www.bjorl.org
Brazilian
Journal
of
OTORHINOLARYNGOLOGY
ORIGINAL
ARTICLE
A
comparative
study
of
osteopontin
and
MMP-2
protein
expression
in
peripheral
and
central
giant
cell
granuloma
of
the
jaw
夽
Nooshin
Mohtasham
a,
Nasrollah
Saghravanian
a,
Bahareh
Fatemi
b,
Mehdi
Vahedi
c,
Monavar
Afzal-Aghaee
d,
Hamideh
Kadeh
e,∗aOralandMaxillofacialDiseaseResearchCenter,MashhadUniversityofMedicalSciences,SchoolofDentistry,Departmentof
OralandMaxillofacialPathology,Mashhad,Iran
bKermanUniversityofMedicalSciences,SchoolofDentistry,DepartmentofEndodontics,Kerman,Iran cKermanUniversityofMedicalSciences,SchoolofDentistry,DepartmentofPeriodontology,Kerman,Iran dMashhadUniversityofMedicalSciences,SocialMedicineSpecialist,Mashhad,Iran
eOralandDentalDiseaseResearchCenter,ZahedanUniversityofMedicalScience,SchoolofDentistry,DepartmentofOral&
MaxillofacialPathology,Zahedan,Iran
Received2June2017;accepted8November2017 Availableonline27December2017
KEYWORDS Osteopontin; MMP-2; PGCG; CGCG; Immunohistochemistry Abstract
Introduction:Oralperipheralandcentralgiantcellgranulomasarelesionswithlittle-known etiologyandpathogenesis.
Objective:Theaimofthisstudywastocomparematrixmetalloproteinases-2andosteopontin proteinexpressioninthemultinucleatedgiantcellsandmononuclearcellsoftheperipheral andcentralgiantcellgranulomalesions.
Methods:Inthisretrospectivestudy,thepresenceofmatrixmetalloproteinases-2and osteo-pontinin37casesofcentralgiantcellgranulomaand37casesofperipheralgiantcellgranuloma paraffinblockswereassessedbystreptavidin-biotinimmunohistochemistry.Independent sam-plet-test,Chi-square,Mann---WhitneytestsandSpearman’srankcorrelationcoefficientwere used.
夽 Pleasecitethisarticle as:MohtashamN, SaghravanianN, FatemiB, Vahedi M,Afzal-Aghaee M,Kadeh H.A comparativestudyof
osteopontinandMMP-2proteinexpressioninperipheralandcentralgiantcellgranulomaofthejaw.BrazJOtorhinolaryngol.2019;85:150---6.
∗Correspondingauthor.
E-mail:[email protected](H.Kadeh).
PeerReviewundertheresponsibilityofAssociac¸ãoBrasileiradeOtorrinolaringologiaeCirurgiaCérvico-Facial.
https://doi.org/10.1016/j.bjorl.2017.11.006
1808-8694/©2017Associac¸˜aoBrasileiradeOtorrinolaringologiaeCirurgiaC´ervico-Facial.PublishedbyElsevierEditoraLtda.Thisisanopen accessarticleundertheCCBYlicense(http://creativecommons.org/licenses/by/4.0/).
Results:The osteopontinwasexpressedinbothmultinucleatedgiantcellsandmononuclear cells in all cases of peripheral and central giant cells granulomas. However, the matrix metalloproteinases-2expressionwaspositivein86.5%ofgiantcellsanditwaspositiveinallof mononuclearcellsinperipheralgiantcellsgranuloma.Incentralgiantcellsgranulomas,91.8% ofgiantcellsandallmononuclearcellswerepositiveformatrixmetalloproteinases-2marker. PercentageandIntensityofstainingweresignificantlyhigherincentralthanperipheralgiant cellslesions,forbothmarkers(p<0.05).
