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1.
Arthritis Res Ther ; 24(1): 188, 2022 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-35941675

RESUMO

BACKGROUND: The upregulation of interferon (IFN)-stimulated genes induced by type I IFNs (namely type I IFN signature) in rheumatoid arthritis (RA) patients had implications in early diagnosis and prediction of therapy responses. However, factors that modulate the type I IFN signature in RA are largely unknown. In this study, we aim to explore the involvement of VGLL3, a homologue of the vestigial-like gene in Drosophila and a putative regulator of the Hippo pathway, in the modulation of type I IFN signature in the fibroblast-like synoviocytes (FLS) of RA patients. METHODS: FLS were isolated from RA and osteoarthritis (OA) patients. Expression of VGLL3 in the synovial tissues and FLS was analyzed by immunohistochemistry and PCR. RNA sequencing was performed in RA-FLS upon VGLL3 overexpression. The expression of IFN-stimulated genes was examined by PCR and Western blotting. RESULTS: VGLL3 was upregulated in the RA synovium and RA-FLS compared to OA. Overexpression of VGLL3 promoted the expression of IFN-stimulated genes in RA-FLS. The expression of STAT1 and MX1 was also upregulated in RA synovium compared to OA and was associated with the expression of VGLL3 in RA and OA patients. VGLL3 promoted the IRF3 activation and IFN-ß1 expression in RA-FLS. Increased IFN-ß1 induced the expression of IFN-stimulated genes in RA-FLS in an autocrine manner. VGLL3 also modulated the expression of the Hippo pathway molecules WWTR1 and AMOTL2, which mediated the regulation of IRF3 activation and IFN-ß1 production by VGLL3 in RA-FLS. CONCLUSIONS: VGLL3 drives the IRF3-induced IFN-ß1 expression in RA-FLS by inhibiting WWTR1 expression and subsequently promotes the type I IFN signature expression in RA-FLS through autocrine IFN-ß1 signaling.


Assuntos
Artrite Reumatoide , Interferon Tipo I , Osteoartrite , Sinoviócitos , Angiomotinas , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Proteínas de Transporte/metabolismo , Células Cultivadas , Fibroblastos/metabolismo , Via de Sinalização Hippo , Humanos , Interferon Tipo I/metabolismo , Osteoartrite/metabolismo , Membrana Sinovial/metabolismo , Sinoviócitos/metabolismo , Fatores de Transcrição/metabolismo
2.
Int J Mol Sci ; 23(13)2022 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-35806074

RESUMO

Extensive angiogenesis is a characteristic feature in the synovial tissue of rheumatoid arthritis (RA) from a very early stage of the disease onward and constitutes a crucial event for the development of the proliferative synovium. This process is markedly intensified in patients with prolonged disease duration, high disease activity, disease severity, and significant inflammatory cell infiltration. Angiogenesis is therefore an interesting target for the development of new therapeutic approaches as well as disease monitoring strategies in RA. To this end, nuclear imaging modalities represent valuable non-invasive tools that can selectively target molecular markers of angiogenesis and accurately and quantitatively track molecular changes in multiple joints simultaneously. This systematic review summarizes the imaging markers used for single photon emission computed tomography (SPECT) and/or positron emission tomography (PET) approaches, targeting pathways and mediators involved in synovial neo-angiogenesis in RA.


Assuntos
Artrite Reumatoide , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/metabolismo , Biomarcadores/metabolismo , Humanos , Imagem Molecular , Neovascularização Patológica/diagnóstico por imagem , Neovascularização Patológica/metabolismo , Tomografia por Emissão de Pósitrons , Membrana Sinovial/diagnóstico por imagem , Membrana Sinovial/metabolismo
3.
Int J Mol Sci ; 23(14)2022 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-35886901

RESUMO

There is growing evidence regarding the role of mitochondrial dysfunction in osteoarthritis (OA) and rheumatoid arthritis (RA). However, quantitative comparison of synovial mitochondrial derangements in these main arthritis forms is missing. A prospective clinical study was conducted on adult patients undergoing knee surgery. Patients were allocated into RA and OA groups based on disease-specific clinical scores, while patients without arthritis served as controls. Synovial samples were subjected to high-resolution respirometry to analyze mitochondrial functions. From the total of 814 patients, 109 cases were enrolled into the study (24 RA, 47 OA, and 38 control patients) between 1 September 2019 and 31 December 2021. The decrease in complex I-linked respiration and dyscoupling of mitochondria were characteristics of RA patients, while both arthritis groups displayed reduced OxPhos activity compared to the control group. However, no significant difference was found in complex II-related activity between the OA and RA groups. The cytochrome C release and H2O2 formation were increased in both arthritis groups. Mitochondrial dysfunction was present in both arthritis groups; however, to a different extent. Consequently, mitochondrial protective agents may have major benefits for arthritis patients. Based on our current study, we recommend focusing on respiratory complex I in rheumatoid arthritis research.


