European Journal of Endocrinology 10.1530/EJE-17-0844 the effectofGHoncollagen markers, suchasPIIINP( imparting a greater effect, whereas testosterone amplifies and testosterone increase collagen markers, with GH when co-administeredwith GH ( andnormal menaregreater of testosteroneinhypopituitary function areamplifiedbytestosterone.Similarlytheeffects GH oncollagensynthesis,fatmass,leantissueandphysical the musclestructureandfunction( anabolic hormonesthatinteractpositivelyinregulating Growth hormone(GH)andtestosteronearepotent Introduction affected bytestosterone.We concludethatGHpositivelyregulatesdecorininhumansagender-dimorphic manner. Conclusion different fromGHalone. and testosteronetreatmentincreasedmeandecorinconcentrationby19.5 P a genderdifference inthedecorinresponsetoGH,withgreaterincreasementhanwomen(∆16.5 Results Main outcomemeasure combination. Women receivedeitherplaceboorGH(2 followed bya6-weekwashoutperiod.Menreceivedplacebo,GH(2 Participants andIntervention Design Objective hypertrophy. WhetherGHandtestosteroneregulatedecorininhumansisnotknown. testosterone. Decorin,amyokineandconnectivetissueprotein,stimulatesaccretionmuscle Context Abstract 5 Wales, Australia, Australia, University, BlacktownClinicalSchoolandResearchCentre,Hospital,Blacktown,NewSouthWales, 1 Neha Bahl in humans Decorin, agrowth hormone-regulated protein School ofMedicine,UniversityNewSouthWales, NewSouthWales, Australia Garvan InstituteofMedicalResearch,Sydney, NewSouthWales, Australia,

https://doi.org/10.1530/EJE-17-0844 www.ej < Clinical Study

0.05 comparedto∆9.4 e-online.org : Randomized,placebo-controlled,double-blindstudy. : GHtreatmentsignificantlyincreasedmeanserumdecorinconcentrationby12.7 : Growthhormone(GH)stimulatesconnectivetissueandmusclegrowth,aneffect thatispotentiatedby 3 School ofComputing,EngineeringandMathematics,Western SydneyUniversity, Penrith,NewSouth : To determinewhetherdecorin is stimulatedbyGHandtestosterone. : GHsignificantlyincreasescirculatingdecorin,aneffect greaterinmenthanwomen.Decorinisnot 1 , 2 , Glenn Stone 4 Centres ofHealthResearch,PrincessAlexandraHospital,Brisbane,Queensland,Australia,and : Serumdecorinconcentration. ± 3 6.5%; , Mark McLean : 96recreationallytrainedathletes(63men,33women)received8 weeksoftreatment © 2018EuropeanSociety ofEndocrinology 4 N Bahlandothers , 1 P 5 ,

= , 2 6 0.16). Testosterone didnotsignificantly changeserumdecorin.CombinedGH , , 3 , 7 4 , Printed inGreatBritain ). The effects of ). Theeffectsof 8 , 2 , Ken K Y Ho 9 ). Both GH ). BothGH 4 , 5 mg/day). ). 1 2 , School ofMedicine,Western Sydney 4 and growth anddifferentiation ( the activityofmyostatin, an inhibitorofmusclecell and differentiationofskeletal musclecellsbyrepressing overexpression ofdecorin enhances theproliferation by inhibitingresponsivenesstoTGF- 16 skeletal muscledifferentiationandrepair( is producedinresponsetoexercise, anditstimulates myokine and connective tissue protein ( decorin Growth hormoneincreases Published byBioscientifica Ltd. ). Decorininducesmyogenicsatellitecellproliferation Vita Birzniece Decorin, asmallleucine-richproteoglycan, is a mg/day), testosterone(250 ± .% ( 3.7% 1 , 2 , 5 P

< Downloaded fromBioscientifica.com at10/02/202107:06:10AM

0.05), achangenotsignificantly ± 4.2%; 18 ). Furthermore,decorin (2018) Endocrinology European Journal of edu.au v.birzniece@westernsydney. Email to VBirzniece should beaddressed Correspondence mg/week) or 178 P

< 178 : 2

0.01. Therewas 178 β :2 10 1 ( , 145–152 ± 12 , 5.3%; 17

11 , 13 ). ). Decorin 145 , In vitro 14 –152 , 15 via freeaccess ,

European Journal of Endocrinology GH, growthhormone;T, testosterone. GH +T T GH Men Women Treatment testosterone, PIIINPanddecorinofthesubjectsinvarioustreatment groups.Dataareshownasmean Table 1 www.eje-online.org Participants self-administered GH (Somatropin,1 GH plustestosterone( 2 ( women wereassignedtoreceiveeither2 randomized study, aspreviouslydescribed( ACTRN012605000508673. with theAustralianNewZealandClinicalTrials Registry Research EthicsCommittee, NSWAustraliaandregistered The studywasapprovedbySt.Vincent’s HospitalHuman All studyparticipantsprovidedwritteninformedconsent. change theirdietorexercise levelthroughoutthestudy. included inthestudy. Participantswereinstructednotto anabolic agents.96athletes(63menand33women)were known cancerorpositiveurinescreenforprohibited diabetes mellitus,cardiovascular, hepaticorrenaldisease, of reported abuseofperformance-enhancingdrugs,history sports competitions at the state or national level, self- described ( sessions inthepastyearwererecruited,aspreviously regularly participatedinatleasttwiceweeklyexercise whohad Healthy recreationalathletesaged18–40 years, Subjects andmethods and women. testosterone regulate circulating decorin inhealthymen of thepresentstudyistoinvestigate whether GHand testosterone ondecorinproductioninhumans.Theaim formation inskeletalmuscle( tissue collagensynthesisandregulatesconnective muscle atrophy( promyogenic genes,whilerepressinggenesinvolvedin overexpression inmuscleincreasestheexpressionof n Placebo GH Placebo mg/day GH(

