Title SPOLNE RAZLIKE U IZRAŽAJU KOŠTANIH
MORFOGENETSKIH PROTEINA I NJIHOVIH INHIBITORA
UNUTAR ZGLOBNO-HIPOKAMPALNE OSI U ARTRITISU
INDUCIRANOM PRISTANOM
Title (english) GENDER-RELATED DIFFERENCES IN EXPRESSION OF
BONE MORPHOGENETIC PROTEINS AND THEIR INHIBITORS
WITHIN JOINT-HIPPOCAMPAL AXIS IN PRISTANE-INDUCED
ARTHRITIS
Author Hrvoje Omrčen
Mentor Tanja Grubić Kezele (mentor)
Mentor Sanja Zoričić Cvek (komentor)
Committee member Jagoda Ravlić-Gulan (predsjednik povjerenstva)
Committee member Drago Batinić (član povjerenstva)
Committee member Dalen Legović (član povjerenstva)
Granter University of Rijeka Faculty of Medicine (Department of Anatomy) Rijeka
Defense date and country 2023-01, Croatia
Scientific / art field, discipline and subdiscipline BIOMEDICINE AND HEALTHCARE Basic Medical Sciences
Universal decimal classification (UDC ) 61 - Medical sciences
Abstract Ciljevi istraživanja: Utvrditi spolne razlike u izražajima BMP-ova (BMP-4, -7) i njihovih inhibitora
(Noggin, Gremlin) u sinovijalnoj membrani, zglobnoj hrskavici i u dentatnoj vijugi hipokampusa,
te u intenzitetu adultne neurogeneze i razinama upalnih citokina (TNF-α i IL-17A) u krvi kao i
njihovu međusobnu korelaciju tijekom tri faze artritisa induciranog pristanom (PIA) – na početku,
na vrhuncu i u remisiji.
Materijali i metode: Istraživanje je provedeno na 140 Dark Agouti štakora, starosti 7 – 8 tjedana.
Analizirani su uzorci mozga, stražnjih stopala i serum. Izražaj BMP-ova i inhibitora te intenzitet
adultne neurogeneze određen je imunohistokemijski s kvantifikacijskom analizom, a razina
citokina ELISA-om. Stupanj upale u zglobu određen je Krenn-ovom i Mankin-ovom
semikvantitaivnom skalom. Rezultati su statistički obrađeni jednosmjernom analizom varijance
(ANOVA), Mann-Whitney U test-om i Pearson-ovom korelacijom (r). Podatci su izraženi kao
srednja vrijednost ± SD, a statisička značajnost uzeta pri vrijednosti p < 0,05.
Rezultati: PIA je započela ranije u mužjaka, ali je tijekom remisije u ženki utvrđena manja regresija
znakova upale. PIA je uzrokovala veći porast izražaja BMP-4, Noggin-a i Gremlin-a u zglobnoj
hrskavici ženki te veći pad BMP-7 u mužjaka. Sinovijalna upala te izražaj BMP-ova i inhibitora su
bili veći u ženki. U hipokampusu PIA je uzrokovala porast izražaja BMP-4, i pad BMP-7 i Noggin-a
u mužjaka, a u ženki pad BMP-4 i Noggin-a. Porast IL-17A u krvi na početku PIA bio je veći u
mužjaka, a u ženki porast TNF-α je bio veći u remisiji. U ženki je tijekom remisije došlo do značajno
većeg porasta broja Ki-67+
, DCX+
i SOX-2
+
stanica i omjera DCX/Ki-67 u subgranularnoj zoni
dentatne vijuge u odnosu na mužjake.
Zaključci: Rezultati dokazuju postojanje spolnih razlika u izražaju BMP-ova i njihovih inhibitora
unutar zglobno-hipokampalne osi, te u razinama TNF-α i IL-17A u krvi. Nadalje, rezultati dokazuju
razliku u korelaciji BMP-ova i inhibitora u zglobu i dentatnoj vijugi s intenzitetom adultne
neurogeneze, upalom u zglobu i razinama citokina među spolovima. To ukazuje na postojanje
različitih mehanizama nastanka i razvoja bolesti, a time i potencijalnih pridruženih
neuropsihijatrijskih komplikacija između spolova u sklopu modela reumatoidnog artritisa.
