Tendon Homeostasis, Tendinopathy and Healing

Alayna E. Loiselle, PhD CMSR T32 Musculoskeletal Basic Science Course April 17th, 2017

Outline

• Overview of tendon structure/ funcon • Effects of Aging • Disrupons in homeostasis • Pathogenesis of tendinopathy/ tendinis • Mechanisms of regeneraon and healing

JOR: New Froners in Tendon Research June 2015 7 Review Arcles 15 Primary Research Papers Tendon Structure & Funcon

• Transmission of forces from muscle to bone

• Movement of nearly the enre skeleton

• Crimp structure increases elascity

• Hierarchical nature allows force conducon disproporonate to size

Nourissat, G. et al. (2015) Tendon injury: from biology to tendon repair Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2015.26 3AB'2(0E(3'&40&(

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JW Chen and JL Galloway. Methods in Cell Biology, Volume 138, 2017, 299–320 IJKL'!MN':@-*$:/*')$(9'O:>>(&:<'P:@' Comparave Anatomy FDS

FDL Mouse

Pulleys Sheath FDL Human FDS

Wong et al. 2006. J. Anatomy Hast et al., 2014 Bone & Joint Tendon Homeostasis Young Aged

• Matrix composion and organizaon is not dramacally different • Decreased proteoglycan content • Changes in cell morphology

Funconal Consequences of Aging? Tendon is not mechanically sensive to aging TT Fascicle FDL FCU

Ackerman et al., 2017. JOR 3'&40&(D(>G%&G(

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N/%"#*E/(9' Tendon Rupture Achilles is most suscepble

Sex-based differences

SR Raikin. Lower extremity Review. 2014 j%2/"B#'4(K0@'02#52%2+(K0/@0&5$(LO'6#2(

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LD= low dose HD= high dose collagenase Orfei C et al. (2016) PLOS ONE 11(8): e0161590. Mechanically Induced Tendinopathy Low level Moderate High level • Fague loaded under anaesthesia Unloaded loading loading loading • Uphill treadmill running • Downhill treadmill running

Induces matrix and cellular changes

Fague Loading Induces Apoptosis

Neviaser A. 2012. J Shoulder Elbow Surg. N Andarawis-Puri et al., 2014. JOR Summary of Tendinopathy

Remodeling Balance Physiological exercise increases: proliferaon collagen producon tenocyc gene expression (w/o chondro/ osteo/adipo) Overuse/ Fague: Matrix Damage Tenocyte apoptosis

Effects of Pathology and/ or co-morbidies: promote degeneraon +/- inflammaon Smoking obesity high cholesterol Future Direcons • Connue to idenfy co-morbidies that predispose or accelerate tendinopathy

• Most clinical data are from late stage pathology

• Beginning to use genec animals models to beer understand tendinopathy 3'&40&(K'5$%&G( •! ((nU99X999(#'&40&(/'B5%/(B/06'4"/'2(B'/(A'5/(

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,#'T(+5'IJKVk';#++%-%'IJJIk'W#$#,]%A>%:+'IJJlk'6#)$:+/('IJJV'' ''' Complicaons of Flexor Tendon Healing Ø Flexor and extensor tendons of the hand are the most commonly injured tendons

Adhesion Ø Fibroc Healing: Exuberant ECM deposion aaches tendon to synovial sheath and surrounding ssues

Ø Healing of flexor tendons is Palmar surface of hand complicated by ROM-liming scar Tendon Medscape.com

in up to 40% of repairs

Ø Oen require a secondary surgical procedure to lyse adhesions Adhesion Centers for Disease Control and Prevention. (2015, January). Strickland, J.W. et al., J Hand Surg [Am] 25(2): p.214-235, (2000). Aydin, A. et al., AOTT 28(1): p.54-9, (2004). >6f"%2%10&(0E(M'675&%65$(?/0B'/1'2(

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Thiruvoth et al. 2015. Plasc and Aesthec Research

AJ Jomas et al. 2014. Advanced Drug Delivery Review Inflammaon

• Begins immediately aer injury, lasts for ~ 1 week Inflammaon Well-regulated inflammaon is beneficial -acvates healing cascade -recruitment/acvaon of cells Excessive/ Chronic inflammaon is pathological -degenerave matrix changes -fibroc healing Benefits of An-inflammatory therapy is controversial Timing may be key! Generally effecve at prevenng excess scar formaon Early inhibion decreases mechanics Delayed healing maintains mechanics Cell-type specific consideraons

Virchenko et al., 2004. Am J Sports Med, Geary et al. 2015. PlosOne

Proliferave/ Granulaon Phase • Lasts a few weeks • Begins ~day 7 in mouse model • Proliferaon of ‘fibroblasts’ • Bridging on injury site • Producon of ECM components (Col1/ Col3) • Rapid deposion of disorganized ECM

Day 3 Day 14 PDGF and bFGF: promote proliferaon -can also cause adhesions TGFB: Smad3-/-, PAI-1-/- reduces adhesions S100a4: Ablaon reduces adhesion formaon

Thomopoulos et al., 2009. JOR, Thomopoulos et al., 2010. JBJS, Katzel et al. 2010. JOR, Awad Lab, Loiselle Lab Remodeling Phase • Lasts many months • Begins ~day 21 in mouse model • Reorientaon of ECM • Mmp-mediated remodeling

Day 21 Cellular Basis of Healing • Time-dependent dynamic cellular environment • Involves mulple cell types • Tenocyte apoptosis • Extrinsic inflammatory cells • Resident tenocytes, epitenon cells, sheath cells, tendon basement membrane cells • Bone marrow derived cells R'$$"$5/(b52%2(0E(K'5$%&G+(k&#/%&2%6(R'$$2(

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• Crical mass of labs studying cell lineage/fate/ funcon • Development of tendon specific tools • Big data and single-cell RNAseq • Idenficaon of new ‘tendon-specific’ markers ''

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