Assuntos
Artrite Reumatoide , Osteoartrite , Adulto , Artrite Reumatoide/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Mitocôndrias , Osteoartrite/metabolismo , Estudos Prospectivos , Líquido Sinovial/metabolismo , Membrana Sinovial/metabolismo
4.
Sci Rep ; 12(1): 11830, 2022 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-35821263

RESUMO

Rheumatoid arthritis (RA) is characterized by joint infiltration of immune cells and synovial inflammation which leads to progressive disability. Current treatments improve the disease outcome, but the unmet medical need is still high. New discoveries over the last decade have revealed the major impact of cellular metabolism on immune cell functions. So far, a comprehensive understanding of metabolic changes during disease development, especially in the diseased microenvironment, is still limited. Therefore, we studied the longitudinal metabolic changes during the development of murine arthritis by integrating metabolomics and transcriptomics data. We identified an early change in macrophage pathways which was accompanied by oxidative stress, a drop in NAD+ level and induction of glucose transporters. We discovered inhibition of SIRT1, a NAD-dependent histone deacetylase and confirmed its dysregulation in human macrophages and synovial tissues of RA patients. Mining this database should enable the discovery of novel metabolic targets and therapy opportunities in RA.


Assuntos
Artrite Experimental , Artrite Reumatoide , Sirtuína 1 , Animais , Artrite Experimental/metabolismo , Artrite Reumatoide/metabolismo , Humanos , Inflamação/metabolismo , Camundongos , Sirtuína 1/metabolismo , Membrana Sinovial/metabolismo
5.
Cell Death Dis ; 13(7): 608, 2022 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-35835748

RESUMO

Abnormal activation of synovial fibroblasts (SFs) plays an important role in rheumatoid arthritis (RA), the mechanism of which remains unknown. The purpose of our study is to comprehensively and systematically explore the mechanism for Semaphorin 5A-mediated abnormal SF activation in RA. Here, we found that Semaphorin 5A levels were significantly higher in synovial fluid and synovial tissue from RA patients compared with osteoarthritis patients. We further found that the mRNA level and protein abundance of Plexin-A1 was elevated in RA SFs compared with OA SFs, while Plexin-B3 expression showed no significant difference. The increased Semaphorin 5A in RA synovial fluid was mainly derived from CD68+ synovial macrophages, and the elevation led to increased binding between Semaphorin 5A and its receptors, thereby promoting cytokine secretion, proliferation, and migration, and decreasing apoptosis. Moreover, the effect of Semaphorin 5A on enhancing activation (cytokine secretion, cell proliferation and migration) and reducing apoptosis of SFs was significantly abolished after knockdown of Plexin-A1 and Plexin-B3 by small interfering RNA. Transcriptome sequencing and protein array detection revealed that Semaphorin 5A activated the PI3K/AKT/mTOR signaling pathway and inhibited ferroptosis. Morphologically, transmission electron microscopy results showed that Semaphorin 5A could significantly eliminate the mitochondrial diminution, membrane density increased and crest ruptured of SFs induced by ferroptosis inducer RSL3. Mechanistically, Semaphorin 5A enhanced GPX4 expression and SREBP1/SCD-1 signaling by activating the PI3K/AKT/mTOR signaling pathway, thus suppressing ferroptosis of RA SFs. In conclusion, our study provided the first evidence that elevated Semaphorin 5A in RA synovial fluid promotes SF activation by suppressing ferroptosis through the PI3K/AKT/mTOR signaling pathway.