Conclusion: Thisstudy showedthattheexpressionofosteopontiningiantcellssupportsthe theory of osteolcasticnature of these cells.Also, the presence ofosteopontin andmatrix metalloproteinases-2 in mononuclear cells may indicate the monocyte-macrophage origin of these cells,as the differentiation ofthe precursors ofthe mononuclear stromal mono-cyte/macrophage toosteoclastsispossiblyaffected bytheexpressionofosteolyticfactors. Also,maybedifferencesinbiologicalbehaviorsoftheselesionsareassociatedwiththelevel ofosteopontinandmatrixmetalloproteinases-2expression.
© 2017 Associac¸˜ao Brasileira de Otorrinolaringologia e Cirurgia C´ervico-Facial. Published by Elsevier Editora Ltda. This is an open access article under the CC BY license (http://
creativecommons.org/licenses/by/4.0/). PALAVRAS-CHAVE Osteopontina; MMP-2; PGCG; CGCG; Imuno-histoquímica
EstudocomparativodaexpressãodasproteínasosteopontinaeMMP-2nogranuloma centraleperiféricodecélulasgigantesdemandíbula
Resumo
Introduc¸ão: Osgranulomasperiféricosecentraisdecélulasgigantessãolesõescometiologia epatogênesepoucoconhecidas.
Objetivo: Compararaexpressãodasproteínasmetaloproteinasesdamatriz-2eosteopontina nascélulasgigantesmultinucleadasecélulasmononuclearesnogranulomaperiféricoecentral decélulasgigantes.
Método: Nesteestudoretrospectivo,apresenc¸ademetaloproteinasesdamatriz-2e osteopon-tinaem37casosdegranulomacentraldecélulasgigantese37casosdegranulomaperiféricode célulasgigantesemblocosdeparafinafoiavaliadaporimuno-histoquímicapela estreptavidina-biotina.Foramusadostestetparaamostraindependente,testedequi-quadrado,Mann-Whitney ecoeficientedecorrelac¸ãodeSpearman.
Resultados: Aosteopontinafoiexpressaemcélulasgigantesmultinucleadasecélulas mononu-clearesem todosos casosde granulomaperiféricodecélulas gigantes egranulomacentral de células gigantes.Noentanto, aexpressão demetaloproteinases damatriz-2 foipositiva em86,5%decélulasgigantesefoipositivaemtodasascélulasmononuclearesemgranuloma periférico decélulas gigantes.Emgranulomacentraldecélulas gigantes,91,8% dascélulas gigantesetodasascélulasmononuclearesforampositivasparaomarcadormetaloproteinases da matriz-2. A porcentageme intensidade de colorac¸ão em granuloma central de células gigantesforamsignificantementemaioresdoqueemgranulomaperiféricodecélulasgigantes paraambososmarcadores(p<0,05).
Conclusão:Esteestudomostrou queaexpressãodeosteopontinaem célulasgigantes apoia ateoriadanaturezaosteoclásticadessascélulas. Alémdisso, apresenc¸a deosteopontinae metaloproteinasesdamatriz-2emcélulasmononuclearespodeindicaraorigemdos monócitos-macrófagos dessas células, uma vez que a diferenciac¸ão dos precursores do monócito/ macrófagoestromalmononuclearemosteoclastosépossivelmenteafetadapelaexpressãode fatores osteolíticos.Alémdisso, asdiferenc¸as noscomportamentosbiológicos dessas lesões estãoassociadasaoníveldeexpressãodeosteopontinaemetaloproteinasesdamatriz-2. © 2017 Associac¸˜ao Brasileira de Otorrinolaringologia e Cirurgia C´ervico-Facial. Publicado por Elsevier Editora Ltda. Este ´e um artigo Open Access sob uma licenc¸a CC BY (http://
creativecommons.org/licenses/by/4.0/).
