Poremećaji izražaja osteoresorptivnoga citokina RANKL u bolesnika s multiplom sklerozom na kliničkom početku bolesti

doctoral thesis

• Title (english): Disturbed expression of the osteoresorptive cytokine RANKL in patients with multiple sclerosis at clinical onset
• Author: Anton Glasnović; MBZ: 291413
• Mentor: Danka Grčević (mentor)
• Committee member: nije dostupno (član povjerenstva)
• Granter: University of Zagreb; School of Medicine; Zagreb
• Defense date and country: 2015-06-18, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Basic Medical Sciences
• Universal decimal classification (UDC): 61 - Medical sciences

Abstract

Multipla skleroza (MS, prema engl. multiple sclerosis) je autoimuna upalna bolest središnjeg
živčanog sustava u čijoj patogenezi imunološki faktori čine glavni mehanizam demijelinizacijskog
oštećenja. Također, bolesnici koji boluju od MS imaju poremećenu koštanu pregradnju, što se
najčešće pripisuje primjeni glukokortikoida i smanjenoj pokretljivosti. Hipoteza ovoga istraživanja je
da u bolesnika koji boluju od MS, osim tih sekundarnih čimbenika osteoporoze, postoji pojačano
djelovanje RANKL (prema engl. receptor-activator of nuclear factor-B ligand)/RANK-signala u
sklopu primarnog autoimunog poremećaja. Stoga smo analizirali parametre koštane pregradnje i upale
u perifernoj krvi i cerebrospinalnom likvoru u MS na kliničkom početku bolesti u odnosu na profil
osteoresorptivne RANKL/RANK-osovine. Na početku bolesti snižena je likvorska koncentracija
neutralizacijskog receptora OPG (prema engl. osteoprotegerin), čime se povećava biološka dostupnost
čimbenika RANKL. U uznapredovaloj bolesti povećan je omjer RANKL/OPG i izražaj aktivacijskog
RANK-receptora u krvi, što odražava povećan proresorptivni potencijal. Profil čimbenika osovine
RANKL/RANK/OPG povezan je s izražajem imunosupresivnih citokina IL-4 i IL-10 te proupalnih
kemokina CCL2 i CXCL12. Izražaj osteoresorptivnog čimbenika RANKL pozitivno korelira, a
neutralizacijskog receptora OPG negativno korelira s težinom bolesti i aktivnošću alkalne fosfataze,
što može upućivati na povezanost aktivnosti osovine, intenziteta bolesti i koštane izgradnje. S obzirom
da osovina RANKL/RANK/OPG sudjeluje u patogenezi i progresiji MS, ti čimbenika mogli bi služiti
kao biomarkeri bolesti i ciljne molekule novijih terapijskih postupaka.

Abstract (english)

Multiple sclerosis (MS) is autoimmune inflammatory disease of the central nervous system in which
immunological factors play the crucial role of demyelinating damage. Also, patients with MS have
deregulated bone remodelling, mainly caused by glucocorticoid treatment and reduced mobility. We
hypothesized that, beside these secondary osteoporotic factors, MS patients have enhanced RANKL
(receptor-activator of nuclear factor-B ligand)/RANK-signal as a part of underlying autoimmune
disturbance. Therefore we analyzed the parameters of bone remodeling and inflammation in peripheral
blood and cerebrospinal fluid in MS patients at clinical onset in relation to osteoresorptive
RANKL/RANK-axis. At MS clinical onset concentrations of decoy receptor OPG (osteoprotegerin)
are decreased in cerebrospinal fluid, increasing the bioavailability of RANKL. Advanced MS is
marked by higher RANKL/OPG ratio and activating RANK-receptor expression in peripheral blood,
which suggests increased proresorptive potential. RANKL/RANK/OPG profile is associated with the
expression of immunosuppressive cytokines IL-4 and IL-10 and proinflammatory chemokines CCL2
and CXCL12. Osteoresorptive factor RANKL is in positive, and decoy receptor OPG is in negative
correlation with disease severity and alkaline phosphatase activity, interconnecting axis activity,
disease intensity and bone formation. Since RANKL/RANK/OPG axis is involved in pathogenesis and
progression of MS, these factors may serve as disease biomarkers and molecular targets of novel
therapeutic approaches.

• Keywords: medicina
• Keywords (english): medicine
• Language: croatian
• URN:NBN: urn:nbn:hr:105:896297
• Study programme: Title: Biomedicine and Health Sciences; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor/doktorica znanosti, područje biomedicine i zdravstva (doktor/doktorica znanosti, područje biomedicine i zdravstva)
• Type of resource: Text
• Extent: 131 str.
• File origin: Born digital
• Access conditions: Open access
• Created on: 2023-05-05 07:41:53