Tendon Homeostasis, Tendinopathy and Healing

Alayna E. Loiselle, PhD CMSR T32 Musculoskeletal Basic Science Course

April 17th, 2017

Outline

•  Overviewoftendonstructure/func1on•  EffectsofAging•  Disrup1onsinhomeostasis•  Pathogenesisoftendinopathy/tendini1s•  Mechanismsofregenera1onandhealing

JOR:NewFron1ersinTendonResearchJune2015

7ReviewAr1cles15PrimaryResearchPapers

TendonStructure&Func1on

Nourissat, G. et al. (2015) Tendon injury: from biology to tendon repair Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2015.26

•  Transmissionofforcesfrommuscletobone

•  Movementofnearlytheen1reskeleton

•  Crimpstructureincreaseselas1city

•  Hierarchicalnatureallowsforceconduc1ondispropor1onatetosize

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FDS

FDL

FDS

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Wongetal.2006.J.Anatomy

Compara1veAnatomy

Hastetal.,2014Bone&Joint

TendonHomeostasisYoung Aged

•  Matrixcomposi1onandorganiza1onisnotdrama1callydifferent•  Decreasedproteoglycancontent•  Changesincellmorphology

Func1onalConsequencesofAging?

Tendonisnotmechanicallysensi1vetoaging

Ackermanetal.,2017.JOR

TTFascicle

FDL

FCU

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SRRaikin.LowerextremityReview.2014

Achillesismostsuscep1ble

Sex-baseddifferences

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CollagenaseInducedTendinopathy

LD=lowdoseHD=highdosecollagenase

Inducesdegenera1vechangesviacollagendegrada1on

OrfeiCetal.(2016)PLOSONE11(8):e0161590.

MechanicallyInducedTendinopathy•  Fa1gueloadedunderanaesthesia•  Uphilltreadmillrunning•  Downhilltreadmillrunning

NeviaserA.2012.JShoulderElbowSurg. NAndarawis-Purietal.,2014.JOR

UnloadedLowlevelloading

Moderateloading

Highlevelloading

Fa1gueLoadingInducesApoptosis

Inducesmatrixandcellularchanges

SummaryofTendinopathy

FutureDirec1ons•  Con1nuetoiden1fyco-morbidi1esthatpredisposeoracceleratetendinopathy•  Mostclinicaldataarefromlatestagepathology

•  Beginningtousegene1canimalsmodelstobelerunderstandtendinopathy

RemodelingBalancePhysiologicalexerciseincreases:prolifera1on

collagenproduc1on tenocy1cgeneexpression(w/ochondro/osteo/adipo)

Overuse/Fa1gue:MatrixDamageTenocyteapoptosis

EffectsofPathologyand/orco-morbidi1es:promotedegenera1on+/-inflamma1on

Smokingobesityhighcholesterol

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Complica1onsofFlexorTendonHealing

CentersforDiseaseControlandPrevention.(2015,January).Strickland,J.W.etal.,JHandSurg[Am]25(2):p.214-235,(2000).Aydin,A.etal.,AOTT28(1):p.54-9,(2004).

Palmarsurfaceofhand

Tendon

Adhesion

Medscape.com

Ø  Flexorandextensortendonsofthehandarethemostcommonlyinjuredtendons

Ø Fibro1cHealing:ExuberantECMdeposi1onalachestendontosynovialsheathandsurrounding1ssues

Ø HealingofflexortendonsiscomplicatedbyROM-limi1ngscarinupto40%ofrepairs

Ø  Oqenrequireasecondarysurgicalproceduretolyseadhesions

Adhesion

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Maximum Load at Failure

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Similari1esbetweenwoundandtendonhealing

AJJomasetal.2014.AdvancedDrugDeliveryReview

Thiruvothetal.2015.Plas1candAesthe1cResearch

Inflamma1on

•  Beginsimmediatelyacerinjury,lastsfor~1week

Well-regulatedinflamma1onisbeneficial-ac1vateshealingcascade

-recruitment/ac1va1onofcellsExcessive/Chronicinflamma1onispathological

-degenera1vematrixchanges-fibro1chealing

Inflamma1on

BenefitsofAn1-inflammatorytherapyiscontroversialTimingmaybekey!

Generallyeffec1veatpreven1ngexcessscarforma1onEarlyinhibi1ondecreasesmechanicsDelayedhealingmaintainsmechanics

Cell-typespecificconsidera1ons

Virchenkoetal.,2004.AmJSportsMed,Gearyetal.2015.PlosOne

Prolifera1ve/Granula1onPhase•  Lastsafewweeks•  Begins~day7inmousemodel•  Prolifera1onof‘fibroblasts’•  Bridgingoninjurysite•  Produc1onofECMcomponents(Col1/Col3)•  Rapiddeposi1onofdisorganizedECM

Day3 Day14PDGFandbFGF:promoteprolifera1on-canalsocauseadhesionsTGFB:Smad3-/-,PAI-1-/-reducesadhesionsS100a4:Abla1onreducesadhesionforma1on

Thomopoulosetal.,2009.JOR,Thomopoulosetal.,2010.JBJS,Katzeletal.2010.JOR,AwadLab,LoiselleLab

RemodelingPhase•  Lastsmanymonths•  Begins~day21inmousemodel•  Reorienta1onofECM•  Mmp-mediatedremodeling

Day21

CellularBasisofHealing

•  Time-dependentdynamiccellularenvironment•  Involvesmul1plecelltypes•  Tenocyteapoptosis•  Extrinsicinflammatorycells•  Residenttenocytes,epitenoncells,sheathcells,tendonbasementmembranecells

•  Bonemarrowderivedcells

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Wheredowegofromhere?

•  Cri1calmassoflabsstudyingcelllineage/fate/func1on

•  Developmentoftendonspecifictools•  Bigdataandsingle-cellRNAseq•  Iden1fica1onofnew‘tendon-specific’markers

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