The hyperplasia and destruction of synovial tissue have an important impact on the development of rheumatoid arthritis(RA), the abnormal proliferation and migration of synovial fibroblast in synovial tissue is similar...The hyperplasia and destruction of synovial tissue have an important impact on the development of rheumatoid arthritis(RA), the abnormal proliferation and migration of synovial fibroblast in synovial tissue is similar to tumor cells. Targeting anomalous synovial fibroblast and designing a high bioavailability nano drug delivery system can reduce the dosage for the treatment of rheumatoid arthritis and it is of great significance to reduce toxic and side effects and improve curative effect. In this experiment, the nobiletin-loaded tetrahedral framework nucleic acids cargo tank was established, carrying antiinflammatory small molecule monomer drug nobiletin with minimal bioavailability. Both in vitro cell experiments and in vivo animal studies proved the nano cargo tank enhance the role of nobiletin in reducing the invasiveness of pathological synovial fibroblast and promote their apoptosis, effectively alleviate the disease development of rheumatoid arthritis.展开更多
The upregulated expression of thioredoxin domain-containing protein 5(TXNDC5)is associated with rheumatoid arthritis in patients and model mice.However,the underlying mechanism by which TXNDC5 influences the pathologi...The upregulated expression of thioredoxin domain-containing protein 5(TXNDC5)is associated with rheumatoid arthritis in patients and model mice.However,the underlying mechanism by which TXNDC5 influences the pathological activation of rheumatoid arthritis synovial fibroblasts(RASFs)remains unknown.In this study,we show that TXNDC5 expression in RASFs and their cytokine production are significantly upregulated in response to LPS,TNF-αand IL-6,but suppressed by transfection with TXNDC5-siRNA.TXNDC5 is further validated as the direct target of NF-κB signaling.Mechanistically,TXNDC5 directly interacts with heat shock cognate 70 protein(HSC70)to sequester it in the cytoplasm,and HSC70 silencing exerts the same effects as TXNDC5 on the biological activity of RASFs(for example,decreased cell viability,invasion and cytokine production).Furthermore,HSC70 activates NF-κB signaling by destabilizing IκBβprotein in the absence of LPS or facilitating its nuclear translocation in the presence of LPS.Importantly,TXNDC5 can also regulate the activity of NF-κB signaling in a HSC70-IκBβ-dependent manner.Taken together,by linking HSC70 and NF-κB signaling,TXNDC5 plays a pro-inflammatory role in RASFs,highlighting a potential approach to treat RA by blocking the TXNDC5/HSC70 interaction.展开更多
Extracellular sulfatase-2(Sulf-2)influences receptor-ligand binding and subsequent signaling by chemokines and growth factors,yet Sulf-2 remains unexplored in inflammatory cytokine signaling in the context of rheumato...Extracellular sulfatase-2(Sulf-2)influences receptor-ligand binding and subsequent signaling by chemokines and growth factors,yet Sulf-2 remains unexplored in inflammatory cytokine signaling in the context of rheumatoid arthritis(RA).In the present study,we characterized Sulf-2 expression in RA and investigated its potential role in TNF-α-induced synovial inflammation using primary human RA synovial fibroblasts(RASFs).Sulf-2 expression was significantly higher in serum and synovial tissues from patients with RA and in synovium and serum from hTNFtg mice.RNA sequencing analysis of TNF-α-stimulated RASFs showed that Sulf-2 siRNA modulated~2500 genes compared to scrambled siRNA.Ingenuity Pathway Analysis of RNA sequencing data identified Sulf-2 as a primary target in fibroblasts and macrophages in RA.Western blot,ELISA,and qRT‒PCR analyses confirmed that Sulf-2 knockdown reduced the TNF-α-induced expression of ICAM1,VCAM1,CAD11,PDPN,CCL5,CX3CL1,CXCL10,and CXCL11.Signaling studies identified the protein kinase C-delta(PKCδ)and c-Jun N-terminal kinase(JNK)pathways as key in the TNF-α-mediated induction of proteins related to cellular adhesion and invasion.Knockdown of Sulf-2 abrogated TNF-α-induced RASF proliferation.Sulf-2 knockdown with siRNA and inhibition by OKN-007 suppressed the TNF-α-induced phosphorylation of PKCδand JNK,thereby suppressing the nuclear translocation and DNA binding activity of the transcription factors AP-1 and NF-κBp65 in human RASFs.Interestingly,Sulf-2 expression positively correlated with the expression of TNF receptor 1,and coimmunoprecipitation assays demonstrated the binding of these two proteins,suggesting they exhibit crosstalk in TNF-αsignaling.This study identified a novel role of Sulf-2 in TNF-αsignaling and the activation of RA synoviocytes,providing the rationale for evaluating the therapeutic targeting of Sulf-2 in preclinical models of RA.展开更多
基金supported by the National Key R&D Program of China (No. 2019YFA0110600)National Natural Science Foundation of China (Nos. 82171006, 81970986)Sichuan Province Youth Science and Technology Innovation Team (No. 2022JDTD0021)。
文摘The hyperplasia and destruction of synovial tissue have an important impact on the development of rheumatoid arthritis(RA), the abnormal proliferation and migration of synovial fibroblast in synovial tissue is similar to tumor cells. Targeting anomalous synovial fibroblast and designing a high bioavailability nano drug delivery system can reduce the dosage for the treatment of rheumatoid arthritis and it is of great significance to reduce toxic and side effects and improve curative effect. In this experiment, the nobiletin-loaded tetrahedral framework nucleic acids cargo tank was established, carrying antiinflammatory small molecule monomer drug nobiletin with minimal bioavailability. Both in vitro cell experiments and in vivo animal studies proved the nano cargo tank enhance the role of nobiletin in reducing the invasiveness of pathological synovial fibroblast and promote their apoptosis, effectively alleviate the disease development of rheumatoid arthritis.
