What in tendinopathy?

NoVOSStockholmJan 2017

Movement(wheel)

BoneCartilage

Tendon

MTJ

IMCT

Muscular force (pedal)

Muscle contraction

Ligament

IMCT - Intramuscular connective tissue

MTJ – Myotendinous junction

Movement(limb)

BoneLigament

Cartilage

Tendon

IMCT

MTJ

Tendinopathy - What can we agree upon?

Repetitive stress (i.e. too much training intensity or volume) that involves the tendon elastic function and results in tendon related symptoms

ClinicalPain and dysfunction of tendon

What is tendinopathy - What can we agree upon?

ClinicalPain with activityTenderness upon palpationSwelling of tendon Impaired performance

Structure - Imaging (US or MRI)Thickening of tendonHypoechoic tendon areas (US)Altered water contentHyperperfusion

Morphology - Histology Cell rounding and reduced numberDisorganized collagen fibrilsFibrils smaller and looser organizedAccum. of proteoglycans, GAG’s and waterVascular growth - angiogenesis

(Pingel et al J.Anat. 224: 548-555, 2014)

(de Mos et al. Am J Sports Med. 37: 1214-22, 2009)

TendinopathyHealthy

(Pingel et al J.Anat. 224: 548-555, 2014)

Healthy

Tendinopathy

(Pingel et al J.Anat. 224: 548-555, 2014)

CLINICAL Decreased performanceSwelling PainSorenessBlood flow BASIC

Morphology altered(disallignment, low cell no.)

Biochemical changes(proteoglycans, water)

Nociceptive subst.Vascularity altered

From perfect function topainfull,impairedactivity

From physiologytopathology

Mechanical damage –acute healing response

Mechanical damage –”shielding off”

Immune response –vasculature permeability

Microdamage –inflammatory response Proteoglycan metabolism

perturbation

Peripheral neural phenotype –primary adrenergic stimulation

Hypoxia, oxidative stress -hypervascularity, nerve ingrowth

Compressive overload

Homeostasis perturbation –constant overload, apoptosis

Primary breakdown –metalloproteinase activity

Genetic predisposition

Tendinopathy pathogenesis

Mechanisms behind tendinopathy (1)

Mechanical damage to tendon region – loading larger than tolerable. Acute healing response – Regeneration of tissuePRO: Fibroblast proliferation, angiogenesis, nerve ingrowthCONTRA: No visualized lession, biochemical profile not like rupture(Perry 2005, Xu 2008, Millar 2009, Millar & Murrell 2012)

Shielding off – theory, Minor mechanical damage followed by region unloadingPRO: Localized region, slow loading effective as treatment, fibrils in tendonCONTRA: Difficult to demonstrate the ”shielding”, sudden onset(Arnozky 2009)

Inflammatory response to microdamagePRO: Early event, HSP+pro-infl.markers, respons to anti-inflammatory treatmentCONTRA: Histological degeneration, no ”inducable” inflamm. in chronic state(Fredberg 2008, Murrell 2010, Pingel 2013)

Mechanisms behind tendinopathy (2)

Proteoglycan metabolism perturbationPRO: Thickening of tendonCONTRA: Primary or secondary event(Caterson 2010)

Hypoxia, oxidative stress – little vasculature, hypervascularity, nerve ingrowthPRO: Less vasculature and rupture, HIF in rotator cuff, apoptosis in tendon CONTRA: No detectable hypoxia(Boushel 2000, Millar 2009, Dean & Carr 2014)

Peripheral neuronal phenotype – Primary neuronal and adrenergic stimulationPRO: Early nociceptors and neuronal activity, accellerated ”exagerated” pain, CONTRA: Difficult to detect early(Dean 2013, Ackermann 2009, Danielson 2007, Forsgren 2009)

Mechanisms behind tendinopathy (3)

Primary breakdown of tendon tissue – activation of matrix metallo-proteinasesPRO: Altered structure of matrixCONTRA: Collagenase model, not detectable in humans(Sun 2008, Orchard 2008)