Clinical Study = 17) orplacebo( This was a double-blind placebo-controlled No studiestodatehaveassessedtheeffectsofGHor Baseline characteristicsofthestudysubjects.Thetableshows theage,bodymassindex(BMI),andserumlevelsofIGF-1, 5 ). Exclusioncriteriawereparticipationin n gwe tsotrn ( testosterone 250 mg/week =15), 16 26.8 29.0 25.2 28.9 29.7 27.8 Age ). Decorinalsostimulatesconnective n

= (year) ± ± ± ± ± ± 16). Menwereassignedtoreceive n 1.3 1.5 1.4 1.3 1.6 1.3

= 16), ordoubleplacebo( 19 , N Bahlandothers 20 BMI 24.4 25.4 23.8 26.1 22.9 22.8 , 21 (kg/m

± ± ± ± ± ± 0.7 1.0 0.7 0.8 0.7 0.8 ). 2 ) mg/day GH 5 ). Briefly, mg/mL; n n IGF-1 113 137 =16). =16), 128 128 110 124 ± ±

± ± ± ± (µg/L) 10.3 10.0 9.5 9.7 9.6 7.9 a functionalmeasureofmusclemass–bodycell and includedleanbodymass(LBM)assessment was measuredbydual-energyx-rayabsorptiometry and changesinbodycomposition.Bodycomposition to GH-regulatedproteins,IGF-Iandcollagenpeptides the effectsofGHalone.We comparedchangesindecorin whether co-administrationwithtestosteroneenhanced women, and testosterone in men. We also investigated were affectedbysupplementationwithGHinmenand function havebeenpublished( I, collagenpeptides,bodycompositionandphysical injections ( from theendofthirdweekasweeklyintramuscular Netherlands; 250 weeks. Testosterone (Sustanon, Organon, Oss, the 6 day inthesecondweekand2.0 evening atdosagesof1.0 Novo Nordisk) or matched placebo subcutaneously each described ( PINP, PIIINP and ICTP were assayed as previously were intra-assay and inter-assay coefficients of variation (CVs) the assayis in duplicatesthesameassayrun.Thesensitivityof 100-fold and all samples for each subject were measured manufacturer instructions.Serumsampleswerediluted the DecorinHumanELISAkit(Abcam)accordingto at and aftera6-weekwashoutperiod(week14)stored during treatment (week4),endof8) Serum sampleswerecollectedatbaseline(week0), Assays as previouslydescribed( (derived bysubtractingextracellularwaterfromtheLBM), decorin Growth hormoneincreases − 80°C foranalysis.Decorinlevelsweremeasuredusing We examinedwhetherserumdecorinconcentrations < 23.1 23.5 25.3 21.9 T 2% and 1.2 1.4 (nmol/L) ± ±

± ± ± ± 5 0.2 0.2 5 1.3 2.0 2.1 1.9 ). ). The effects of the interventions on IGF- ). The effects of the interventions < gm with 1.5 pg/mL < 12%, respectively. IGF-1,testosterone, mg/week) orplacebowasadministered PIIINP 4.0 4.1 4.2 3.4 3.7 4.5 4 Downloaded fromBioscientifica.com at10/02/202107:06:10AM mg/day inthefirstweek,1.5 ). ± ± ± ± ± ±

(µg/L) 0.2 0.3 0.4 0.2 0.2 0.3 4 > ± mg/day fortheremaining , 93% recovery rate.The93% recovery

