Smoothened Regulates Migration of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis via Activation of Rho GTPase Signaling

Peng, Wei; Zhu, Shang Ling; Zhang, Bai Yu; Shi, Yi Ming; Feng, Xiao; Liu, Fang; Huang, Jian; Zheng, Song Guo

doi:10.3389/fimmu.2017.00159

Cited by 22 publications

(21 citation statements)

References 27 publications

(27 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…At the same time, EMT dynamics, as well as the acquisition of stem-like phenotypes are characterized by selective activation of Rho GTPases (Yoon et al, 2017 ). Interestingly, recent studies link Hh pathway to Rho GTPases activation, providing potential molecular mechanisms for our observations (Peng et al, 2017 ).…”

Section: Discussionmentioning

confidence: 56%

SMO Inhibition Modulates Cellular Plasticity and Invasiveness in Colorectal Cancer

et al. 2018

View full text Add to dashboard Cite

HIGHLIGHTS Preliminary results of this work were presented at the 2016 Academic Surgical Congress, Jacksonville (FL), February 2–4 2016 (Original title: Selective Smo-Inhibition Interferes With Cellular Energetic Metabolism In Colorectal Cancer)This study was funded by “Sapienza—University of Rome” (Funds for young researchers) and “AIRC” (Italian Association for Cancer Research)Hedgehog inhibitor was kindly provided by Genentech, Inc.®.Colon Cancer (CC) is the fourth most frequently diagnosed tumor and the second leading cause of death in the USA. Abnormalities of Hedgehog pathway have been demonstrated in several types of human cancers, however the role of Hedgehog (Hh) in CC remain controversial. In this study, we analyzed the association between increased mRNA expression of GLI1 and GLI2, two Hh target genes, and CC survival and recurrence by gene expression microarray from a cohort of 382 CC patients. We found that patients with increased expression of GLI1 showed a statistically significant reduction in survival. In order to demonstrate a causal role of Hh pathway activation in the pathogenesis of CC, we treated HCT 116, SW480 and SW620 CC cells lines with GDC-0449, a pharmacological inhibitor of Smoothened (SMO). Treatment with GDC-0449 markedly reduced expression of Hh target genes GLI1, PTCH1, HIP1, MUC5AC, thus indicating that this pathway is constitutively active in CC cell lines. Moreover, GDC-0449 partially reduced cell proliferation, which was associated with upregulation of p21 and downregulation of CycD1. Finally, treatment with the same drug reduced migration and three-dimensional invasion, which were associated with downregulation of Snail1, the EMT master gene, and with induction of the epithelial markers Cytokeratin-18 and E-cadherin. These results were confirmed by SMO genetic silencing. Notably, treatment with 5E1, a Sonic Hedgehog-specific mAb, markedly reduced the expression of Hedgehog target genes, as well as inhibited cell proliferation and mediated reversion toward an epithelial phenotype. This suggests the existence of a Hedgehog autocrine signaling loop affecting cell plasticity and fostering cell proliferation and migration/invasion in CC cell lines. These discoveries encourage future investigations to better characterize the role of Hedgehog in cellular plasticity and invasion during the different steps of CC pathogenesis.

show abstract

Section: Discussionmentioning

confidence: 56%

SMO Inhibition Modulates Cellular Plasticity and Invasiveness in Colorectal Cancer

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Rheumatoid arthritis (RA) is a chronic inflammatory bone-destructive disorder with autoimmune features ( 1 ). It is driven by diverse cellular and humoral immune responses, resulting in articular synovial inflammation and bone destruction ( 2 , 3 ). Type II collagen (CII)-induced arthritis (CIA) is a valuable animal model for investigating the pathological development of RA and for evaluating potential therapies ( 4 ).…”

Section: Introductionmentioning

confidence: 99%

Apremilast Ameliorates Experimental Arthritis via Suppression of Th1 and Th17 Cells and Enhancement of CD4+Foxp3+ Regulatory T Cells Differentiation

Chen

Wang

et al. 2018

Front. Immunol.