Assuntos
Artrite Reumatoide , Ferroptose , Osteoartrite , Semaforinas , Artrite Reumatoide/metabolismo , Citocinas/metabolismo , Fibroblastos/metabolismo , Humanos , Osteoartrite/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Semaforinas/genética , Semaforinas/metabolismo , Transdução de Sinais , Membrana Sinovial/metabolismo , Serina-Treonina Quinases TOR/metabolismo
6.
Genome Med ; 14(1): 78, 2022 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-35879783

RESUMO

BACKGROUND: Synovial fibroblasts (SFs) are specialized cells of the synovium that provide nutrients and lubricants for the proper function of diarthrodial joints. Recent evidence appreciates the contribution of SF heterogeneity in arthritic pathologies. However, the normal SF profiles and the molecular networks that govern the transition from homeostatic to arthritic SF heterogeneity remain poorly defined. METHODS: We applied a combined analysis of single-cell (sc) transcriptomes and epigenomes (scRNA-seq and scATAC-seq) to SFs derived from naïve and hTNFtg mice (mice that overexpress human TNF, a murine model for rheumatoid arthritis), by employing the Seurat and ArchR packages. To identify the cellular differentiation lineages, we conducted velocity and trajectory analysis by combining state-of-the-art algorithms including scVelo, Slingshot, and PAGA. We integrated the transcriptomic and epigenomic data to infer gene regulatory networks using ArchR and custom-implemented algorithms. We performed a canonical correlation analysis-based integration of murine data with publicly available datasets from SFs of rheumatoid arthritis patients and sought to identify conserved gene regulatory networks by utilizing the SCENIC algorithm in the human arthritic scRNA-seq atlas. RESULTS: By comparing SFs from healthy and hTNFtg mice, we revealed seven homeostatic and two disease-specific subsets of SFs. In healthy synovium, SFs function towards chondro- and osteogenesis, tissue repair, and immune surveillance. The development of arthritis leads to shrinkage of homeostatic SFs and favors the emergence of SF profiles marked by Dkk3 and Lrrc15 expression, functioning towards enhanced inflammatory responses and matrix catabolic processes. Lineage inference analysis indicated that specific Thy1+ SFs at the root of trajectories lead to the intermediate Thy1+/Dkk3+/Lrrc15+ SF states and culminate in a destructive and inflammatory Thy1- SF identity. We further uncovered epigenetically primed gene programs driving the expansion of these arthritic SFs, regulated by NFkB and new candidates, such as Runx1. Cross-species analysis of human/mouse arthritic SF data determined conserved regulatory and transcriptional networks. CONCLUSIONS: We revealed a dynamic SF landscape from health to arthritis providing a functional genomic blueprint to understand the joint pathophysiology and highlight the fibroblast-oriented therapeutic targets for combating chronic inflammatory and destructive arthritic disease.


Assuntos
Artrite Reumatoide , Análise de Célula Única , Animais , Artrite Reumatoide/genética , Artrite Reumatoide/patologia , Fibroblastos/metabolismo , Humanos , Inflamação/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia
7.
Pol J Pathol ; 73(1): 21-26, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35848477

RESUMO

In this study, the immunohistochemical EnVision method was applied to detect CD3, CD4 and CD8 in synovial tissues of 40 patients with rheumatoid arthritis (RA) and 10 patients with osteoarthritis (OA). In 92.5% (37/40) RA cases, lymphocytes were focally aggregated, and even germinal centers appeared, forming lymphoid follicle-like structures. The expression of CD3, CD4, and CD8 were high in synovial tissue of RA group, but low in OA group. The number of CD3, CD4+, and CD8+ lymphocytes in OA group were significantly lower than that in RA group (p < 0.05); CD4+lymphocytes in RA accounted for the majority, and mostly were focally distributed. The number of CD8+lymphocytes in the synovial tissue were small, and were mostly scattered. The number of CD4+lymphocytes were significantly higher than CD8+lymphocytes (p<0.05). Compared with the OA group, the number of CD4+T and CD8+T lymphocytes in RA group were higher, and the ratio of CD4/CD8 was higher in RA group (p < 0.05). In conclusion, the CD3, CD4 and CD8 with high level may promote the occurrence and development of RA. The ratio of CD4+/CD8+ may be used as a reference index for the diagnosis and prognosis of RA.