Introduction
Peripheralgiantcellgranuloma(PGCG)isarelatively com-monlesionobservedasaredorpurplenodularmassonthe
gingivaoredentulousalveolarridge.1---3Thislesionoriginates
fromthe periodontalligament and growsslowly.4---6 PGCG
canoccuratanyage,especiallyinthesixthandfifthdecades oflife,withlittletendencyforfemales.1
Centralgiantcellgranuloma(CGCG)islesscommonthan PGCGandoccurscentrallyin thejawbone.7
Radiographi-cally,this lesion is observed as unilocular or multilocular radiolucencywithspecified limits.1,7 It has different
clin-ical features and may be a slow-growing asymptomatic lesion or a painful lesion with rapid growth and high recurrence.8,9
Both PGCG and CGCG have similar histopathologic featuresandarecharacterizedbythepresenceof Multinu-cleatedGiantCells(MGCs)inabackgroundofmononuclear mesenchymal cells. However, despite these similarities, the two lesions are different in terms of biological behavior.7---10 CGCG isamoreaggressivelesionwitha
ten-dency to rapid growth, high recurrence, root resorption and bone perforation; while PGCG is a lesion with low recurrence, and in some cases may cause bone surface resorption.7,9Despitethevariousstudiesinthisregard,the
reason for different clinical behaviors of these lesions is unknown.1
Ontheotherhand,althoughmulti-nucleargiantcellsare thehallmarkoftheselesions,thehistogenesisofthegiant cells has not been specified yet.5,7,11 Some investigators
believe that the giant cells show the immunohistochem-istry characteristics of osteoclasts,5,7 while others have
suggested the phagocytic and endothelial cells origin for thesecells.8,12 Itis alsoindicated thatthe stromal
mono-nuclearcellsplayanimportantroleintheevolutionofgiant cells.13,14
Osteopontin is a non-collagenous protein and a highly phosphorylatedsialoprotein with high capacityto bind to calcium, and is produced by differentiating osteoblasts, differentiated osteoblasts, osteocytes, and osteoclasts.15
Osteopontin plays an important role in physiological bone remodeling, especially bone resorption through modulating.16 It can also play an important role in the
formation of chronic inflammation, granuloma formation, migrationofhistocytes,andphagocytosis.17
Matrix metalloproteinases (MMP) are a family of zinc-dependent endopeptidases which are able to degrade organic matrix in physiological PH. Previous studies have suggestedthat MMPs areinvolved in bone resorption pro-cess, and MMP2 and MMP9 (A and B gelatinases) can be producedbyosteoblastsorosteoclasts.18Itisreportedthat
MMP-9playsanimportantroleintheprocessesof angiogen-esis,boneresorptionandregulatingnon-mineralizedbone matrixproteolysis.19
Ingiantcelllesions,notonlythegiantcellsbutalso stro-malcellsareinvolvedintheproductionoftissue-destructive enzymessuchasMMPs.However,fewstudieshavebeen con-ductedontheroleofMMPsinthepathogenesisofGiantcell lesions.19,20
Accordingtoour knowledge,nosimilarstudy hasbeen doneoncomparingtheMMP-2andosteopontin expression inthe peripheral andcentral giantcell granuloma lesions in the jaws. Considering the microscopic similarities of PGCG and CGCG and differences in their biologic behav-ior,weevaluatedtheexpressionofMMP-2andosteopontin proteins in thesetwo lesionsby immunohistochemistry in thisstudy, topossiblyconfirm theosteoclastic phenotype of MGCs and the relationship of this immunohistochem-ical divergence with different behaviors of PGCG and CGCG.
Methods
In thisretrospective study following approval ofthe local EthicsCommittee(910127)atotalof74casesincluded 37 PGCGand37casesofCGCGwereevaluated immunohisto-chemicallyforosteopontinandMMP-2proteinexpression.
