Inhibition of Notch signalling ameliorates experimental inflammatory arthritis

Abstract

ObjectiveTo test the hypothesis that Notch signalling plays a role in the pathogenesis of rheumatoid arthritis (RA) and to determine whether pharmacological inhibition of Notch signalling with γ-secretase inhibitors can ameliorate the RA disease process in an animal model.MethodsCollagen-induced arthritis was induced in C57BL/6 or Notch antisense transgenic mice by immunisation with chicken type II collagen (CII). C57BL/6 mice were administered with different doses of inhibitors of γ-secretase, an enzyme required for Notch activation, at disease onset or after onset of symptoms. Severity of arthritis was monitored by clinical and histological scores, and in vivo non-invasive near-infrared fluorescence (NIRF) images. Micro-CT was used to confirm joint destruction. The levels of CII antibodies and cytokines in serum were determined by ELISA and bead-based cytokine assay. The expression levels of cytokines were studied by quantitative PCR in rheumatoid synovial fibroblasts.ResultsThe data show that Notch signalling stimulates synoviocytes and accelerates their production of proinflammatory cytokines and immune responses involving the upregulation of IgG1 and IgG2a. Pharmacological inhibition of γ-secretase and antisense-mediated knockdown of Notch attenuates the severity of inflammatory arthritis, including arthritis indices, paw thickness, tissue damage and neutrophil infiltration, and reduces the levels of active NF-κB, ICAM-1, proinflammatory cytokines and matrix metalloproteinase-3 activity in the mouse model of RA.ConclusionsThese results suggest that Notch is involved in the pathogenesis of RA and that inhibition of Notch signalling is a novel approach for treating RA.

Knockdown MiR-302b Alleviates LPS-Induced Injury by Targeting Smad3 in C28/I2 Chondrocytic Cells

“…Activation of Notch pathway is crucial for OA development [28, 29]. Notch signaling may contribute to enhanced production of inflammation-related molecules in OA synoviocytes and chondrocytes [30, 31]. Targeting Notch signaling during OA leads to the restitution of the typical chondrocyte phenotype and even to chondrocyte redifferentiation during the pathology [32].…”

Transcription factor Hes1 modulates osteoarthritis development in cooperation with calcium/calmodulin-dependent protein kinase 2

“…Down-regulation of these two genes by Hes1 knockout may be essential in suppression of OA development in Col2a1-Cre ERT ;Hes1 fl/fl mice, because intra-articular manipulation can induce inflammatory response in knee joints in our OA model. Furthermore, two recent studies show that inhibition of Notch signaling ameliorates experimentally induced inflammatory arthritis (38,39). Together, these data indicate that the Notch-Hes1 signaling pathway may play essential roles in inflammatory arthritis and in OA.…”

HES factors regulate specific aspects of chondrogenesis and chondrocyte hypertrophy during cartilage development

“…AOS is an autosomal dominant disorder caused by mutations in RBPJ and/or NOTCH1 genes resulting in Notch LOF, although no additional molecular mechanisms underlying this disease are known (Hassed et al, 2012;Stittrich et al, 2014). Notch signaling defects, either GOF or LOF, have also been implicated in osteoarthritis (Mahjoub et al, 2012;Hosaka et al, 2013;Mirando et al, 2013;Sassi et al, 2014;Liu et al, 2015), rheumatoid arthritis (Nakazawa et al, 2001;Park et al, 2015) and osteoporosis (Engin et al, 2008;Hilton et al, 2008;Majewski et al, 2011;Simpson et al, 2011), and have been associated with a predisposition to pathologic fractures (Kung et al, 2010). Studies like the one presented here further our understanding of the molecular players and events that Notch signaling might control during normal skeletal development, as well as our understanding of how they contribute to the pathology of certain skeletal diseases and injury processes.…”