s 5 . e ). . m . 178 :2 Decorin 5953 6304 5748 5748 6127 6481

± ± ± ± ± ± (pg/mL) 312 448 269 275 349 203 146 mg/ via freeaccess

European Journal of Endocrinology GH, growthhormone;T, testosterone. a

Men combined treatments.Women receivedeitherplaceboorGH(2 and aftera6-weekwashoutperiod(week14).Menreceived either placebo,GH(2 Table 2 Women Women andmen Serum testosteroneincreasedsignificantly( or whencombinedwithtestosterone,respectively. 144 In men,IGF-1significantly( administration increasedIGF-1by86 other endpointmeasures. between baseline serum decorin concentrations and any ( serum levelsofdecorinandthecollagenmarker, PIIINP there wasapositiveandsignificantcorrelationbetween decorin levelsbetweenthetreatmentgroups.Atbaseline, ( measures ofbodymassindex(BMI),IGF-1andPIIINP serum concentrationofdecorin,andpreviouslyreported Table 1 Results MA, USA)( Statistical analyseswereperformedusingRStudio(Boston, and correlationswereconsideredsignificantat and bodycomposition.Unadjusted decorin concentrationandtheIGFaxis,collagenmarkers used fortheanalysisofcorrelationbetweenserum significant at and differencesrelativetotheplacebogroupconsidered mean effects atindividualtimepoints.Dataareexpressedas post hoc way ANOVA for repeated measures, followed by Dunnett’s Treatment effectsondecorinlevelswereevaluatedbyone- Statistical analysis Decorin significantlydifferent from week0withingroup( 5 R Clinical Study ). Therewerenosignificantdifferencesinthebaseline =0.34, ± Indicative of the effect of intervention, inwomenGH Indicative oftheeffectintervention,

23% and160 ± showsthebaselinecharacteristicsof96subjects,

s multiplecomparisontesttoevaluatetreatment . e Mean serumdecorinconcentrationsbeforetreatment(week 0),duringtreatment(week4),endof8) P . m

< 22 .

Multiplicityadjusted 0.01). Therewerenosignificantassociations ). P

<

0.05. Spearman’s rankcorrelationwas ± 16 16 15 16 17 16 32 32

24% whentreatedwithGHalone n

GH +T T GH Placebo GH Placebo GH Placebo Treatment

P N Bahlandothers

<

0.0001) increasedby P P valuesarereported, valuesarereported, ± 2 ( 12% P P

<

< 0.05); 5953 6304 5748 5748 6127 6481 5950 6114 0.0001). P P

< < Week 0 0.01) 0.05. b ± ± ± ± ± ± ± ± Decorin atweek14significantlydifferent fromweek8within group( 312 448 269 275 349 203 223 181 mg/day). Dataareshownasmean P ( alone. comparedtoGH effect oftheco-treatmentwasobserved levels (∆ 19.5 of testosteronewithGHsignificantlyincreaseddecorin levels (∆4.2 treatment didnotsignificantlyaffectcirculating decorin did notchangeduringplacebotreatment.Testosterone in women(9.4 was greaterinmen(16.5 withdrawal ( eight weeksofGHtreatment,returningtobaselineafter concentration increasedsignificantly( hormone treatmentsandwithdrawal.Themeandecorin vs 31.2 32.2 in mentreatedwithtestosteronealone(23.5 GH-responsive proteinsinblood. decorin inducedbyGHcorrelatedwiththoseofother additional effect to that of GH alone. The changes in did notaffectdecorinandco-treatmenthave with theeffectgreater in menthan in women.Testosterone GH significantlyincreasesserumdecorinconcentration GH ortestosteroneinhumans.Ourdatademonstratethat This studyinvestigatedwhetherdecorinisregulatedby Discussion positive correlation with changes in LBM ( ( decorin Growth hormoneincreases P i. 3 Fig.

<

<

0.001) andbodycellmass(

0.001) withchangesinIGF-1,PINP, ICTPandPIIINP Changes inserumdecorincorrelatedsignificantly 2 Table ±

2.5 ). Changesinserumdecorinshowedsignificant ± Serum decorin 1.7nmol/L). nmol/L) orwhencombinedwithGH(23.1 6600 6664 6408 5930 6491 6220 6452 6075 showsserumdecorinlevelsduringthe Fig. 1A Week 4 ± ± mg/day), testosterone(250 3.6%; 3.7% ± ± ± ± ± ± ± ± ± 355 505 413 285 364 329 269 216 6.5%; ). Theincreaseindecorinconcentration a a P (pg/mL) P

< =0.30; 0.01; P Downloaded fromBioscientifica.com at10/02/202107:06:10AM =0.16; ± 5.3%; 7061 6547 6721 5816 6591 6218 6652 6017 ± Fig. 2

s Week 8 . R i. 2 Fig. e . =0.31; m ± ± ± ± ± ± ± ± i. 1B Fig. . 368 492 465 297 434 220 312 185 ). However, no additive P

< ). Co-administration 178 a a a 0.05, mg/week), or P www.eje-online.org :2

). Decorinlevels < P 0.05).

< i. 1C Fig. .1 during 0.01) 5438 5937 5965 5487 5902 6189 5931 5838 Week 14 P

< 0.05). ± ± ± ± ± ± ± ± ± R . vs 2.0 250 426 373 320 352 300 252 225 =0.50; ) than 147 ± 1.3 b b b b b via freeaccess

European Journal of Endocrinology www.eje-online.org undertaken in rodents observed anincreaseindecorin undertaken inrodentsobserved testosterone. To ourknowledge,onlyonepreviousstudy and (C)men.Dataaremean treatment group(menandwomencombined),(B) 6-week washoutperiod)frombaseline(week0)for:(A)GH treatment), week8(endoftreatment)and14(aftera percentage changesinserumdecorinatweek4(during response tohormonetreatment.Dataarepresentedasmean Change inserumdecorinconcentrationmenandwomen Figure 1 A C B Clinical Study