Constant overload on tendon ”work horse” cells – less synthesis, more degradation. Accumulation of tissue between fasiclesPRO: Synthesis and degradation increased with exercise, recoveryCONTRA: Link to pathology lacking(Miller 2005, Magnusson 2010, Heinemeier 2013)

Mechanisms behind tendinopathy (4):

Compressive load induced tendinopathyPRO: Compression points, collagen II+aggrecan formation, fibrocartilage finding, rounded cellsCONTRA: Other locations than enthesopathy, other histological findings(Benjamin 1998, Milz 2002, Lyman 2004, Scott 2007, Cook 2012)

Immune response – vasculature permeability to innate immune systemPRO: Permeable vessels, oxidative stress, few immuncomp. cells in tendonCONTRA: No in vivo detection of response(Tempfer/Bauer 2009,2011)

Genetic factors determine who will be injuredPRO: Correlates to polymorphism in e.g. Collagen V CONTRA: Overruled by many other things(Collins 2010)

Mechanisms behind tendinopathy – where are we?”The 3 most likely mechanisms....out of many”

Mechanical damage to tendon region (”a small partial rupture”). Inflammation, regeneration and healing response, Shielding off

Constant overload on tendon cells (”disturbed homeostasis”). Interfascicular cell-tissue disturbance, fibril fragments.

Compressive load (”altered connective tissue”)Fibrocartilagenous changes at insertional points, hypoxia

Mechanical damage to tendon region (”a small partial rupture”). Inflammation, regeneration and healing response, Shielding off

(Jones et al. Arthr.Reum. 54: 832-42, 2006)

Proteolytic signalling (MMP)in tendinopathy

Different mRNA profile in tendinopathy andtendon rupture (-)

Matrix metalloproteinase (MMP)

Fibroblast proliferation, angiogenesis, nerve ingrowth (+)Early (but not late) presence of inflammation (+)Localized area – ”shielded off?” (+/-)No convincing imaging technique has demonstrated fibril damage (-)No increased rupture risk (-)

Tendinopathy Rupture

Control

Mechanisms behind tendinopathy – where are we?”The 3 most likely mechanisms....out of many”

Mechanical damage to tendon region (”a small partial rupture”). Inflammation, regeneration and healing response, Shielding off

Constant overload on tendon cells (”disturbed homeostasis”). Interfascicular cell-tissue disturbance, fibril fragments.

Compressive load (”altered connective tissue”)Fibrocartilagenous changes at insertional points, hypoxia

Mechanical loading of tendon:

Collagen in fibrils/fascicles – no turnover(95% stable structures after adolescence)

High turnover Collagen

(5% - fibril fragments inter-fascicular?)

Non-collagenous matrix molecules

(Proteoglycans, a) large: aggrecan, versicanb) SLRP: decorin (80%), biglycan, lumican, fibromodulin)

COMP, Lubrican, Elastin, Tenascin-C, Fibronectin

Cross-links

(a) enzymatic: lysyl oxydase initiated, b) advanced glycation endproducts (AGE’s))

z z z

z z z

z z z

Fibroblasts responsive to physiological loading?“Daily work horses” – “between fascicles/outer layer”

Fibroblasts relatively “dormant” under normal conditions

2. Mechanical loadingstimulates turnoverin a small pool of collagenand cross-links that modifiesmechanical properties

1. Collagen fibril formation and adaptation is very dynamic in childhood/adolesence (large pool) –after that time the main structures (”wires”) are stable

Tendon

(Heinemeier et al, FASEB J, 27: 2074-9,2013)

B

f

10 μm

n

c

f

B

(Haraldsson et al. Matrix Biol, 2007)

Inter-fascicular space: Highly cellular, fibril fragments, vascular, nerves

Accumulationof matrix betweenfascicles ?