A streptavidin-biotin immunohistochemistry standard methodwasused.Forimmunohistochemicalstaining,4m sections were cut from paraffin blocks; sections deparaf-finizedinXyleneandrehydratedusingagradedethanol.The tissue was incubated in 30% hydrogen peroxide-methanol for30mintoblockendogenousperoxidaseactivityandthe slideswerewashedinPhosphateBufferedSaline(PBS).For antigenretrieval,theslideswereimmersedincitrate solu-tionandweremicrowavedfor15min.Followingthesections were incubated with protein block in order to eliminate background staining.Thenthe slideswereincubatedwith primaryantibodiesofMMP-2(Code:NCL-MMP2-507,Clone: 17B11,Novocastra,UnitedKingdom;Dilute1:50)and osteo-pontin (Code: NCL-O-PONTIN, Clone: OP3N, Novocastra, United Kingdom;Dilute 1:80) accordingtomanufacturer’s instruction.Thesectionswerewashed3timeswithPBSat room temperature.Immune complexes were treatedwith secondary antibody and detected by streptavidin peroxi-dase(NovolinkPolymerDetectionSystem:CodeRE7230-K). Immunoreactivitywasvisualizedwithdiaminobenzidineand wascounterstained withMayerhematoxylinandafter dry-ing, the sections were mounted. Sections of ulcerative colitisandgallbladderwereusedaspositivecontrolfor MMP-2 and osteopontin respectively and as a negative control primaryantibodywasomitted.
ForassessmentofMMP-2andosteopontinpositivity,the numberofpositivecellswascountedin5microscopicfields inhotspot(themostpopulatedareasbycells)witha mag-nification of 100 with light microscope (Leica Galen III, USA). Percentage ofcell stainingwasscored according to others studies21,22: negative (no staining), 0%---5% stained
cells (−), 5%---25% stainedcells (+),25%---50% stainedcells (++), 50%---75% stainedcells (+++), 75%---100% stainedcells (++++). Intensity of staining was scored as: negative (no staining), mild (light brown staining of the cells), severe (dark brownstainingof thecells)andmoderate (between mildandseverestainingofthecells).
Statisticalanalysis
Dataanalysiswasperformed in SPSSversion21 (SPSSInc, Chicago,IL)usingKolmogorov---Smirnovtesttoevaluate nor-maldistributionof quantitativedata,independentsample
t-test tocomparenormallydistributed quantitative varia-bles(agebetweenPGCGgroupandCGCGgroup),Chi-square test toqualitativevariables (genderbetween PGCGgroup andCGCGgroup)andMann---Whitneytestforother qualita-tivevariables(cellstainingpercentageandstainingintensity inPGCGandCGCG).p-valuelessthan0.05wasconsidered statisticallysignificant.
Results
Inthisstudy,37PGCGand37CGCGcaseswereexamined. Demographicdataof thesubjectsareseparatelyshown in
Table1 SummaryofthedemographicdataofPGCGandCGCGlesions.
Lesions Age Gender
Mean±SD Range p-value Male Female p-value
PGCG 35.08±20.63 10---71
0.06 15(40) 22(60) 0.47
CGCG 26.9±15.14 6---76 13(38.24) 21(61.76)
PGCG,peripheralgiantcellgranuloma;CGCG,centralgiantcellgranuloma.
Table2 ImmunereactivityoftheMMP-2inlesionsofPGCGandCGCG.
PGCG CGCG MGCn(%) MCn(%) MGCn(%) MCn(%) Negative 5(13.5) 0 3(8.1) 0 + 22(59.5) 9(24.3) 7(18.9) 6(16.2) ++ 8(21.6) 22(59.5) 14(37.8) 13(35.6) +++ 1(2.7) 5(13.5) 12(32.4) 17(45.9) ++++ 1(2.7) 1(2.7) 1(2.7) 1(2.7) p-value 0.000 0.16
PGCG,peripheralgiantcellgranuloma;CGCG,centralgiantcellgranuloma;MGC,multinucleatedgiantcell;MC,mononuclearcell.
Figure1 Immunohistochemicalstainingof(a)MMP-2ingiantcellsofCGCGwithmildintensitystaining(×400).(b,c)Osteopontin ingiantcellsandmononuclearcellsofPGCGwithsevereintensitystaining(×400).(d)Osteopontiningiantcellsandmononuclear cellsofPGCGwithmoderateintensitystaining(×400).