Very littleisknownaboutdecorin regulation by GHor Decorin, %change from baseline Decorin, %change from baseline Decorin, %change from baseline –1 –1 –1 10 15 20 25 –5 –5 –5 10 15 20 25 10 15 20 25 0 0 0 0 5 0 5 0 5 0481 04 04 Wo All subjects(n=96) Men (n=63 men ±

(n=33 s . e . m ) . * N Bahlandothers ** P ) * 81 81

< .5 ** 0.05, P 4 4 4

< 0.01. weeks weeks week Placeb GH GH Placeb GH Placeb s o o o baseline (week0).Dataareshownasmean treatment) andweek14(aftera6-weekwashoutperiod)from decorin atweek4(duringtreatment),8(endof hormone treatment.Meanpercentagechangesinserum Change inserumdecorinconcentrationmenresponseto Figure 2 production intheextracellularmatrixofdeveloping importance inboneand tendon tissuerepair( levels correlated with those of PIIINP, which has particular to collagentypesIandIII( role incollagenformationandhasbeenshowntobind on collagentissueformation.Decorinisknowntoplay a synthesis ( the markersPINPandPIIINP, indicativeofcollagen have previouslyreportedthatGHsignificantlyincreases muscle andtendoncollagensynthesis( play aroleincollagentissueanabolism.GHstimulates postulate thattheupregulationofdecorinbyGHmay production mayinpartbeGHmediated. findings provide evidence that the stimulation of decorin exercise alsostimulates the releaseofGH( rise inblooddecorinduringexercise ( and proteinproductioninmuscle,contributingtoa that exercise positivelyregulates decoringeneexpression muscle structureandfunction.Thereisstrongevidence and repair ( extracellular matrixandregulatesgenesformusclegrowth production inhumans. study isthefirsttoreportthatGHstimulatesdecorin circulating decorinwas notmeasured( expression in tendon during immobilization; however, didnotaffectdecorinmRNA administration for2 weeks incisors inresponsetoGH( role inthestructuralproperties ofmuscleandboneby assembly and mineralization ( Furthermore, decorinmodulates bonecollagenmatrix Decorin, %change from baseline decorin Growth hormoneincreases –10 As decorinstimulatescollagenfibrillogenesis( Decorin isastructuralproteinintheskeletalmuscle – 25 10 15 20 5 0 5 5 16 ). Thus,GHexertsasignificantpositiveeffect 0481 , 18 ), suggesting a role in the regulation of Downloaded fromBioscientifica.com at10/02/202107:06:10AM 28 * , 23 31 * 29 ). Inyoungmales,GH ). Thus, decorin plays a ). Inourstudy, decorin 178 4 ± :2 15 24

s week . 24 e , . , m ). Thus,our 16 25 27 . * s ). Because P , ), andwe

< 26 GH+T T GH Placeb 0.05. 11 ), our 148 ), we 30 via freeaccess o ). European Journal of Endocrinology for eachcorrelation. Spearman correlationcoefficients and PIIINP inmen(solidcircles)and women(clearcircles).The week 8frombaseline,vsthechanges inIGF-1,PINP, ICTP, and Relation betweenchangesinserum decorinconcentrationsat Figure 3 Clinical Study