Tendon clock controls many genes

0610007L01Rik 0610010B08Rik 1110008P14Rik 1110067D22Rik 1700008N17Rik 1700020I14Rik 1700066M21Rik 1810009A15Rik 1810013L24Rik

1810030O07Rik 1810043H04Rik 1810063B05Rik 2010002N04Rik 2310008H04Rik 2310011J03Rik 2310015B20Rik 2510009E07Rik 2610002J23Rik

2610301B20Rik 2810410L24Rik 3110052M02Rik 4432414F05Rik 4930402H24Rik 5430440L12Rik 5930412G12Rik 6030422H21Rik 6330412A17Rik

6430548M08Rik 9030425E11Rik 9030425E11Rik 9130023H24Rik 9130221H12Rik 9630025H16Rik 9930013L23Rik A230070E04Rik A730090H04Rik

A830039N20Rik Aak1 Aars Abcg5 Abl1 Abr Acadm Acap3 Actr1b Adam17 Adam19 Adamts20 Adamts4 Adamts4 Adarb1 Adarb1 Adm Adm Adrb1 Aen Agfg1

Agpat2 Ahctf1 Ahsa2 AI314180 AI448984 Akap17b Akap17b Akt2 Alkbh2 Amhr2 Anapc16 Ankrd11 Ankrd37 Ankrd46 Ankrd50 Anp32a Anp32a Anxa7 Anxa7

Apcdd1 Apcdd1 Apcdd1 Apcdd1 Api5 Araf Arhgap20 Arhgap20 Arhgap21 Arhgap29 Arhgap5 Arhgef25 Arid2 Arl3 Armc8 Armcx1 Arntl Arrdc3 Atad2 Atad2b Atg2b

Atg2b Atp8b2 Atxn7l1 AU022121 Avpi1 AW125324 Baiap2l1 BC046404 Bcl7c Bcor Bhlhe40 Blm Bmp2k Bms1 Bola2 Brd2 Brd3 Btbd1 Btg1 Bud31 ///

LOC100045848 Bzw1 C1qbp C80893 Camk2g Camkk1 Camsap1 Capn2 Caprin1 /// Gm20253 Cblb Cbx4 Cbx6 /// Npcd /// Nptxr Ccar1 Ccdc28b Ccdc43 Ccdc90a

Ccdc93 Ccl24 Ccm2 Ccng1 Cd2ap Cdc25a Cdc25b Cdc42 Cdc42 Cdk2 Cdk2ap2 Cdon Cebpb Cebpb Cep68 Cflar Cgrrf1 Chordc1 Chst11 Cisd3 Ckb Cks1b Clcf1

Cldn3 Clip1 Clock Clock Clock Clspn Cml3 Cmtm3 Cmtm6 Cmtm6 Commd7 Commd7 Coq10b Coro2b Coro2b Cox17 Cox19 Cpeb4 Cpeb4 Cpne2 Creb1 Creld1

Crls1 Cry1 Crybg3 Ctcf Ctdspl2 Ctgf Cx3cr1 Cyb5d1 Cyp26a1 D10Wsu52e D16Ertd472e D16H22S680E D7Wsu130e D9Ertd402e Dapk1 Dapk2 Dbp Dbp Dcaf4

Dclk2 Dcun1d3 Dcun1d3 Ddit4l Ddit4l Ddit4l Ddx3x Dennd4a Dennd4c Denr Dexi Dhdds Dip2a Dkk2 Dlg1 Dlgap1 Dll1 Dmpk Dmtf1 Dnajb1 Dnajc27 Dock11 Dpm1

Dscr3 Dtx4 Dusp11 Dusp14 Dusp8 Dut Dync2h1 Dynll1 Dyrk1a E130006N16Rik Ech1 Eef2k Eef2k Eef2k Efna1 Efna1 Efna5 Egln3 Egln3 Ehd2 Ehd3 Eif4a1 Eif4e