Assuntos
Artrite Reumatoide , Artrite Reumatoide/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Humanos , Membrana Sinovial/química , Membrana Sinovial/metabolismo
8.
JCI Insight ; 7(13)2022 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-35801586

RESUMO

IL-1 receptor-activated kinase 1 (IRAK1) is involved in signal transduction downstream of many TLRs and the IL-1R. Its potential as a drug target for chronic inflammatory diseases is underappreciated. To study its functional role in joint inflammation, we generated a mouse model expressing a functionally inactive IRAK1 (IRAK1 kinase deficient, IRAK1KD), which also displayed reduced IRAK1 protein expression and cell type-specific deficiencies of TLR signaling. The serum transfer model of arthritis revealed a potentially novel role of IRAK1 for disease development and neutrophil chemoattraction exclusively via its activity in nonhematopoietic cells. Consistently, IRAK1KD synovial fibroblasts showed reduced secretion of neutrophil chemoattractant chemokines following stimulation with IL-1ß or human synovial fluids from patients with rheumatoid arthritis (RA) and gout. Together with patients with RA showing prominent IRAK1 expression in fibroblasts of the synovial lining, these data suggest that targeting IRAK1 may be therapeutically beneficial. As pharmacological inhibition of IRAK1 kinase activity had only mild effects on synovial fibroblasts from mice and patients with RA, targeted degradation of IRAK1 may be the preferred pharmacologic modality. Collectively, these data position IRAK1 as a central regulator of the IL-1ß-dependent local inflammatory milieu of the joints and a potential therapeutic target for inflammatory arthritis.


Assuntos
Artrite Reumatoide , Quinases Associadas a Receptores de Interleucina-1 , Neutrófilos , Membrana Sinovial , Animais , Artrite Reumatoide/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Interleucina-8/metabolismo , Camundongos , Neutrófilos/metabolismo , Membrana Sinovial/metabolismo
9.
Bioengineered ; 13(5): 13632-13642, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35653787

RESUMO

This study aimed to explore the effects of plumbagin on rheumatoid arthritis (RA) and its mechanism. The RA cell model was simulated following the treatment of interleukin-1ß (IL-1ß). After the treatment of various concentrations of plumbagin, the impact of plumbagin on the cell viability was examined by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The collagen-induced arthritis (CIA) model was established using the solution of bovine type II collagen. Hematoxylin-eosin staining was used to observe the changes of ankle joint tissue, while enzyme-linked immunosorbent assay and western blot were applied to detect the level of inflammatory cytokines. Plumbagin inhibited the viability of human fibroblast-like synoviocytes (HFLS) at the concentration of 1 ~ 3.5 µM. The inhibitory effect of 1 µM plumbagin on cell proliferation was similar to that of methotrexate, the drug used as the positive control. Plumbagin downregulated the levels of inflammatory cytokines and matrix metalloproteinases (MMPs) in IL-1ß-treated HFLS, and suppressed the activation of IκB and nuclear factor kappa-B (NF-κB) as well as the entry of p65 into the nucleus. It was also demonstrated in animal experiments that plumbagin inhibited the activation of NF-κB pathway, down-regulated the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and MMPs, and alleviated joint damage in CIA-modeled mice. Collectively speaking, plumbagin might down-regulate the levels of inflammatory cytokines and MMPs through inhibiting the activation of the NF-κB pathway, thereby attenuating RA-induced damage to cells and joints.Abbreviations: CIA: Collagen-induced arthritis; ELISA: Enzyme-linked immuno sorbent assay; HFLS: Human fibroblast-like synoviocytes; IL-6: Interleukin-6; IL-1ß: Interleukin-1ß; NF-κB: nuclear factor kappa-B; MTT: 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; MMPs: Matrix metalloproteinase; OD: Optical density; RA: Rheumatoid arthritis; SDS: Sodium dodecyl sulfate; SD: Standard deviation; TNF-α: Tumor necrosis factor-α; PVDF: Polyvinylidene fluoride.


Assuntos
Artrite Experimental , Artrite Reumatoide , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Bovinos , Células Cultivadas , Citocinas/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Metaloproteinases da Matriz/metabolismo , Metaloproteinases da Matriz/farmacologia , Metaloproteinases da Matriz/uso terapêutico , Camundongos , NF-kappa B/metabolismo , Naftoquinonas , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
10.
Arthritis Res Ther ; 24(1): 134, 2022 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-35659346