Abstract (english) Objectives: To determine gender differences in the expression of BMPs (BMP-4, -7) and their inhibitors
(Noggin, Gremlin) in the synovial membrane, articular cartilage and dentate gyrus of the hippocampus,
and in the intensity of adult neurogenesis and levels of inflammatory cytokines (TNF-α and IL-17A) in the
blood as well as their correlation with each other during three stages of pristane-induced arthritis (PIA) -
at the onset, at the peak and in remission.
Materials and methods: The study was conducted on 140 Dark Agouti rats, aged 7-8 weeks. Brain,
hindfoot, and serum samples were analyzed. The expression of BMPs and inhibitors and the intensity of
adult neurogenesis were determined immunohistochemically by quantification analysis, and cytokine
levels by ELISA. The degree of inflammation in the joint was determined by Krenn and Mankin
semiquantitative scoring. The results were statistically processed by one-way analysis of variance
(ANOVA), Mann-Whitney U test and Pearson's correlation (r). Data were expressed as mean ± SD, and
statistical significance was taken at p <0.05.
Results: The onset of PIA was earlier in males, and they recovered better during remission. BMP-4, Noggin,
and Gremlin in the articular cartilage during PIA were upregulated more in females, and BMP-7 was
downregulated more in males. Synovial inflammation and synovial BMPs and their inhibitors were
upregulated more in females. PIA caused hippocampal BMP-4 upregulation and downregulation of BMP7 and Noggin in males, and in females BMP-4 and Noggin were downregulated. The increase in IL-17A at
the onset of PIA was higher in males, and in females the increase in TNF-α was higher in remission. During
remission, females had a significantly higher increase in the number of Ki-67+
, DCX+ and SOX-2
+
cells and
the DCX/Ki-67 ratio in the subgranular zone of dentate gyrus compared to males.
Conclusions: Results show gender differences in the expression of BMPs and their inhibitors within the
joint-hippocampus axis, and in the levels of TNF-α and IL-17A in the blood. Furthermore, the results
demonstrate differences in correlations of BMPs and inhibitors in the joint and dentate gyrus with the
intensity of adult nerogenesis and inflammation between genders. This indicates the existence of different
mechanisms of disease onset and development, and thus potential associated neuropsychiatric
complications of rheumatoid arthritis between genders.
Keywords
adultna neurogeneza
koštani morfogenetski proteini
artritis induciran pristanom
reumatoidni artritis
Keywords (english)
adult neurogenesis
bone morphogenetic proteins
pristane-induced arthritis
rheumatoid arthritis
Language croatian
URN:NBN urn:nbn:hr:184:575283
Promotion 2023
Project Number: uniri-biomed-18-41 Title: Kvaliteta života u oboljelih od autoimunih i neautoimunih bolesti lokomotornog sustava Title: The quality of life in patients with autoimmune and non-autoimmune diseases of locomotor system Leader: Tanja Grubić Kezele Jurisdiction: Croatia Funder: NadSve Funding stream: Nema
Project Number: uniri-biomed-18-197 Title: Izražaj proupalnih i fibrotičkih citokina u osteoartritisu i sindromu karpalnog tunela Title: The expression of the proinflammatory and fibrotic cytokines during osteoartrhritis and carpal tunnel syndrom Leader: Sanja Zoričić Cvek Jurisdiction: Croatia Funder: NadSve Funding stream: Nema
Study programme Title: Biomedicine Postgraduate (doctoral) study programme Study programme type: university Study level: postgraduate Academic / professional title: doktor/doktorica znanosti, područje biomedicine i zdravstvo (doktor/doktorica znanosti, područje biomedicine i zdravstvo)
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Created on 2023-01-18 12:14:29