Eif4g2 Elk3 Elovl3 Enox2 Enpep Ephb3 Epm2aip1 Errfi1 Esyt1 Exoc4 Exoc4 Exosc10 Ext1 Fah Fam110b Fam110b Fam115a Fam118a Fam118b Fam118b Fam35a

Fam53b Fam76a Fam83d Fam89b Far1 Far1 Fas Fbxo18 Fbxo28 Fgf1 Fgfr2 Fkbp2 Fkbp3 Fkbp5 Fkbp5 Flot1 Flrt2 Fmo1 Fnta Foxk2 Foxn3 Foxred2 Frmd6 G2e3

Gal3st4 Gatad2b Gfpt1 Ggnbp1 Ggta1 Ggta1 Gltpd1 Gltscr1 Gm10913 Gm11827 Gm129 Gm13889 Gm19974 Gm20559 Gm4944 Gm8801 Gm9769 Gm9840

Gmcl1 Golgb1 Gpkow Gpr107 Gpr126 Gprin2 Gpsm2 Grasp Grem2 Grid2 Grk5 Grpel2 Gsdmd Gtf3c4 Gtf3c6 Gtpbp5 H13 H47 Haghl Haghl Hars Has2 Hax1 Hebp2

Hexim1 Hint1 Hlf Hlf Hmgn1 Hnrnph1 Hnrnpu Hnrnpu Hnrnpul2 Hnrpll Hoxa5 Hoxb5 Hoxc13 Hp1bp3 Hps1 Hps6 Hspa4 Ier5 Ifnar2 Ifrd2 Igsf8 Ikzf4 Ilk Immt Inhba

Ino80 Insig2 Insig2 Ints5 Ints6 Ints6 Ip6k2 Irf2 Irf2bp2 Irs3 Ism1 Ism1 Itgax Itpkc Jun Jun Kank2 Kank2 Kank3 Kbtbd11 Kcnh1 Kcnn4 Kctd15 Kctd2 Kdm2b Khdrbs1

Khdrbs1 Khdrbs1 Khnyn Kif1c Klf13 Klf13 Klhdc8a Klhl8 Kremen1 Lactb2 Lama3 Layn Lclat1 Ldb2 Ldb2 Lefty1 Leng1 Leo1 Lgr4 Lhfpl2 Lifr Lmf1 Lnx2 Lonrf1 Lonrf3

Loxl4 Lpar6 Lrrc4 Lrrc4 Lta4h Luc7l3 Maml1 Maml1 Map3k6 Map4k4 Mapkapk3 March1 Marveld1 Marveld1 Mast4 Mat2a Mat2a Mat2a Mat2a Mat2a Mbd4 Mbd4

Mbd4 Mcm9 Mdp1 Me3 Med24 Mex3b Mex3d Mfap3 Mfsd7b Mga Mia3 Mical1 Mina Mkl2 Mkln1 Mlh3 Mlxip Mmp11 Mmp14 Mob1a Mob3a Mob4 Mrm1 Mrpl24

Mrpl33 Mrpl52 Msl1 Msl1 Msl1 Msl2 Mtf1 Mthfr Mto1 Mtor Mtrf1l Mtus1 Mus81 Musk Mut Muted Myo1c Myo9a Naa35 Nap1l4 Naprt1 Narf Ncaph2 Nde1 Ndrg3

Ndufa12 Neat1 Nfkbie Nfyb Nipa2 Nln Nmt2 Npas2 Nqo2 Nr1d1 Nr1d2 Nrip1 Nrm Nrn1 Nt5e Ntf3 Nuak2 Nudt7 Nufip2 Nup153 Nup62 Nup62 Odz4 Opa3 Osbpl2

Osbpl3 Pabpc4l Paqr7 Pard6g Parp11 Patl2 Pdcd10 Pdcd4 Pde4d Pdrg1 Pdxk Pdzd8 Pdzrn3 Per1 Per2 Per2 Per3 Per3 Per3 Per3 Pfkp Pfn2 Phactr1 Phf15 Phf23