RESUMO

OBJECTIVES: Methotrexate (MTX) is an anchor drug for the treatment of rheumatoid arthritis (RA). However, the precise mechanisms by which MTX stalls RA progression and alleviates the ensuing disease effects remain unknown. The aim of the present study was to identify novel therapeutic target molecules, the expression patterns of which are affected by MTX in patients with RA. METHODS: CD4+ T cells from 28 treatment-naïve patients with RA before and 3 months after the initiation of MTX treatment were subjected to DNA microarray analyses. The expression levels of semaphorin 3G, a differentially expressed gene, and its receptor, neuropilin-2, were evaluated in the RA synovium and collagen-induced arthritis synovium. Collagen-induced arthritis and collagen antibody-induced arthritis were induced in semaphorin3G-deficient mice and control mice, and the clinical score, histological score, and serum cytokines were assessed. The migration and proliferation of semaphorin 3G-stimulated bone marrow-derived macrophages were analyzed in vitro. The effect of local semaphorin 3G administration on the clinical score and number of infiltrating macrophages during collagen antibody-induced arthritis was evaluated. RESULTS: Semaphorin 3G expression in CD4+ T cells was downregulated by MTX treatment in RA patients. It was determined that semaphorin 3G is expressed in RA but not in the osteoarthritis synovium; its receptor neuropilin-2 is primarily expressed on activated macrophages. Semaphorin3G deficiency ameliorated collagen-induced arthritis and collagen antibody-induced arthritis. Semaphorin 3G stimulation enhanced the migration and proliferation of bone marrow-derived macrophages. Local administration of semaphorin 3G deteriorated collagen antibody-induced arthritis and increased the number of infiltrating macrophages. CONCLUSIONS: Upregulation of semaphorin 3G in the RA synovium is a novel mechanism that exacerbates joint inflammation, leading to further deterioration, through macrophage accumulation.


Assuntos
Artrite Experimental , Artrite Reumatoide , Semaforinas , Animais , Artrite Experimental/patologia , Artrite Reumatoide/tratamento farmacológico , Proliferação de Células , Colágeno/metabolismo , Humanos , Inflamação/patologia , Macrófagos/metabolismo , Metotrexato/farmacologia , Metotrexato/uso terapêutico , Camundongos , Neuropilina-2/metabolismo , Semaforinas/metabolismo , Membrana Sinovial/metabolismo
11.
Nutrients ; 14(11)2022 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-35684149

RESUMO

Glucose is the most important source of energy and homeostasis. Recent investigations are clarifying that glucose metabolism might be altered in rheumatoid arthritis (RA), which would play a role in the inflammatory phenotype of rheumatoid synovial fibroblasts. It may also play a role in a variety of autoimmune diseases' pathophysiology by modulating immune responses and modifying autoantigen expressions. The research into glucose and its metabolism could lead to a better understanding of how carbohydrates contribute to the occurrence and duration of RA and other autoimmune diseases.


Assuntos
Artrite Reumatoide , Membrana Sinovial , Fibroblastos/metabolismo , Glucose/metabolismo , Humanos , Inflamação/metabolismo , Membrana Sinovial/metabolismo
12.
Mol Med ; 28(1): 64, 2022 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-35690741

RESUMO

BACKGROUND: Hypoxia is one of the important characteristics of synovial microenvironment in rheumatoid arthritis (RA), and plays an important role in synovial hyperplasia. In terms of cell survival, fibroblast-like synovial cells (FLSs) are relatively affected by hypoxia. In contrast, fibroblast-like synovial cells from patients with RA (RA-FLSs) are particularly resistant to hypoxia-induced cell death. The purpose of this study was to evaluate whether fibroblast-like synovial cells in patients with osteoarthritis (OA-FLSs) and RA-FLSs have the same adaptation to hypoxia. METHODS: CCK-8, flow cytometry and BrdU were used to detect the proliferation of OA-FLSs and RA-FLSs under different oxygen concentrations. Apoptosis was detected by AV/PI, TUNEL and Western blot, mitophagy was observed by electron microscope, laser confocal microscope and Western blot, the state of mitochondria was detected by ROS and mitochondrial membrane potential by flow cytometry, BNIP3 and HIF-1α were detected by Western blot and RT-qPCR. The silencing of BNIP3 was achieved by stealth RNA system technology. RESULTS: After hypoxia, the survival rate of OA-FLSs decreased, while the proliferation activity of RA-FLSs further increased. Hypoxia induced an increase in apoptosis and inhibition of mitophagy in OA-FLSs, but not in RA-FLSs. Hypoxia led to a more lasting adaptive response. RA-FLSs displayed a more significant increase in the expression of genes transcriptionally regulated by HIF-1α. Interestingly, they showed higher BNIP3 expression than OA-FLSs, and showed stronger mitophagy and proliferation activities. BNIP3 siRNA experiment confirmed the potential role of BNIP3 in the survival of RA-FLSs. Inhibition of BNIP3 resulted in the decrease of cell proliferation, mitophagy and the increase of apoptosis. CONCLUSION: In summary, RA-FLSs maintained intracellular redox balance through mitophagy to promote cell survival under hypoxia. The mitophagy of OA-FLSs was too little to maintain the redox balance of mitochondria, resulting in apoptosis. The difference of mitophagy between OA-FLSs and RA-FLSs under hypoxia is mediated by the level of BNIP3 expression.


