Poremećaji izražaja osteoresorptivnoga citokina RANKL u bolesnika s multiplom sklerozom na kliničkom početku bolesti [Disturbed expression of the osteoresorptive cytokine RANKL in patients with multiple sclerosis at clinical onset]

Glasnović, Anton (2015) Poremećaji izražaja osteoresorptivnoga citokina RANKL u bolesnika s multiplom sklerozom na kliničkom početku bolesti [Disturbed expression of the osteoresorptive cytokine RANKL in patients with multiple sclerosis at clinical onset]. PhD thesis, Sveučilište u Zagrebu.

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Abstract

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.

Abstract in Croatian

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.

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