Δ Decorin (pg/ml) Δ Decorin (pg/ml) Δ Decorin (pg/ml) Δ Decorin (pg/ml) –500 –250 –500 –250 –500 –250 –500 –250 2500 5000 2500 2500 5000 5000 2500 5000 0 0 0 0 0 0 0 0 0 0 0 0 – – – – 10 10 10 50 00 00 Δ IGF-1(µg/L) Δ PIIINP 01 ΔI ΔP CTP 1002 1002 INP 51 (µg/L (µg/L (µg/L) N Bahlandothers 02 P ) valuesareindicated 00 00 ) 01 03 30 30 P<0.00 R=0.43 P<0.00 R=0.39 P<0.00 R=0.55 P<0.00 R=0.52 52 04 04 1 1 1 1 00 00 0 0 well-known genderdifferenceintheresponsetoGH. the greaterincreaseindecorinmencouldrelateto women ( ICTP, PIIINP)toamuchgreaterextentinmenthan this study, GHtherapyincreasedcollagenmarkers(PINP, estrogens ontheGHreceptorsignalinginwomen( effectsof difference maybeattributedtotheinhibitory markers ( regard toIGF-1,bodycompositionandbonemetabolism and exhibitsignificantlygreaterresponsestoGHwith more sensitivetoGHreplacementtherapythanwomen dimorphic ( actions of GH on a range of biological effects are sexually weight-adjusted doseofGHinmenthanwomen.The in menthanwomen,thefaceofalowerbody co-regulated byGH. positively regulatingcollagensynthesis,aneffectwhichis increase forIGF-1andPIIINP, respectively ( administration inmenwas around140%and250% GH doping.Inourstudy, thepeakresponsetoGH IGF-1 mayregulatecirculating decorin. directly stimulatesdecorinproduction.Thus,GHthrough other connectivetissuemarkers,itisplausiblethatIGF-1 metabolism ( that IGF-1 plays an important role in connective tissue increases circulating collagenmarkers,providingevidence Laron syndrome of GHinsensitivity, IGF-1 administration to bindIGF-1enhance its effects on collagen ( is aninducerofdecorinsynthesis( 45 decorin productioninadose-dependentmanner( decorin. does notallowtodifferentiateGHandIGF-1effecton muscle, tendonandcartilage( stimulates thelocalproductionofIGF-1intissuessuchas 1. Besides increasing the levels of circulating IGF-1, GH its receptor or indirectly via actions mediated by IGF- effect oftestosteroneoncirculating decorininmen. of thesehormones.Thisimpliesminimalphysiological significant effect on decorin by the co-administration GH effectoncollagenmarkerPIIINP( 2 anabolism, dose dependently increasing muscle mass ( Testosterone isapotentstimulatorofskeletalmuscle testosterone eitheraloneorco-administeredwithGH. aneffectof by testosteronebecausewedidnotobserve decorin Growth hormoneincreases , ). Furthermore,connectivetissuegrowthfactor(CTGF) 3 The genderdifferenceindecorincannotbeexplained We agreaterincreaseindecorinlevels observed IGF-1 andPIIINPareendorsed biomarkersfor GH mayexertitsanaboliceffectsdirectlythrough ). Although testosterone substantially amplifies the 5 36 In vitro ). Asdecorinalsoisaconnectivetissueprotein, 32 , 37 48 , 33 , ). Asdecorinlevelschangeinparallelto 38 reportssuggestthatIGF-1stimulates , 34 , 39 , 35 ). Thisclinicallysignificantgender Downloaded fromBioscientifica.com at10/02/202107:06:10AM ). InGH-deficientadults,menare 41 , 46 42 ) andhasbeenshown 178 ). Ourstudydesign 5 ), we observed no ), weobserved www.eje-online.org :2 5 ). Decorin 43 40 47 149 , ). In ). In 44 via freeaccess 1 , , European Journal of Endocrinology www.eje-online.org References Technology andtheArts). Research ProgramoftheDepartmentCommunications,Information Doping AgencyandtheAustralianGovernment(throughAnti-Doping input intheoriginalstudy. FundingwasprovidedbytheWorld Anti- Clifford, Kin-ChuenLeung,IreneWalker andKennethGrahamfortheir research nursesforclinicalassistance;UdoMeinhardt,AnneNelson,David The authorsthankallvolunteersfortheirparticipationinthestudy; Acknowledgements World Anti-DopingAgencyandtheAustralianGovernment. Funding perceived asprejudicingtheimpartialityofthisstudy. The authorsdeclarethatthereisnoconflictofinterestcouldbe Declaration ofinterest tendon andbone. anabolism, enhancingthestructuralpropertiesofmuscle, of decorin by GH may play a role in collagen tissue dependent manner. We postulate that the upregulation that GH increases serum decorin levels in a gender- significant effectondecorinconcentration. We conclude effect greaterinmenthanwomen.Testosterone hasno healthy adultsincreasescirculating decorin,withthe supplementation doesnotincreasecirculating decorin. rate, indicating that in healthy adults testosterone administration 3–4 timesthat of normalproduction supraphysiological dosesofintramusculartestosterone nosignificanteffectoncirculatingobserved decorinusing studied instead of healthy adults. Nevertheless, we had beenusedorpatientswithhypogonadismare different dosesordurationoftestosteroneadministration Furthermore, theeffectoftestosteronemaybeapparentif of decorinmaynotreflecttissueconcentrationdecorin. potential tobeusedasamarkerforGHdopinginsport. in womenalsoindicatesthatdecorinmaynothavea and largevariationindecorinduringGHadministration GH withdrawal. Furthermore, the rather small increase placebo ( were significantlyhigherintheGHgroupcomparedto from GH,collagenmarkers(PINP, ICTPandPIIINP) weeksofwithdrawal supraphysiological doses. After 6 levels increasedby16.5%duringGHadministrationat 1 Clinical Study Kadi F. Cellularandmolecularmechanisms responsibleforthe action oftestosteroneonhumanskeletal muscle.Abasisforillegal In summary, weshowthatadministrationofGHin There are some limitationstoour study. Serum levels 5 ), whereasdecorinreturnedtobaselineupon N Bahlandothers