Table1.ThemeanageofPGCGcaseswas35.08±20.63,and inCGCGitwas26.9±15.14,butthisdifferencewasnot sta-tistically significant (p=0.06;Independent sample t-test).
Also,about60%ofcasesinboth PGCGandCGCGoccurred infemales,butthedifferencebetweenthetwogroupswas notstatisticallysignificant(p=0.47;Chi-SquareTest).
Highpercentageofgiantcellsandmononuclearcellsin both lesions were positive for MMP-2 (Table 2) (Fig. 1a). TheMMP-2stainingwasnotsignificantlydifferentbetween the mononuclear and giant cells in CGCG (p=0.16), but TheMMP-2stainingwassignificantlydifferentbetweenthe mononuclearandgiantcellsinPGCG(p<0.000).
Table3 ImmunoreactivityoftheosteopontininlesionsofPGCGandCGCG. PGCG CGCG MGCn(%) MCn(%) MGCn(%) MCn(%) Negative 0 0 0 0 + 5(13.5) 5(13.5) 0 1(2.7) ++ 12(32.4) 16(43.2) 1(2.7) 5(13.5) +++ 11(29.7) 8(21.6) 13(35.1) 12(32.4) ++++ 9(24.3) 8(21.6) 23(62.2) 19(51.4) p-value 0.56 0.18
PGCG,peripheralgiantcellgranuloma;CGCG,centralgiantcellgranuloma;MGC,multinucleatedgiantcell;MC,mononuclearcell.
Table4 StainingintensityoftheosteopontininlesionsofPGCGandCGCG.
OPN PGCG CGCG MGCn(%) MCn(%) MGCn(%) MCn(%) Negative 0 0 0 0 Mild 5(13.5) 4(10.8) 1(2.7) 3(8.1) Moderate 25(67.6) 26(70.3) 18(48.6) 17(45.9) Severe 7(18.9) 7(18.9) 18(48.6) 17(45.9) p-value 0.82 0.65
PGCG,peripheralgiantcellgranuloma;CGCG,centralgiantcellgranuloma;MGC,multinucleatedgiantcell;MC,mononuclearcell.
Table5 StainingintensityoftheMMP-2inlesionsofPGCGandCGCG.
MMP-2 PGCG CGCG MGCn(%) MCn(%) MGCn(%) MCn(%) Negative 3(8.1) 0 3(8.1) 0 Mild 23(62.2) 24(64.9) 11(29.7) 12(32.4) Moderate 11(29.7) 13(35.1) 23(62.2) 24(64.9) Severe 0 0 0 1(2.7) p-value 0.93 0.39
PGCG,peripheralgiantcellgranuloma;CGCG,centralgiantcellgranuloma;MGC,multinucleatedgiantcell;MC,mononuclearcell.
According to the Mann---Whitney test, the Median of
MMP-2staininginthegiantcellwasstatisticallysignificant betweentwo lesions(p<0.000). This differencewas also statistically significant in mononuclear cells between the CGCGandPGCG(p=0.015).
Allgiantandmononuclearcellswerepositivefor osteo-pontin in PGCG and CGCG (Table 3) (Fig. 1b---d). The percentage of cell staining for osteopontin was higher in giantcellsthanthemononuclearcellsinboth lesions,but thisdifferencewasnotstatisticallydifferentinbothgroups (PGCG---p=0.56;CGCG---p=0.18).
According to the Mann---Whitney test, the Median of osteopontinstainingingiantcellswasstatisticallydifferent betweentwolesions(p<0.000).Alsoinmononuclearcells, thedifferencewasstatisticallydifferentbetweenPGCGand CGCG(p<0.000).
Table 4 shows the staining intensity of giant cells and mononuclearcells for osteopontin in the lesions. Accord-ing to this table, the difference of osteopontin staining
intensitybetweenthemononuclearandmultinucleargiant cells in CGCG (p=0.65) and between the mononuclear and giant cells in PGCG (p=0.82) was not statistically significant.