基金This work was supported by the National Natural Science Foundation of China(No.81572254)China Postdoctoral Science Foundation(2016M600541)+1 种基金the Key Research and Development Project of Shandong(2016GSF201166)the Shandong Taishan Scholarship(No.tsqn20161076)and the Innovation Project of Shandong Academy of Medical Sciences.
文摘The upregulated expression of thioredoxin domain-containing protein 5(TXNDC5)is associated with rheumatoid arthritis in patients and model mice.However,the underlying mechanism by which TXNDC5 influences the pathological activation of rheumatoid arthritis synovial fibroblasts(RASFs)remains unknown.In this study,we show that TXNDC5 expression in RASFs and their cytokine production are significantly upregulated in response to LPS,TNF-αand IL-6,but suppressed by transfection with TXNDC5-siRNA.TXNDC5 is further validated as the direct target of NF-κB signaling.Mechanistically,TXNDC5 directly interacts with heat shock cognate 70 protein(HSC70)to sequester it in the cytoplasm,and HSC70 silencing exerts the same effects as TXNDC5 on the biological activity of RASFs(for example,decreased cell viability,invasion and cytokine production).Furthermore,HSC70 activates NF-κB signaling by destabilizing IκBβprotein in the absence of LPS or facilitating its nuclear translocation in the presence of LPS.Importantly,TXNDC5 can also regulate the activity of NF-κB signaling in a HSC70-IκBβ-dependent manner.Taken together,by linking HSC70 and NF-κB signaling,TXNDC5 plays a pro-inflammatory role in RASFs,highlighting a potential approach to treat RA by blocking the TXNDC5/HSC70 interaction.
基金This study was supported by the NIH/NIAMS F31 Fellowship AR-076204-01(RJS)Rheumatology Research Foundation Graduate Student Preceptorship Award(RJS/SA)NIH/NIAMS R01 Grant AR-072615(SA).
文摘Extracellular sulfatase-2(Sulf-2)influences receptor-ligand binding and subsequent signaling by chemokines and growth factors,yet Sulf-2 remains unexplored in inflammatory cytokine signaling in the context of rheumatoid arthritis(RA).In the present study,we characterized Sulf-2 expression in RA and investigated its potential role in TNF-α-induced synovial inflammation using primary human RA synovial fibroblasts(RASFs).Sulf-2 expression was significantly higher in serum and synovial tissues from patients with RA and in synovium and serum from hTNFtg mice.RNA sequencing analysis of TNF-α-stimulated RASFs showed that Sulf-2 siRNA modulated~2500 genes compared to scrambled siRNA.Ingenuity Pathway Analysis of RNA sequencing data identified Sulf-2 as a primary target in fibroblasts and macrophages in RA.Western blot,ELISA,and qRT‒PCR analyses confirmed that Sulf-2 knockdown reduced the TNF-α-induced expression of ICAM1,VCAM1,CAD11,PDPN,CCL5,CX3CL1,CXCL10,and CXCL11.Signaling studies identified the protein kinase C-delta(PKCδ)and c-Jun N-terminal kinase(JNK)pathways as key in the TNF-α-mediated induction of proteins related to cellular adhesion and invasion.Knockdown of Sulf-2 abrogated TNF-α-induced RASF proliferation.Sulf-2 knockdown with siRNA and inhibition by OKN-007 suppressed the TNF-α-induced phosphorylation of PKCδand JNK,thereby suppressing the nuclear translocation and DNA binding activity of the transcription factors AP-1 and NF-κBp65 in human RASFs.Interestingly,Sulf-2 expression positively correlated with the expression of TNF receptor 1,and coimmunoprecipitation assays demonstrated the binding of these two proteins,suggesting they exhibit crosstalk in TNF-αsignaling.This study identified a novel role of Sulf-2 in TNF-αsignaling and the activation of RA synoviocytes,providing the rationale for evaluating the therapeutic targeting of Sulf-2 in preclinical models of RA.