Assuntos
Artrite Reumatoide , Osteoartrite , Sinoviócitos , Artrite Reumatoide/genética , Proliferação de Células/genética , Células Cultivadas , Fibroblastos/metabolismo , Humanos , Hipóxia/metabolismo , Proteínas de Membrana/genética , Osteoartrite/genética , Osteoartrite/metabolismo , Proteínas Proto-Oncogênicas , Membrana Sinovial/metabolismo , Sinoviócitos/metabolismo
13.
Mediators Inflamm ; 2022: 2606916, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35693109

RESUMO

Background: Rheumatoid arthritis (RA) and osteoarthritis (OA) are common joint diseases associated with changes in local, as well as systemic bone structure and osteoclast function. We investigated how the different soluble inflammatory stimuli in these diseases can affect osteoclastogenesis and bone resorption in vitro. Methods. Human peripheral blood mononuclear cell-derived osteoclasts were cultured on bone slices with serum from treatment-naïve RA patients and healthy controls and with synovial fluid samples acquired from RA and OA patients. The concentrations of 29 different cytokines and related proteins, including RANKL and OPG, were analyzed in the fluids tested. Results: RA serum and synovial fluid increased both osteoclastogenesis and bone resorption. Osteoclastogenesis and activity increased more in the cultures containing OA than RA synovial fluid. The osteoclasts cultured in different culture media exhibited different phenotypes, especially the cells cultured with OA synovial fluid were generally larger and had more nuclei. A general increase in proinflammatory cytokines in RA synovial fluid and serum was found. Surprisingly, OA synovial fluid showed lower levels of osteoclastogenesis inhibiting cytokines, such as IL-4 and IL-10, than RA synovial fluid, which at least partly explains more pronounced osteoclastogenesis. No significant difference was found in RANKL or OPG levels. Conclusion: The proinflammatory stimulus in OA and RA drives the monocyte differentiation towards inflammatory osteoclastogenesis and altered osteoclast phenotype.


Assuntos
Artrite Reumatoide , Reabsorção Óssea , Osteoartrite , Artrite Reumatoide/metabolismo , Reabsorção Óssea/metabolismo , Citocinas/metabolismo , Humanos , Leucócitos Mononucleares/metabolismo , Monócitos/metabolismo , Osteoartrite/metabolismo , Osteoclastos/metabolismo , Osteogênese , Líquido Sinovial/metabolismo , Membrana Sinovial/metabolismo
14.
Int J Mol Sci ; 23(12)2022 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-35743247

RESUMO

Osteoarthritis (OA) is characterized by the infiltration and adhesion of monocytes into the inflamed joint synovium. Interleukin (IL)-17 is a critical inflammatory mediator that participates in the progression of OA, although the mechanisms linking IL-17 and monocyte infiltration are not well understood. Our analysis of synovial tissue samples retrieved from the Gene Expression Omnibus (GEO) dataset exhibited higher monocyte marker (CD11b) and vascular cell adhesion molecule 1 (VCAM-1) levels in OA samples than in normal, healthy samples. The stimulation of human OA synovial fibroblasts (OASFs) with IL-17 increased VCAM-1 production and subsequently enhanced monocyte adhesion. IL-17 affected VCAM-1-dependent monocyte adhesion by reducing miR-5701 expression through the protein kinase C (PKC)-α and c-Jun N-terminal kinase (JNK) signaling cascades. Our findings improve our understanding about the effect of IL-17 on OA progression and, in particular, VCAM-1 production and monocyte adhesion, which may help with the design of more effective OA treatments.


Assuntos
MicroRNAs , Osteoartrite , Fibroblastos/metabolismo , Humanos , Interleucina-17/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Monócitos/metabolismo , Osteoartrite/genética , Osteoartrite/metabolismo , Membrana Sinovial/metabolismo , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/metabolismo
15.
Adv Rheumatol ; 62(1): 21, 2022 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-35725524

