Up-regulated DERL3 in fibroblast-like synoviocytes exacerbates inflammation of rheumatoid arthritis

Geng, Manman; Xu, Ke; Meng, Liesu; Xu, Jing; Jiang, Congshan; Guo, Yue; Ren, Xiaoyu; Li, Xiaowei; Peng, Yizhao; Wang, Si; Huang, Fei; Zhang, Jing; Zhu, Wenhua; Lu, Shemin

doi:10.1016/j.clim.2020.108579

Cited by 8 publications

(6 citation statements)

References 38 publications

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“…We validated high expression of MZB1, OLFM4, DERL3, and S100P in RA synovial tissues, of which DERL3 is an ER-associated degradation component; we have, for the first time, reported that its effects in FLS exacerbate inflammation of RA. DERL3 knockdown also showed its therapeutic effect in vivo, which indicated its promising clinical application value . Other proteins, according to the current research, such as TPD52L1, MFAP5, and MZB1 also showed a close relationship with RA pathology, and we will also explore this further, so that our TMT results may provide more valuable research targets on RA pathogenesis.…”

Section: Discussionmentioning

confidence: 61%

“…DERL3 knockdown also showed its therapeutic effect in vivo, which indicated its promising clinical application value. 25 Other proteins, according to the current research, such as TPD52L1, MFAP5, and MZB1 also showed a close relationship with RA pathology, and we will also explore this further, so that our TMT results may provide more valuable research targets on RA pathogenesis.…”

Section: Discussionmentioning

confidence: 66%

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Quantitative Proteomic Analysis of Synovial Tissue Reveals That Upregulated OLFM4 Aggravates Inflammation in Rheumatoid Arthritis

Ren

Geng

et al. 2021

J. Proteome Res.

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Tandem mass tag (TMT)-coupled liquid chromatography coupled with tandem mass spectrometry is a powerful method to investigate synovial tissue protein profiles in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). Protein was isolated from synovial tissue samples of 22 patients and labeled with a TMT kit. Over 500 proteins were identified as the differential expression protein on comparing RA and OA synovial tissue, including 239 upregulated and 271 downregulated proteins. Data are available via ProteomeXchange with identifier PXD027703. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis showed that the majority participated in the developmental processes and protein processing in the endoplasmic reticulum. Olfactomedin 4 (OLFM4), a secreted glycoprotein, in joint inflammation of RA was explored. OLFM4 was upregulated in RA synovial tissue samples. In fibroblast-like synoviocytes (FLS), inflammation cytokines, TNF-α, interleukin (IL)-1β, and LPS can upregulate OLFM4. After OLFM4 knockdown under TNF-α stimulation, RA FLS proliferation was inhibited and the expression of CXCL9, CXCL11, and MMP-1 was decreased. Overall, the RA synovial tissue protein expression profile by proteomic analysis shows some unique targets in RA pathophysiology, and OLFM4 in FLS plays an important role in RA joint inflammation. OLFM4 can be a promising therapeutic target in RA synovial tissue.

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Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 66%

Quantitative Proteomic Analysis of Synovial Tissue Reveals That Upregulated OLFM4 Aggravates Inflammation in Rheumatoid Arthritis

Ren

Geng

et al. 2021

J. Proteome Res.

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“…Chronic endoplasmic reticulum stress serves as the underlying cause of hyperproliferation and excessive production of proinflammatory cytokines in rheumatoid arthritis fibroblast-like synoviocytes (Geng et al, 2020). In addition, rheumatoid arthritis fibroblast-like synoviocytes are resistant to apoptosis induced by endoplasmic reticulum stress (Kabala et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Azithromycin alleviates the severity of rheumatoid arthritis by targeting the unfolded protein response component of glucose‐regulated protein 78 (GRP78)