Phlda1 Phldb2 Phlpp1 Pias4 Pitpnc1 Pitpnc1 Pja1 Pja2 Pknox2 Plat Plat Plcb4 Plcd1 Plekhg1 Plekhh3 Plin2 Plin3 Plk3 Plxna2 Plxna2 Plxnd1 Pold2 Pole2 Polr1a

Polr1e Polr2e Pop1 Ppil3 Ppm1b Ppp2r3c Ppp2r5a Ppt2 Pqlc1 Pqlc1 Prkdc Prmt2 Prr5l Prss39 Psmb3 Ptbp1 Ptcra Ptges2 Ptpn13 Ptprd Ptprd Ptprm Pura Pxk Pycrl

Rab33b Rab42-ps Rab43 Rabgap1l Rai14 Rap1a Rapgef2 Rasgrf2 Rassf7 Rbfox2 Rbm14 Rbm43 Rcbtb2 Rcc1 Rest Rfx1 Rfx7 Rhoj Rif1 Rit1 Rmnd5b Rnf111

Rnf144b Rnf181 Ror1 Rora Rora Rpap2 Rpl37a Rpl7l1 Rpl7l1 Rps19bp1 Rps6ka3 Rras2 Rsad1 Rspry1 Rspry1 Rufy1 Rusc2 S1pr2 Samd4 Samd4 Sarnp Sash1

Sdccag3 Sec61a2 Sema4d Senp5 Serpine1 Serpinf1 Sertad2 Sertad3 Sesn3 Sfmbt1 Sfpq Sfpq Sfpq Sfswap Sgk1 Sgms2 Sh3rf2 Shank3 Shisa2 Shisa2 Sik1 Sik3

Slc14a2 Slc15a4 Slc16a1 Slc16a10 Slc18a1 Slc25a24 Slc25a29 Slc25a29 Slc35d1 Slc35e1 Slc40a1 Slc44a1 Slc4a4 Slc4a4 Slc4a4 Slc4a7 Slc5a6 Slc7a4 Slco3a1

Smarcad1 Smek2 Smek2 Smtnl2 Snai2 Snhg1 Snord104 Snx18 Snx5 Socs5 Son Sox4 Sox4 Sox4 Sox4 Sp1 Sphk2 Spice1 Spinlw1 Spon2 Spon2 Spry2 Spsb1

Spsb1 Spsb1 Spsb3 Srgap3 Srsf1 Srsf1 Srsf1 Srsf2 Srsf7 Ss18 Ssbp1 Ssbp2 Ssbp2 St3gal6 St8sia1 Stambpl1 Stard5 Stard5 Stard5 Stk24 Stk35 Stk38l Stk38l

Stx12 Stx2 Stx4a Supt3h Suv420h1 Swap70 Sys1 Syt17 Sytl2 Tapt1 Tardbp Tbc1d10a Tbc1d24 Tbcc Tbl1xr1 Tef Telo2 Tesk1 Tfdp2 Tgfa Tgfbr3 Thap2 Thbs2

Thbs4 Thra Thra Tia1 Tirap Tlr2 Tmcc2 Tmem144 Tmem194 Tmem37 Tmem39b Tmem51 Tmem52 Tmem55b Tmem57 Tmem64 Tnfaip3 Tnfrsf11b Tnfrsf12a

Tnfrsf12a Tnfrsf19 Tnfrsf22 Tnks Top3b Tor1aip2 Tox Tox Traf6 Traf6 Trim2 Trim2 Trim2 Trim27 Trim27 Trim3 Trnau1ap Trp63 Trpc1 Trub1 Trub2 Tsc22d3

Tsc22d3 Tspan2 Tspan2 Tsr1 Tsr1 Ttc7 Ttyh2 Tug1 Twf2 Twist1 Txnrd1 Uba3 Uba3 Uba6 Uba6 Ubash3b Ubash3b Ubc Ubc Ubc Ube2z Unc119b Usp2 Usp2

