoarthritis, fibrosis, tumor spread). Both integrins might be el
C
scenario. excellent biomarkers for chondrocyte-specific and fibroblast-
Choiceofmodelorganism.Themouseisnottheoptimalorganism specificprocesses. of
foranalysingcell–collageninteractionsinthemusculoskeletalsystem,in l
thattheroleofcollagen-bindingintegrinsmightbeunderestimated–as Acknowledgements na
illustratedbytheseverechondrodysplasiaindogswithanα10-truncating WethankMarionKusche-Gullberg(UniversityofBergen)forusefulcommentsand ur
mutation(Kyöstiläetal.,2013). MalcolmHicks(translatorinKuopio,Finland)forhelpwithlanguageeditingwhen o
preparingthismanuscript. J
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COMMENTARY JournalofCellScience(2016)129,653-664doi:10.1242/jcs.180992
Competinginterests Chen,X.,Moeckel,G.,Morrow,J.D.,Cosgrove,D.,Harris,R.C.,Fogo,A.B.,
Theauthorsdeclarenocompetingorfinancialinterests. Zent, R. and Pozzi, A. (2004). Lackof integrin alpha1beta1 leadsto severe
glomerulosclerosisafterglomerularinjury.Am.J.Pathol.165,617-630.
Funding Chen,X.,Su,Y.,Fingleton,B.,Acuff,H.,Matrisian,L.M.,Zent,R.andPozzi,A.
(2005).Anorthotopicmodeloflungcancertoanalyzeprimaryandmetastatic
ThisworkwassupportedbytheEEAgrantPolandNorwayMOMENTO(ID197066),
NSCLCgrowthinintegrinalpha1-nullmice.Clin.Exp.Metastasis22,185-193.
theNorwegianCentreofExcellencegrantResearchCouncilofNorway(ID223250)
Chen,X.,Abair,T.D.,Ibanez,M.R.,Su,Y.,Frey,M.R.,Dise,R.S.,Polk,D.B.,
andtheWesternNorwayRegionalHealthAuthority(ID911899).
Singh,A.B.,Harris,R.C.,Zent,R.etal.(2007).Integrinalpha1beta1controls
reactive oxygen species synthesis by negatively regulating epidermal growth
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