decorin Growth hormoneincreases 15 14 13 12 11 10 6 5 9 8 7 4 3 2 Heinemeier KM, Bjerrum SS,Schjerling P &Kjaer M.Expression Li Y, Li J,Zhu J,Sun B,Branca M,Tang Y, Foster W, Xiao X&Huard J. Henningsen J, Rigbolt KT, Blagoev B,Pedersen BK &Kratchmarova I. Bianco P, Fisher LW, Young MF, Termine JD &Robey PG.Expression Danielson KG, Baribault H,Holmes DF, Graham H,Kadler KE& Brandan E, Fuentes ME&Andrade W. Theproteoglycandecorin Keenan BS, Richards GE,Ponder SW, Dallas JS,Nagamani M& Nelson AE, Meinhardt U,Hansen JL,Walker IH, Stone G, Birzniece V, Meinhardt UJ, Umpleby MA,Handelsman DJ&Ho KK. Johannsson G, Gibney J,Wolthers T, Leung KC&Ho KK. Gibney J, Wolthers T, Johannsson G,Umpleby AM&Ho KK. Growth Meinhardt U, Nelson AE,Hansen JL,Birzniece V, Clifford D, Woodhouse LJ, Gupta N,Bhasin M,Singh AB,Ross R,Phillips J Bhasin S, Woodhouse L, Casaburi R,Singh AB,Bhasin D,Berman N, of extracellularmatrixcomponents and relatedgrowthfactorsin doi.org/10.1038/sj.mt.6300250) muscle regeneration. Decorin genetransferpromotesmuscle celldifferentiationand (https://doi.org/10.1074/mcp.M110.002113) differentiation. Dynamics oftheskeletalmusclesecretomeduringmyoblast org/10.1177/38.11.2212616) andCytochemistry Histochemistry in developinghumanskeletalandnon-skeletaltissues. and localizationofthetwosmallproteoglycansbiglycandecorin 729–743. fibril morphologyandskinfragility. Iozzo RV. Targeted disruptionofdecorinleadsto abnormalcollagen ofCellBiology Journal is synthesizedandsecretedbydifferentiatedmyotubes. org/10.1210/jc.2010-2521) Endocrinology andMetabolism testosterone anddihydrotestosteroneongrowthhormone Smith ER. Androgen-stimulatedpubertalgrowth:theeffectsof doi.org/10.1210/jc.2008-0402) Clinical EndocrinologyandMetabolism placebo-controlled studyinyoungrecreationalathletes. influence ofgenderandtestosterone:arandomizeddouble-blind Pharmacodynamics ofgrowthhormoneabusebiomarkersandthe Howe CJ, Leung KC,Seibel MJ,Baxter RC,Handelsman DJ body proteinanabolismoccursintheliver. Interaction betweentestosteroneandgrowthhormoneonwhole- doi.org/10.1210/jc.2005-0553) Clinical EndocrinologyandMetabolism men. hormone onextracellularwaterinhypopituitary Independent andcombinedeffectsoftestosteronegrowth (https://doi.org/10.1152/ajpendo.00483.2004) of Physiology:EndocrinologyandMetabolism men. and energymetabolisminhypopituitary hormone andtestosteroneinteractpositivelytoenhanceprotein 76 delayed puberty. insulin-like growthfactor-Iinthetreatmentofshortstatureand (https://doi.org/10.7326/0003-4819-152-9-201005040-00007) a randomizedtrial. body compositionandphysicalperformanceinrecreationalathletes: Leung KC, Graham K&Ho KK.Theeffectsofgrowthhormoneon org/10.1210/jc.2003-031492) Endocrinology andMetabolism adipose tissuedistributioninhealthyyoungmen. & Bhasin S.Dose-dependenteffectsoftestosteroneonregional of Physiology:EndocrinologyandMetabolism dose-response relationshipsinhealthyyoungmen. Chen X, Yarasheski KE, Magliano L,Dzekov C 522–528. performance enhancement. 996–1001. (https://doi.org/10.1083/jcb.136.3.729) (https://doi.org/10.1038/bjp.2008.118) Molecular andCellularProteomics Journal ofClinicalEndocrinologyandMetabolism Journal Annals of Internal Medicine Annals ofInternal 1991 Molecular Therapy Downloaded fromBioscientifica.com at10/02/202107:06:10AM 55 British Journal ofPharmacology British Journal 2011 2004 209–216. 1990 96 89 Journal ofCellBiology Journal 2008 2005 1060–1067. 718–726. 38 2007 1549–1563. 2005 2001 93 90 178 Journal ofClinical Journal 15 2010 2213–2222. 3989–3994. et al American Journal American Journal :2 2010 1616–1622. (https://doi. 289 281 (https://doi. Journal ofClinical Journal . Testosterone 152 American Journal American Journal E266–E271. E1172–E1181. (https://doi. 9 Journal of Journal 2482–2496. Journal of Journal 568–577. European Journal of Journal 1997 2008 (https:// (https:// et al (https:// 150 . 136 1993 154 via freeaccess