Usp24 Usp54 Utp11l Vdac3 Vhl Vps13a Vps33b Vps36 Vps8 Wasl Wdr4 Wdr75 Wdr77 Wdr77 Wdr92 Wee1 Wee1 Wrb Xpo1 Ybx2 Ywhab Ywhaq Ywhaq Ywhaq

Zbtb16 Zbtb16 Zbtb2 Zbtb42 Zc3h12c Zdhhc18 Zdhhc23 Zfp12 Zfp131 Zfp185 Zfp185 Zfp292 Zfp295 Zfp322a Zfp322a Zfp324 Zfp329 Zfp426 Zfp518a Zfp52 Zfp628

>745 rhythmic genes in tendon =

potentially 745 biological processes

63377

142140

220

484

tendon (745)

cartilage (615)

skeletal muscle (295)

CT3

CT7

CT11

CT15

CT19

CT23

Yeung et al Sci Rep, 2014

For at ændre ”Enhedens

navn” og ”Sted og dato”:

(Spiesz EM et al J Orthop Res 33: 889-897, 2015)

Matrix remodeling and inflammation related primarilyto the inter-fascicular area

Bovine (cow) flexor tendonssubjected tocyclic uniaxial loading (1-10% strain)

Collagen in fibrils/fascicles –no turnover(95% stable)High turnover Collagen(5% - fibril fragments inter-fascicular?)

Non-uniform aponeurosis displacement result inshear forces between soleus and gastrocnemius of 3-4 mm

(Bojsen-Moller et al JAP 2004)

-3 -2 -1 0 1 2 3 4

0

10

20

30

40

50

60

70

80

90

100

110

Pla

nta

rfle

xor

mo

men

t (N

m)

Shear (mm)

Knee flexion Knee extension

SOL MG

A

ML

P

Sol

Sol

Sol

Gas

Gas

Gas

Mechanisms behind tendinopathy – where are we?”The 3 most likely mechanisms....out of many”

Mechanical damage to tendon region (”a small partial rupture”). Inflammation, regeneration and healing response, Shielding off

Constant overload on tendon cells (”disturbed homeostasis”). Interfascicular cell-tissue disturbance, fibril fragments.

Compressive load (”altered connective tissue”)Fibrocartilagenous changes at insertional points, hypoxia

(Benjamin personal communication)

Achilles tendon insertionCompressive load (”altered connective tissue”)Fibrocartilagenous changes at insertional points, hypoxia

Collagen type II

For at ændre ”Enhedens

navn” og ”Sted og dato”:

(Dean et al BJSM, 2015)

Increased number of inflammatory cells are presentin tendinopathic tendons - revival of ”tendinitis”?

(Science Transl Med, 2015)

Human supraspinatus/subscapularis tendonMacrophages

Inflammation markers

Tendinopathy - What are the challenges?

20 years ago: ”Tendinitis”....to tendinopathy...”free choice” of treatment10 years ago: Starting to get the treatments clinically investigatedToday: Starting to get the theories for tendinopathy pathogenesis tested

De facto challenges in the clinical-paraclinical-theoretical interface:Mismatch between symptoms and imaging findings (e.g. flow)

Mismatch between tissue pathology and perceived pain

Mismatch between general tendon tissue changes (disorganized matrix, rounded cells) and specific regional presentations (anatomy), differential locations (insertion vs mid-substance) and variation in patient characteristics (e.g. age)

Not 100% effective treatment (Strength training around 75%), combinations?

We have a good idea of what tendinopathy isbut we dont know for sure what the pathogensis is

When we try to treat tendinopathy, we need to consider what we think the etiology/pathogenesis andthe presentation ofthe injury is

Thank you:

www.ismc.dk

Musculoskeletal Rehabilitation Research Unit

Institute for Sports MedicineSports Traumatologyand Arthroscopy

Karl Kadler, Machester Univ, UKBénédicte Chazaud, Univ Lyon, France