Zhang

Song

et al. 2021

British J Pharmacology

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Background and Purpose: Azithromycin is a macrolide antibiotic with antiinflammatory properties. We aim to substantiate the treatment potential of azithromycin in rheumatoid arthritis.Experimental Approach: Gene expression profiles were collected by RNA sequencing and the effects of azithromycin were assessed by in vitro and in vivo assays on the effects of azithromycin-mediated blockade of glucose-regulated protein 78 (GRP78).Anti-inflammatory activity of azithromycin was measured in fibroblast-like synoviocytes from rheumatoid arthritis patients and in collagen-induced arthritis in DBA/1 mice. Characterization of the binding of azithromycin to GRP78 was performed using drug affinity responsive target stability, proteomics and cellular thermal shift assays. Azithromycin-mediated inhibition of GRP78 and its relationship to its anti-arthritic activity was assessed.Key Results: Azithromycin reduced proinflammatory factor production, cell migration, invasion and chemoattraction and enhanced apoptosis, reducing the deleterious inflammatory response of rheumatoid arthritis fibroblast-like synoviocytes in vitro.Azithromycin ameliorated the severity of collagen-induced arthritis lesions as efficiently as the TNFα inhibitor etanercept. Transcriptional analyses suggested that azithromycin treatment impairs signalling cascades associated with cholesterol and lipid biosynthesis. GRP78 was identified as a novel target of azithromycin.Azithromycin-mediated activation of the unfolded protein response via the inhibition of GRP78 activity is required not only for inducing the expression of C/EBP-Abbreviations: CHOP, C/EBP homologous protein/DNA damage-inducible transcript 3; DARTS, drug affinity responsive target stability; INSIG, insulin inducible gene; MS, mass spectrometry; qRT-PCR, quantitative real-time PCR; siRNA, small interfering RNA; SREBP, sterol-regulatory element binding protein.Yongli Zhang and Luna Ge contributed equally to this work.

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“…In parallel, c-Jun Nterminal kinase (JNK) was identified as one of the downstream molecules mediating the sonic hedgehog (SHH) signaling pathway in patients with RA (35), and IL-34 has been proven as one of a key soluble mediator in controlling migration and proliferation of RA-derived FLS via ERK1/2 and AKT signalling pathways (36). Furthermore, studies performed in humans and animal models demonstrated that DELR3, an endoplasmic reticulum-associated degradation protein, expressed in RAderived FLS, is involved in inflammatory processes by increased production of cytokines and chemokines such as IL-6 and IL-8, as well as the metalloproteinases MMP-1 and MMP-13 (37). Moreover, CXCL1/CXCR2 axis (chemokine-ligand 1 and its receptor) activation may induce IL-6 production in FLS derived from both RA and osteoarthritis (38) and the alarmin IL-33 is able to modulate some mechanisms regulating proliferation and apoptosis in RA-derived FLS via NF-κB pathway (39).…”

Section: Environmental Factorsmentioning

confidence: 99%

One year in review 2021: pathogenesis of rheumatoid arthritis

Picerno

Ferro

Adinolfi

et al. 2021

Clinical and Experimental Rheumatology

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Rheumatoid arthritis (RA) is a chronic autoimmune disease characterised by local and systemic inflammation where the close interaction between immune cells and soluble mediators leads to amplification and perpetuation of inflammatory and remodelling processes. The research carried out in the last year in the field of RA has made it possible to identify new mechanisms involved in the pathogenesis of the disease, enabling the discovery of new potential therapeutic targets. Thus, in this review we summarise new insights in RA pathogenesis, resulting from a literature research date published in the last year.

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Up-regulated DERL3 in fibroblast-like synoviocytes exacerbates inflammation of rheumatoid arthritis

Cited by 8 publications

References 38 publications

Quantitative Proteomic Analysis of Synovial Tissue Reveals That Upregulated OLFM4 Aggravates Inflammation in Rheumatoid Arthritis

Quantitative Proteomic Analysis of Synovial Tissue Reveals That Upregulated OLFM4 Aggravates Inflammation in Rheumatoid Arthritis

Azithromycin alleviates the severity of rheumatoid arthritis by targeting the unfolded protein response component of glucose‐regulated protein 78 (GRP78)

One year in review 2021: pathogenesis of rheumatoid arthritis

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