Mammalian target of rapamycin signaling is crucial for joint destruction in experimental arthritis and is activated in osteoclasts from patients with rheumatoid arthritis

Abstract

Objective. Activation of the mammalian target of rapamycin (mTOR) pathway is important for immune cell activation and bone metabolism. To date, the contribution of mTOR signaling to joint inflammation and structural bone and cartilage damage is unknown. The aim of this study was to investigate the potential of inhibiting mTOR as a treatment of inflammatory arthritis.Methods. Human tumor necrosis factortransgenic mice in which inflammatory arthritis was developing were treated with 2 different mTOR inhibitors, sirolimus or everolimus. The effects of treatment on clinical disease activity, inflammation, and localized joint and cartilage destruction were studied. In addition, the effects of mTOR inhibition on osteoclast survival and expression of key molecules of osteoclast function were analyzed in vitro. Moreover, synovial tissue from patients with rheumatoid arthritis (RA) was assessed for activation of the mTOR pathway.Results. Inhibition of mTOR by sirolimus or everolimus reduced synovial osteoclast formation and protected against local bone erosions and cartilage loss. Clinical signs of arthritis improved after mTOR inhibition, and histologic evaluation showed a decrease in synovitis. In vitro, mTOR inhibition down-regulated the expression of digestive enzymes and led to osteoclast apoptosis. Moreover, mTOR signaling was shown to be active in the synovial membrane of patients with RA, particularly in synovial osteoclasts.Conclusion. Signaling through mTOR is an important link between synovitis and structural damage in inflammatory arthritis. Current pharmacologic inhibitors of mTOR could be effective in protecting joints against structural damage.

Mammalian Target of Rapamycin in Inflammatory Skin Conditions

“…All these data underline the possible involvement of mTOR in cutaneous inflammatory diseases. Indeed, it is reported that mTOR is implicated in the development of several inflammatory and metabolic disorders, such as diabetes, metabolic syndrome, rheumatoid arthritis and Crohn's disease (11,12,(22)(23)(24)(25)(26)(27) (12). In addition, mTOR has been reported to be related to the triggering of Crohn's disease; indeed, mTOR plays a major role in the regulation of autophagy (23) the impairment of which represents a critical initiating point in this disease pathogenesis (24,25).…”

Nutrient signaling pathways and rheumatic diseases

“…Кроме того, доклинические исследова-ния свидетельствуют о том, что блокирование mTOR при-водит к уменьшению размеров припухлости конечностей у грызунов и синовита при индуцировании артрита антиге-нами [154,155].…”

“…Активность СПМТ обнаружена в синовиальной мем-бране больных ревматоидным артритом (РА), в частности в синовиальных остеокластах [155]. А пролиферация сино-виальных фибробластов, индуцированная тромбоцитар-ным ростовым фактором, у больных РА подавлялась при ингибировании mTOR рапамицином.…”

“…Также важно отметить, что сигнальные пути нескольких остеокласто-генных факторов, таких как КСФМ, RANKL (лиганд ре-цепторного активатора ядерного фактора каппа В) и ФНОБ, могут активировать mTOR как общую мишень, что следует из ингибирования фосфорилирования белка S6, S6-киназы и 4E-BP1 в остеокластах ингибитором mTOR сиролимусом [167]. При этом ингибирование mTOR сиролимусом или рапамицином снижало скорость форми-рования синовиальных остеокластов, индуцировало их апоптоз и подавляло резорбцию кости и хряща в экспери-ментах in vitro [155,157,167]. В опытах на животных было показано, что другой ингибитор mTOR, эверолимус, также способен подавлять активность остеокластов, ингибируя экспрессию катепсина К -протеазы, ответственной за по-терю костной ткани, индуцированную овариэктомией [168].…”

Target of Rapamycin (TOR) and Autophagy in Chronic Hepatitis C Virus Infection: Relation to Disease Activity

“…It is likely that dysregulation of the mTOR-autophagy pathway may contribute too many human disorders including viral infections [22]. Inflammatory disorders [23,24] and cancer [25,26] and could be an attractive avenue for future therapeutic approaches [16]. The aim of the present work was to study the role of mTOR and autophagy in the progression of HCV-related liver disease.…”