European Journal of Endocrinology

30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 Clinical Study Miedel EL, Brisson BK,Hamilton T, Gleason H,Swain GP, Lopas L, Thieszen SL &Rosenquist TH.Expression ofcollagensanddecorin Brown DC &Vogel KG. Characteristicsoftheinvitrointeraction Doessing S, Heinemeier KM,Holm L,Mackey AL,Schjerling P, Sutton J &Lazarus L.Growthhormoneinexercise: comparison Pritzlaff CJ, Wideman L, Weltman JY, Abbott RD,Gutgesell ME, Boesen AP, Dideriksen K,Couppe C,Magnusson SP, Schjerling P, Zhang CZ, Li H,Bartold PM,Young WG &Waters MJ. Effectof R CoreDevelopmentTeam. R:ALanguageandEnvironmentfor Neame PJ, Kay CJ,McQuillan DJ,Beales MP&Hassell JR. Weber IT, Harrison RW &Iozzo RV. Modelstructureofdecorinand Vogel KG &Trotter JA. Theeffectofproteoglycansonthe Kishioka Y, Thomas M,Wakamatsu J, Hattori A,Sharma M, Li X, McFarland DC&Velleman SG. Extracellularmatrix Kanzleiter T, Rath M,Gorgens SW, Jensen J,Tangen DS, Kolnes AJ, Dopkin D, Perosky JE,Kozloff KM,Hankenson KD org/10.1016/S0945-053X(05)80006-X) pattern formation. during aorticarch development:implicationsformatrix artery 8832(11)80016-8) collagen. of asmallproteoglycan(PGII)bovinetendonwithtypeI org/10.1113/jphysiol.2009.179325) synthesis. tendon andskeletalmusclewithoutaffectingmyofibrillarprotein et al Rennie M, Smith K,Reitelseder S,Kappelgaard AM,Rasmussen MH Physiology of physiologicalandpharmacologicalstimuli. Applied Physiology intensity onpulsatilegrowthhormonereleaseinmen. Hartman ML, Veldhuis JD &Weltman A. Impactofacuteexercise doi.org/10.1113/jphysiol.2013.261263) administration. and rehabilitationinyoungmales:effectofgrowthhormone matrix geneexpressionandfunctionalresponsestoimmobilisation Boesen M, Kjaer M&Langberg H.Tendon andskeletalmuscle 1636–1643. odontogenesis intheratincisor. growth hormoneonthedistributionofdecorinandbiglycanduring Vienna, Austria,2015.Accessedfrom Statistical Computing.RFoundationfor (https://doi.org/10.1007/s000180050048) and lumican. Independent modulationofcollagenfibrillogenesisbydecorin 1996 implications forcollagenfibrillogenesis. 173X(87)80002-X) Related Research morphology ofcollagenfibrilsformedinvitro. org/10.1002/jcp.21371) activity. differentiation ofmyogeniccellsthroughsuppressingmyostatin Kambadur R &Nishimura T. Decorinenhancestheproliferationand (https://doi.org/10.1016/j.domaniend.2008.06.002) satellite cells. differentiation Decorinandtransforminggrowthfactor-beta1in to transforminggrowthfactor-beta1duringcellproliferationand proteoglycan decorin-mediatedmyogenicsatellitecellresponsiveness 1089–1094. Biochemical andBiophysicalResearch Communications is regulatedbycontractionandinvolvedinmusclehypertrophy. Kolnes KJ, Lee S,Eckel J,Schurmann A org/10.1111/j.1600-0838.2011.01414.x) of MedicineandScienceinSports human tendonandmuscleafteracuteexercise. . Growthhormonestimulatesthecollagensynthesisinhuman 271 Journal ofCellularPhysiology Journal Matrix 31767–31770. 1976 Journal ofPhysiology Journal (https://doi.org/10.1177/00220345950740100301) (https://doi.org/10.1016/j.bbrc.2014.06.123) Domestic AnimalEndocrinology Cellular andMolecularLifeSciences 1987 1989 41 Journal ofPhysiology Journal 1999 523–527. Matrix Biology 7 9 105–114. 468–478. 87 498–504. 2010 2013 Journal ofDentalResearchJournal 1995 (https://doi.org/10.1016/S0174- (https://doi.org/10.1016/S0934- 2013 588 2008 23 http://www.R-project.org/ N Bahlandothers 14 et al e150–e161. 341–351. Journal ofBiologicalChemistry Journal 573–582. 591 215 . Themyokinedecorin 2008 6039–6052. 856–867. Journal ofApplied Journal 2000 Collagen and Scandinavian Journal Scandinavian Journal 35 (https://doi. et al 2014 (https://doi. (https://doi. 263–273. 57 . Journal of Journal