RESUMO

OBJECTIVES: To describe the feature of expression of syndecan-4 in serum, synovial fluid (SF) and synovium in rheumatoid arthritis (RA) patients, and to analyze the correlation of syndecan-4 with disease activity and serological characteristic of RA. METHODS: Syndecan-4 in sera of 60 RA patients, 20 osteoarthritis (OA) patients, 20 healthy controls, and in SF of 25 RA patients and 25 OA patients were tested by enzyme linked immunosorbant assay. The expressions of syndecan-4 in synovium of RA and OA patients were detected by immunohistochemistry. The expression of syndecan-4 on synovial fibroblasts from RA and OA patients were detected by immunofluorescence. The correlation between serum syndecan-4 concentration and disease activity were analyzed in RA patients. RESULTS: The serum syndedcan-4 concentration was significantly higher in RA patients than in OA patients and healthy controls, and was higher in rheumatoid factor (RF)-positive RA patients than in RF-negative ones. Syndecan-4 concentration in SF of RA patients was comparable with OA patients. Syndecan-4 expression in synovial tissue was similar between RA and OA patients. The syndecan-4 concentration was significantly lower in SF than in serum of RA and OA patients. Syndecan-4 concentration in both serum and SF was positively correlated with disease activity of RA patients. CONCLUSION: The serum syndecan-4 concentration was higher in RA patients than in OA patients, and significantly higher in RF-positive RA patients than in RF-negative ones. Syndecan-4 concentration in both serum and SF was positively correlated with disease activity of RA patients.


Assuntos
Artrite Reumatoide , Osteoartrite , Sindecana-4 , Artrite Reumatoide/diagnóstico , Humanos , Osteoartrite/diagnóstico , Sindecana-4/metabolismo , Líquido Sinovial , Membrana Sinovial/metabolismo
16.
J Interferon Cytokine Res ; 42(6): 279-289, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35699481

RESUMO

Rheumatoid arthritis (RA) is a systemic immune disease. Rho family GTPase 3 (RND3) has been reported to play an important role in inflammatory diseases. In this study, the expression of RND3 in RA was analyzed by gene chips. After RND3 was overexpressed, cell counting kit-8 assay was to detect the viability of fibroblast-like synovial cells (RA-FLSs). Transwell assays were to appraise the migratory and invasive capacities of RA-FLSs. Enzyme-linked immunosorbent assay (ELISA) and Western blot analysis were to estimate inflammatory response. In addition, MMP3 and MMP9 levels were also tested by ELISA analysis. After forkhead box M1 (FOXM1) was overexpressed, RND3 expression was detected by Western blot. The transcriptional relationship between FOXM1 and RND3 was predicted by HumanTFDB and JASPAR databases. Luciferase reporter and chromatin immunoprecipitation assays verified the binding ability of FOXM1 and RND3. The role of FOXM1/RND3 axis in RA was detected again by functional experiments. Western blot detected the expression of Rho/ROCK pathway-related proteins. RND3 expression was downregulated in RA. Overexpression of RND3 reduced the proliferation, migration, invasion, and inflammation of RA-FLSs. RND3 was inhibited by FOXM1 transcription, and upregulated FOXM1 reduced the inhibitory effect of RND3 overexpression on cell growth and inflammation, which might be associated with the Rho/ROCK pathway. RND3 transcriptionally regulated by FOXM1 inhibited the migration and inflammation of RA-FLSs in RA through the Rho/ROCK pathway.


Assuntos
Artrite Reumatoide , Fibroblastos , Membrana Sinovial , Proteínas rho de Ligação ao GTP , Quinases Associadas a rho , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Movimento Celular , Proliferação de Células , Células Cultivadas , Fibroblastos/metabolismo , Fibroblastos/patologia , Proteína Forkhead Box M1/genética , Proteína Forkhead Box M1/metabolismo , Humanos , Inflamação/genética , Inflamação/metabolismo , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia , Proteínas rho de Ligação ao GTP/genética , Proteínas rho de Ligação ao GTP/metabolismo , Quinases Associadas a rho/metabolismo
17.
Zhen Ci Yan Jiu ; 47(6): 471-8, 2022 Jun 25.
Artigo em Chinês | MEDLINE | ID: mdl-35764512