Self Cite

View full text Add to dashboard Cite

Apremilast is a novel phosphodiesterase 4 (PDE4) inhibitor suppressing immune and inflammatory responses. We assessed the anti-inflammatory effects of Apremilast in type II collagen (CII)-induced arthritis (CIA) mouse model. To determine whether Apremilast can ameliorate arthritis onset in this model, Apremilast was given orally at day 14 after CII immunization. Bone erosion was measured by histological and micro-computed tomographic analysis. Anti-mouse CII antibody levels were measured by enzyme-linked immunosorbent assay, and Th17, Th1 cells, and CD4+Foxp3+ regulatory T (Treg) cells were assessed by flow cytometry in the lymph nodes. Human cartilage and rheumatoid arthritis (RA) synovial fibroblasts (RASFs) implantation in the severe combined immunodeficiency mouse model of RA were used to study the role of Apremilast in the suppression of RASF-mediated cartilage destruction in vivo. Compared with untreated and vehicle control groups, we found that Apremilast therapy delayed arthritis onset and reduced arthritis scores in the CIA model. Total serum IgG, IgG1, IgG2a, and IgG2b were all decreased in the Apremilast treatment groups. Moreover, Apremilast markedly prevented the development of bone erosions in CIA mice by CT analysis. Furthermore, in the Apremilast treated group, the frequency of Th17 cells and Th1 cells was significantly decreased while Treg cells’ frequency was significantly increased. The high dose of Apremilast (25 mg/kg) was superior to low dose (5 mg/kg) in treating CIA. Apremilast treatment reduced the migratory ability of RASFs and their destructive effect on cartilage. Compared with the model group, Apremilast treatment significantly reduced the RASFs invasion cartilage scores in both primary implant and contralateral implant models. Our data suggest that Apremilast is effective in treating autoimmune arthritis and preventing the bone erosion in the CIA model, implicating its therapeutic potential in patients with RA.

show abstract

“…FLSs have been demonstrated to participate in almost all of the pathological events and play an important role in RA pathogenesis [ 5 , 35 ]. The aggressive proliferation of FLS and their secretions such as proinflammatory cytokines and matrix-degrading enzymes lead to synovial hyperplasia, persistent synovitis, and joint damage in RA patients [ 6 ].…”

Section: Discussionmentioning

confidence: 99%

Jatrorrhizine Hydrochloride Suppresses Proliferation, Migration, and Secretion of Synoviocytes In Vitro and Ameliorates Rat Models of Rheumatoid Arthritis In Vivo

Qiu

Sun

et al. 2018

IJMS

View full text Add to dashboard Cite

Jatrorrhizine hydrochloride (JH), an active component isolated from the traditional Chinese herb Coptis chinensis, has been reported to have antimicrobial, antitumor, antihypercholesterolemic, and neuroprotective activities. However, its antirheumatoid arthritis (RA) property remains unknown. In this study, a collagen-induced arthritis (CIA) rat model was used to evaluate the therapeutic effects of JH on RA by using arthritis score, radiological evaluation, and histopathological assessment. The in vitro effects of JH on proliferation, migration, and production of inflammatory mediators in RA-derived fibroblast-like synoviocyte MH7A cells were determined by the EdU incorporation assay, wound healing assay, real-time PCR, and ELISA, respectively. The in vivo studies showed that JH treatment significantly prevented the progression and development of RA in CIA rats through anti-inflammation and suppressing bone destruction. The in vitro studies revealed that JH could effectively attenuate the destructive phenotypes of MH7A cells, including inhibiting proliferation, migration, and production of inflammatory mediators. Further mechanistic analysis demonstrated that JH suppressed tumor necrosis factor alpha (TNFα)-stimulated activations of nuclear factor of kappaB (NF-κB) and mitogen-activated protein kinases (MAPKs) (ERK and p38) leading to the downregulation of proinflammatory cytokines, which might be beneficial to the antiproliferative and antimigratory activities of FLS cells. Collectively, our results demonstrated that JH has a great potential to be developed into a novel therapeutic agent for treating RA.

show abstract

Smoothened Regulates Migration of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis via Activation of Rho GTPase Signaling

Cited by 22 publications

References 27 publications

SMO Inhibition Modulates Cellular Plasticity and Invasiveness in Colorectal Cancer

SMO Inhibition Modulates Cellular Plasticity and Invasiveness in Colorectal Cancer

Apremilast Ameliorates Experimental Arthritis via Suppression of Th1 and Th17 Cells and Enhancement of CD4+Foxp3+ Regulatory T Cells Differentiation

Jatrorrhizine Hydrochloride Suppresses Proliferation, Migration, and Secretion of Synoviocytes In Vitro and Ameliorates Rat Models of Rheumatoid Arthritis In Vivo

Contact Info

Product

Resources

About