859–863. (https://doi. 1995 450 (https://

74

decorin Growth hormoneincreases 38 35 34 33 32 31 45 44 43 42 41 40 39 37 36 Blackman MR, Sorkin JD,Munzer T, Bellantoni MF, Busby- Gotherstrom G, Bengtsson BA,Bosaeus I,Johannsson G& Longobardi S, Keay N,Ehrnborg C,Cittadini A,Rosen T, Dall R, Dall R, Longobardi S,Ehrnborg C,Keay N,Rosen T, Jorgensen JO, Mochida Y, Parisuthiman D,Pornprasertsuk-Damrongsri S, Holladay C, Abbah SA,O’Dowd C,Pandit A &Zeugolis DI. Mullen LM, Best SM,Ghose S,Wardale J, Rushton N&Cameron RE. D’Avis PY, Frazier CR,Shapiro JR&Fedarko NS.Age-related changes Sadowski CL, Wheeler TT, Wang LH &Sadowski HB.GHregulation Isgaard J, Nilsson A,Vikman K &Isaksson OG.Growthhormone Leung KC, Johannsson G,Leong GM&Ho KK.Estrogenregulation Johannsson G, Bjarnason R,Bramnert M,Carlsson LM,Degerblad M, Hayes FJ, Fiad TM&McKenna TJ.Genderdifferenceinthe Burman P, Johansson AG,Siegbahn A,Vessby B &Karlsson FA. Johansson AG. Genderdifferenceingrowthhormoneresponse org/10.1210/jc.2006-1487) Endocrinology andMetabolism of growthhormonereplacementinadults. Svensson J. A10-year, prospectivestudyofthemetaboliceffects of ClinicalEndocrinologyandMetabolism blind, placebo-controlledstudy. TheGH-2000StudyGroup. adults anditspotentialasamarkerofGHabuseinsports:double hormone (GH)effectsonboneandcollagenturnoverinhealthy Boroujerdi MA, Bassett EE,Healy ML,Pentecost C 4193–4200. Study Group. on theinsulin-likegrowthfactoraxisinwomenandmen.GH-2000 four weeksofsupraphysiologicalgrowthhormoneadministration Cuneo RC, Boroujerdi MA,Cittadini A,Napoli R matbio.2008.11.003) Matrix Biology Decorin modulatescollagenmatrixassemblyandmineralization. Atsawasuwan P, Sricholpech M,Boskey AL&Yamauchi M. (https://doi.org/10.1002/jor.22838) early remodeling. Type IIIcollagenmodulatesfracturecallusboneformationand Preferential tendonstemcellresponse togrowthfactor Medicine cartilage repairinvitro. Bioactive IGF-1releasefromcollagen-GAG scaffoldtoenhance cells. in effectsofinsulin-likegrowthfactorIonhumanosteoblast-like (https://doi.org/10.1210/endo.142.9.8365) C2C12 skeletalmusclecells. of IGF-Iandsuppressorcytokinesignalinggeneexpressionin org/10.1677/joe.0.1200107) muscle. regulates thelevelofinsulin-likegrowthfactor-ImRNAinratskeletal (https://doi.org/10.1210/er.2003-0035) of growthhormoneaction. Metabolism mass index,age,andgender. adults isdependentonthelevelofGH-bindingprotein,body responsiveness togrowthhormone(GH)treatmentinGH-deficient Manhem P, Rosen T, Thoren M&Bengtsson BA.Theindividual 0495(99)90077-X) Metabolism response ofgrowthhormone(GH)-deficientadultstoGHtherapy. and Metabolism replacement therapythanwomen. Growth hormone(GH)-deficientmenaremoreresponsivetoGH adults. healthy agedwomenandmen:arandomizedcontrolledtrial. Tobin JD Whitehead J, Stevens TE,Jayme J,O’Connor KG,Christmas C, 2002 Biochemical Journal 288 Journal ofEndocrinologicalInvestigation Journal Journal ofEndocrinology Journal 2015 et al 2282–2292. 1996 1999 . Growthhormoneandsexsteroidadministrationin 2009 Journal ofClinicalEndocrinologyand Metabolism Journal 26 1997 81 5325. 48 Journal of Orthopaedic Research ofOrthopaedic Journal 1575–1581. 28 308–313. 82 (https://doi.org/10.1001/jama.288.18.2282) 44–52. 550–555. Journal ofMaterialsScience:in Journal 1997 Downloaded fromBioscientifica.com at10/02/202107:06:10AM Endocrine Reviews Endocrinology 2007 Journal ofClinicalEndocrinologyand Journal 324 (https://doi.org/10.1016/j. (https://doi.org/10.1016/S0026- 1989 753–760. 92 Journal ofClinicalEndocrinology Journal 120 1442–1445. 2000 107–112. 2001 178 Journal ofClinical Journal 2004 1999 85 www.eje-online.org :2 2015 142 1505–1512. et al et al (https://doi. 25 22 (https://doi. 3890–3900. . Theeffectof 693–721. 58–60. 33 . Growth 675–684. 2000 Journal Journal JAMA 151 via freeaccess 85

European Journal of Endocrinology www.eje-online.org

47 46 Clinical Study Lam S, vanderGeest RN,Verhagen NA, vanNieuwenhoven FA, Vial C, Gutierrez J,Santander C,Cabrera D&Brandan E.Decorin Blom IE, Aten J,Goldschmeding R,Daha MR&vanKooten C. 2011 LRR12 inhibitingitsbiologicalactivity. interacts withconnectivetissuegrowthfactor(CTGF)/CCN2by Medicine supplementation. 286 2016 24242–24252. 10 783–798. Journal ofTissueJournal EngineeringandRegenerative (https://doi.org/10.1074/jbc.M110.189365) (https://doi.org/10.1002/term.1852) N Bahlandothers Journal ofBiologicalChemistry Journal

Accepted 14November2017 Revised versionreceived3November2017 Received 12October2017

decorin Growth hormoneincreases 48 Klinger B, Jensen LT, Silbergeld A&Laron Z.Insulin-likegrowth doi.org/10.1046/j.1365-2265.1996.7990809.x) Laron syndrome. factor-I raisesserumprocollagenlevelsinchildrenandadultswith doi.org/10.2337/diabetes.52.12.2975) production byhighglucose. renal fibroblastsandcooperateintheinductionofcollagen Connective tissuegrowthfactorandigf-Iareproducedbyhuman Clinical Endocrinology Downloaded fromBioscientifica.com at10/02/202107:06:10AM Diabetes 2003 1996 52 178 45 2975–2983. :2 423–429. (https:// (https:// 152 via freeaccess