Fenotipska i funkcijska karakterizacija osteoklastnih progenitora u bolesnika s reumatoidnim artritisom [Phenotypic and functional characterization of osteoclast progenitors in patients suffering from reumathoid arthritis]

Šućur, Alan (2017) Fenotipska i funkcijska karakterizacija osteoklastnih progenitora u bolesnika s reumatoidnim artritisom [Phenotypic and functional characterization of osteoclast progenitors in patients suffering from reumathoid arthritis]. PhD thesis, Sveučilište u Zagrebu.

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Abstract

Rheumatoid arthritis (RA) is a chronic joint disease marked by persistent inflammation and joint destruction. The mechanisms leading to joint destruction involve differentiation and activation of osteoclasts. Peripheral blood (PB) monocyte pool contains osteoclast progenitors (OCP) which contribute to osteoresorption in inflammatory arthritides, and are influenced by cytokine and chemokine milieu. This work aimed to compare the phenotype, frequency and differentiation potential of OCPs in the peripheral blood and synovial fluid of patients suffering from RA and psoriatic arthritis (PsA) to those of healthy controls and to define importance of chemokine signals for migration and activation of OCPs. The results showed that the OCP population was moderately enlarged among PB cells in RA and correlated with levels of TNF-α, rheumatoid factor, CCL2 and CCL5. Compared to PB, RANK+ subpopulation was expanded in SF and correlated with the number of tender joints. PsA patients could be distinguished by increased RANK expression rather than total OCP population. OCPs from arthritic patients had higher expression of CCR1, CCR2, CCR4, CXCR3 and CXCR4. In parallel, RA patients had increased levels of CCL2, CCL3, CCL4, CCL5, CXCL9 and CXCL10, with significant elevation in SF vs PB for CXCL10. Subset expressing CXCR4 positively correlated with TNF-α, bone resorption marker and rheumatoid factor, and was reduced in patients treated with DMARD. CCR4+ subset showed significant negative trend during anti-TNF treatment. CCL2, CCL5 and CXCL10 had similar osteoclastogenic effects, with CCL5 showing greatest chemotactic action on OCPs. In conclusion, this work identified effects of selected chemokines on stimulation of OCP mobilization, tissue homing and maturation. Novel insights into migratory behaviors and functional properties of circulatory OCPs in response to chemotactic signals could open ways to new therapeutic targets in RA.

Abstract in Croatian

Reumatoidni artritis (RA) je kronična bolest zglobova obilježena trajnom upalom i razaranjem zglobova. Mehanizmi koji dovode do oštećenja zglobova uključuju diferencijaciju i aktivaciju osteoklasta. Monocitna populacija stanica periferne krvi sadrži osteoklastne progenitore (OCP, prema engl. osteoclast progenitors) koji pridonose osteoresorpciji u upalnim artritisima pod utjecajem raznih citokina i kemokina. Cilj ovog rada bio je usporediti fenotip, udio i diferencijacijski potencijal populacije OCP u perifernoj krvi i sinovijalnoj tekućini bolesnika koji boluju od RA i psorijatičnog artritisa (PsA) u usporedbi s zdravim kontrolama te definirati važnost kemokinskih signala za migraciju i aktivaciju populacije OCP. Rezultati su pokazali da je populacija OCP značajno povećana u perifernoj krvi u RA te korelira s koncentracijama TNF-α, reumatoidnog faktora, CCL2 i CCL5. U odnosu na krv, subpopulacija RANK+ je povećana u sinovijalnoj tekućini i korelirala s brojem bolnih zglobova. Bolesnici koji boluju od PsA su se razlikovali od kontrolne skupine po većem udjelu stanica RANK+, no ne i udjelom same populacije OCP. Populacija OCP u artritisu ima povećan izražaj kemokinskih receptora CCR1, CCR2, CCR4, CXCR3 i CXCR4. Istovremeno, bolesnici koji boluju od RA imaju povišene koncentracije kemokinskih liganda CCL2, CCL3, CCL4, CCL5, CXCL9 i CXCL10 u krvi, sa značajnim povećanjem CXCL10 u sinovijalnoj tekućini u odnosu na krv. Subpopulacija OCP CXCR4+ korelira s koncentracijama TNF-α, markerom koštane resorpcije i RF, te je smanjena u bolesnika na DMARD-terapiji. Udio populacije OCP CCR4+ pokazuje značajan negativan trend tijekom anti-TNF terapije. Ligandi CCL2, CCL5 i CXCL10 imaju slične osteoklastogene učinke, s tim da CCL5 pokazuje najveći kemotaksijski učinak na populaciju OCP. Zaključno, ovaj rad identificira učinke odabranih kemokina na poticanje perifernih stanica OCP, njihovu migraciju u zahvaćene zglobove i sazrijevanje u funkcionalne osteoklaste. Nova saznanja o migracijskim i funkcionalnim svojstvima populacije OCP mogla bi uputiti na učinkovitije terapijske pristupe u RA.

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