However,accordingtoMann---Whitneytest,median stain-ingintensityofosteopontiningiantcellsbetweenthetwo lesionswasstatisticallysignificant(p=0.003).Also,the dif-ference was statistically significant in mononuclear cells betweenthetwolesions(p=0.035).
Table 5 shows the staining intensity of giant cells and mononuclearcellsforMMP-2inthelesions.MMP-2staining intensitybetweenmultinuclearandmononucleargiantcells in CGCG (p=0.39) and between multinuclear and mono-nucleargiantcellsinPGCG(p=0.34)wasnotsignificant.
Themedianstainingintensity ofMMP-2inmultinuclear giantcellswasnotstatisticallysignificantbetweenthetwo lesions (p=0.14). But the differencewas not statistically significant in mononuclear cells between the two lesions (p=0.05;Mann---Whitney)
Also Spearman’s rank correlation coefficient showed a significant correlation between osteopontin and MMP-2 in both PGCG (p=0.004, r=0.332) and CGCG (p=0.019,
r=0.273).
Discussion
Peripheral and central giant cell granulomas include non-neoplastic lesions with little-known etiology and pathogenesis. Various histological, immunohistochemical, enzymaticandultrastructuralstudieshavebeenconducted to determine the role and origin of giant cells in these lesions,buttheirnaturestillremains unknown.7Thus,we
decidedtocomparethetwoproteinsinvolvedinboneand connective tissue resorption (osteopontin and MMP-2) in giant cells andmononuclear cells of theselesions.In this study,allgiantcellsandmononuclearcellsofCGCGPGCG werepositiveforosteopontin.AlsofortheMMP-2,most mul-tinucleatedgiantandmononuclearcellsinbothlesionswere positiveforthismarker,andthiswassignificantlyhigherin CGCG comparedtoPGCGin bothmultinuclearand mono-nuclearcells.
In2011,Matosetal.19examinedtheexpressionofMMP-9
in thecentral andperipheral giant cellgranuloma lesions in jaws. The results revealed higher MMP-9 expression in centralgiantcellgranulomaandsuggestedthatMMP-9may play an importantrole in theprocess of osteoclastogene-sis of theCGCG lesions. Also,in the present study, given thehigherpresenceofMMP-2inCGCGlesions,thismarker maybeinvolvedintheosteoclastogenesisprocessofCGCG lesions.
In 2010, Tobon et al.20 examined the relationship
betweentheexpressionofMMP-9andMMP-1withthe clini-calbehaviorofgiantcelllesionsininvasiveandnon-invasive forms. The resultsshowed that both proteasesare signif-icantly higher in invasive lesions, which is in compliance withour studyin terms of the relativedifferences in the biologicbehaviorofperipheralandcentralgiantcell granu-lomalesions,asMMP-2washigherininvasivelesionsinour study.
In a studyconducted in 2010by Friedrich etal.,23 the
factorsindicatingthedifferentiationandactivityof osteo-clasts,suchasMMP-9,wereevaluatedusingtheMicroarray technique.Thesefactors werefoundinall studiedlesions includinggiantcelllesionsofthejaw,tendonsheaths,and salivaryglands.Theresultsofthisstudyshowedthat cellu-laringredientsforalllesionsisindependentofthelocation and giant celllesionsat all site includesimilar osteolytic proteasesandexpressmetaboliccytokinesthataffect the bone metabolism. Despite differencesin method, expres-sionofMMP-9asanosteolyticfactoringiantcelllesionsof jawisconsistentwithourstudy.
InastudybyLiuetal.24 toevaluatethecharacteristics
of osteoclastic giant cell in giant cell lesions of the jaw, Immunohistochemical(IHC)studiesshowedthatgiantcells and anumber of mononuclear cells in theselesions were largelypositiveforMMP-9.Also,intheirstudy,MGCsingiant celllesionsofthejawshowedosteoclasticcharacteristics. Also,inourstudy,theexpressionofMMP-2inmultinucleated giantcellsmayindicatetheroleofgiantcellsinosteolytic andproteolyticactivitiesintheselesions.
