mimmunМедицинская иммунологияMedical Immunology (Russia)1563-06252313-741XSPb RAACI10.15789/1563-0625-2016-2-107-118mimmun-993Research ArticleОБЗОРЫREVIEWSКУЛЬТУРА ФИБРОБЛАСТОПОДОБНЫХ СИНОВИАЛЬНЫХ КЛЕТОК БОЛЬНЫХ РЕВМАТОИДНЫМ АРТРИТОМ: СВОЙСТВА И ВОЗМОЖНОСТИCULTURES OF FIBROBLAST-LIKE SYNOVIAL CELLS FROM PATIENTS WITH RHEUMATOID ARTHRITIS: PROPERTIES AND OPPORTUNITIESШнайдерМ. А.SchneiderM. A.

аспирант лаборатории клинической иммунофармакологии,

630047, г. Новосибирск, ул. Ядринцевская, 14

Research Fellow, PhD student, Laboratory of Clinical Immunopharmacology,

630047, Novosibirsk, Yadrintsevskaya str., 14

minerva1986@mail.ruШиринскийВ. С.ShirinskyV. S.

д.м.н., профессор, заведующий лабораторией клинической иммунофармакологии,

г. Новосибирск

PhD, MD (Medicine), Professor, Head, Laboratory of Clinical Immunopharmacology,

Novosibirsk

ШиринскийИ. В.ShirinskyI. V.

д.м.н., ведущий научный сотрудник лаборатории клинической иммунофармакологии,

г. Новосибирск

PhD, MD (Medicine), Leading Research Associate, Laboratory Clinical Immunopharmacology,

Novosibirsk

ФГБНУ «Научно-исследовательский институт фундаментальной и клинической иммунологии»РоссияInstitute of Fundamental and Clinical ImmunologyRussian Federation201614042016182107118Copyright © Шнайдер М.А., Ширинский В.С., Ширинский И.В., 20162016Шнайдер М.А., Ширинский В.С., Ширинский И.В.Schneider M.A., Shirinsky V.S., Shirinsky I.V.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.mimmun.ru/mimmun/article/view/993

В обзоре представлены данные литературы о структуре синовиальной оболочки у здоровых людей и больных ревматоидным артритом in vivo, рассмотрены особенности фибробластоподобных синовиальных клеток больных ревматоидным артритом (РА) в культуре in vitro, включая морфологию, фенотип, функциональные свойства клеток культуры. Описан стандартный протокол культивирования ФСК in vitro. Подчеркивается, что ФСК характеризуются автономностью функционирования, способностью к инвазивному росту, способностью к миграции в различные, в том числе интактные, суставы, лежащей в основе полиартикулярного поражения при ревматоидном артрите (РА). Особое внимание посвящено характеристике стабильного фенотипа фибробластоподобных синовиальных клеток как результату эпигенетических нарушений: изменениям метилирования ДНК, ацетилирования гистонов, функции микроРНК. ФСК больных РА характеризуются стабильным, возникающим in vivo и сохраняющимся после неоднократных пассажей in vitro тотальным гипометилированием ДНК. При РА ряд промоторов специфических генов (в частности CXCL12, IL-6), играющих существенную роль в патогенезе РА, находится в состоянии гипометилирования. В то же время в ФСК выявляются и гиперметилированные промоторы некоторых генов (гена рецептора смерти 3). Важным механизмом персистенции воспаления при РА является повышение ацетилирования гистонов в промоторах генов, ответственных за продукцию провоспалительных белков, в частности ММP1. Изменения в ацетилировании гистонов в ФСК связаны с высоким уровнем убиквитин-подобного белка SUMO-1 и параллельным снижением уровня специфической протеазы SENP1. Роль ацетилирования гистонов в патогенезе РА подтверждается эффективностью ингибитора деацетилазы гистонов трихостатина A при коллаген-индуцированном артрите у мышей. Содержание микроРНК-155 и микроРНК-146а стабильно повышено в культуре ФСК, так же как и в синовиальной ткани, синовиальной жидкости и МНК ПК пациентов с РА. Экспрессия микроРНК-124а снижена в ФСК от больных РА по сравнению с ОФСК. Экспрессия микроРНК-203 в ФСК также постоянно повышена. Уровень микроРНК-203 повышен в ФСК не только пациентов с многолетним РА по сравнению с остеоартритом и нормальными ФСК, а также у пациентов с ранним РА.

Заключается, что фибробластоподобные синовиальные клетки являются ключевыми клеточными элементами, участвующими в патогенезе ревматоидного артрита, и исследования, посвященные нарушениям их эпигенетической регуляции, находятся в самом начале своего пути. Ферменты и молекулярные комплексы, участвующие в этих процессах, являются потенциальными терапевтическими мишенями.

The present review contains data from literature concerning the in vivo structure of synovial membranes in healthy people and patients with rheumatoid arthritis (RA). The properties of in vitro cultured fibroblast-like synovial cells (FLS) from RA patients are considered, including FLS morphology, phenotype and function. A standard protocol of in vitro FLS culturing is described. Notably, the FLS are characterized by autonomic functioning, ability for invasive growth/migration, e.g., into non-affected joints. These FLS properties may a reason of multiple joint involvement typical to RA. Special attention is drawn to characterization of stable phenotypic profile of FLS which results from certain epigenetic disturbances, i.e., changes of the DNA methylation, histone acetylation, and micro-RNA effects.

The FLS from RA patients are characterized with stable and extensive hypomethylation of genes which occurs in vivo and persists after repeated culture passages. Some promoters of genes involved into RA pathogenesis (for example, CXCL12, IL-6) are hypomethylated. By contrary, some other gene promoters (e.g., the death receptor 3 gene) are shown to be hypermethylated. An increased histone acetylation of genes encoding proinflammatory mediators (such as MMP1) may be an important mechanism of persistent inflammation in RA. Changes in histone acetylation in FLS are related to high levels of ubiquitin-like SUMO-1 protein and concurrent decrease in specific protease SENP1activity. A role of histone acetylation in RA pathogenesis is supported by efficacy of a histone deacetylase inhibitor (Trichostatin A) in collagen-induced murine arthritis. Local concentrations of micro RNA-155, micro-RNA-146а, and micro-RNA-203 are permanently increased in FLS cultures, synovial tissues, and PBMC of the RA patients. Expression of micro RNA-124а is decreased in FLS from RA, as compared with OA FLS.

One may conclude that the fibroblast-like synovial cells are key cellular elements involved in the pathogenesis of rheumatoid arthritis, and the studies of their impaired epigenetic regulation are at their initial stage. Enzymes and molecular complexes involved in these processes may represent potential therapeutic targets for the treatment of RA.

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The authors declare that there are no conflicts of interest present.