InastudyconductedbyCarlsonetal.,1722casesof
gran-ulomatouslesionswereexaminedintermsoftheexpression levelsofosteopontin,andtheresultsshowedanover expres-sionofosteopontinmRNAinmultinucleargiantcells.Inour study,thepercentage of stainingof osteopontin in multi-nucleatedgiantcellswashighercomparedtomononuclear cells in peripheral and central giant cell granulomas,but thedifference wasnot significantly different. The differ-enceinresultsmaybeduetodifferenttechniquesofthese twostudies.
In2011,Torabiniaetal.7reportedtheexpressionofTRAP
(indicatedtheosteoclasticactivityofthecells)in multinu-cleatedgiant cells and anumber of mononuclear cells in peripheralandcentralgiantcellgranulomalesionsand sug-gestedthatgiantcellsrepresentosteoclasticphenotypein PGCGandCGCG.Also,agroupofstromalmononuclearcells thatshowedthismarkercanbeconsideredasprogenitorsof giantcells.Inourstudy,osteopontin,whichisan osteoclas-ticmarker,wasexpressedhigherinmultinuclearcellsthan mononuclearcells.
InastudybyRabinovichetal.,25theexpressionofMMP2,
9instromalcellsofgiantcelltumorinboneindicatesthe roleofthesecellsinstromalgelatindegradationandbone invasion.Similarly,inourstudy,stromalcellsandgiantcells inthecentralgiantcellgranulomaexpressedMMP-2,which indicates therole of mononuclear cells and giant cells in destroyingthebonematrix.
Also,inastudyonexaminingtheosteoclasticmarkersof RANKLandosteoprotegrininPGCG,Fanourakisetal.6
indi-catedtheosteoclasticnatureofgiantcells,butthepossible osteoclasticnatureof thestromalmonocyteswas ambigu-ouslyreported. This study is similar tothe current study regardingindicatingtheosteoclasticnatureofgiantcells.
Contrary tothecurrent study which indicates thatthe osteopontinandMMP-2markerscouldexplainthedifferent clinicalbehaviorsofCGCG andPGCG,in astudyby Souza etal.,26theexpressionofP53,MDM-2,PCNA,Ki-67inCGCG
andPGCGwasnotsignificantlydifferentanddidnotexplain their different behavior. Also, in a study by Moradzadeh et al.5 in 2013 to examine the expression of Src protein
inthecentral andperipheral giantcell granuloma,it was concludedthatMGCsshowedsimilaritieswithosteoclastin theselesions,andthismarkermaybeusedasanew ther-apeutictarget for inhibiting theactivity of osteoclasts in theselegions.Thisstudywassimilartoourstudy interms ofpresence ofan osteoclastic naturein giant cells inthe mentionedlesions.But theysuggest that Srcmarker does notexplainthedifferent biologicalbehavior ofPGCGand CGCG.In our study,both osteopontin and MMP-2markers inCGCGwerehigherthanPGCGandthiscanbeindicative ofthefactthatdifferencesinbiologicalbehaviorsofthese lesionsareassociatedwiththeexpressionofosteolyticand proteolyticmarkers.
Conclusion
According to the results of current study, the expres-sion of osteopontin in giant cells supports the theory of osteolcastic nature of these cells. Also, the pres-enceof thismarker and MMP-2in mononuclearcells may indicate the monocyte-macrophage origin of these cells,
as differentiation of the precursors of the mono-nuclear stromal monocyte/macrophageto osteoclasts arepossibly affectedbytheexpressionof osteolyticfactors.Also,due tothesignificantdifferencebetweenmarkerexpressionof osteopontinandMMP-2inPGCGandCGCG, itcanbesaid thatdifferencesinbiologicalbehaviorsoftheselesionsare associated with the level of expression of osteolytic and proteolyticmarkers.
Funding
ThisworkwassupportedbytheResearchCouncilofMashhad UniversityofMedicalSciences(grantnumber:910127).
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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