RESUMO

OBJECTIVE: To observe the effect of electroacupuncture (EA) on pyroptosis-related proteins in synovium of knee joint in rats with knee osteoarthritis(KOA), in order to explore its mechanism underlying improvement of KOA. METHODS: Forty male SD rats were randomly divided into control, model, EA and medication groups, with 10 rats in each group. The KOA model was established by injecting 0.2 mL 4% papain solution into the right intra-articular cavity, followed by repeating the injection again on day 4 and 7 after the first injection. After successful modeling, rats of the EA group received EA stimulation of "Neixiyan" (EX-LE4) and "Dubi"(ST35) on the right limb for 15 min, once every day, 6 days per week, for a total of 4 weeks, and those of the medication group received gavage of celecoxib 24 mg/kg, once every day, 6 days per week, for a total of 4 weeks. The severity of dysfunction of the right knee was assessed by using Lequesne's score. Serum interleukin(IL)-1ß and IL-18 contents were detected by ELISA. Histopathological changes of the synovium tissue of the right knee joint were observed to give score (synovial pathological score) after H.E. staining. The expression position and intensity of Nod-like receptor pyrin domain 3 (NLRP3) in syno-vial tissue were observed by immunohistochemistry. The expression levels of NLRP3, apoptosis-associated speck-like protein containing card (ASC), Caspase-1, Gasdermin D(GSDMD), IL-1ß and IL-18 mRNAs and proteins (including GSDMD-N) in the synovial tissue of the right knee joint were detected by real-time fluorescence quantitative PCR and Western blot, separately. RESULTS: Compared with the control group, the model group had a significant increase in the Lequesne's score, synovial pathological score, serum IL-1ß and IL-18 contents, and the expression levels of NLRP3, ASC, Caspase-1, GSDMD, IL-1ß, IL-18 mRNAs and proteins and GSDMD-N protein (P<0.01). Whereas relevant to the model group, both the EA and medication groups had marked lower levels of Lequesne's score and synovial pathological score, serum IL-1ß and IL-18 contents, and expression levels of NLRP3, ASC, Caspase-1, IL-1ß, IL-18 mRNAs and proteins, GSDMD mRNA and GSDMD-N protein (P<0.01, P<0.05). Comparison between two intervention groups showed that the contents of serum IL-1ß and IL-18, and the expression levels of IL-1ß mRNA and protein were significantly higher in the EA group than in the medication group (P<0.05, P<0.01). No significant differences were found between the EA and medication groups in the Lequesne's score, synovial pathological score, NLRP3, ASC, Caspase-1 and IL-18 mRNAs and proteins, as well as GSDMD mRNA (P>0.05). CONCLUSION: EA can alleviate the inflammatory response of synovial tissues of knee joints in KOA rats, which may be related to its function in down-regulating the expression levels of synovial NLRP3, ASC, Caspase-1, IL-1ß and IL-18 mRNAs and proteins, and GSDMD mRNA and GSDMD-N proteins, reducing the occurrence of pyroptosis.


Assuntos
Eletroacupuntura , Osteoartrite do Joelho , Animais , Caspases/uso terapêutico , Interleucina-18/uso terapêutico , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Osteoartrite do Joelho/genética , Osteoartrite do Joelho/terapia , Piroptose/genética , RNA Mensageiro , Ratos , Ratos Sprague-Dawley , Membrana Sinovial/metabolismo
18.
Adv Mater ; 34(30): e2202715, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35671349

RESUMO

Osteoarthritis (OA) is a low-grade inflammatory and progressive joint disease, and its progression is closely associated with an imbalance in M1/M2 synovial macrophages. Repolarizing pro-inflammatory M1 macrophages into the anti-inflammatory M2 phenotype is emerging as a strategy to alleviate OA progression but is compromised by unsatisfactory efficiency. In this study, the reprogramming of mitochondrial dysfunction is pioneered with a camouflaged meta-Defensome, which can transform M1 synovial macrophages into the M2 phenotype with a high efficiency of 82.3%. The meta-Defensome recognizes activated macrophages via receptor-ligand interactions and accumulates in the mitochondria through electrostatic attractions. These meta-Defensomes are macrophage-membrane-coated polymeric nanoparticles decorated with dual ligands and co-loaded with S-methylisothiourea and MnO2 . Meta-Defensomes are demonstrated to successfully reprogram the mitochondrial metabolism of M1 macrophages by scavenging mitochondrial reactive oxygen species and inhibiting mitochondrial NO synthase, thereby increasing mitochondrial transcription factor A expression and restoring aerobic respiration. Furthermore, meta-Defensomes are intravenously injected into collagenase-induced osteoarthritis mice and effectively suppress synovial inflammation and progression of early OA, as evident from the Osteoarthritis Research Society International score. Therefore, reprogramming the mitochondrial metabolism can serve as a novel and practical approach to repolarize M1 synovial macrophages. The camouflaged meta-Defensomes are a promising therapeutic agent for impeding OA progression in tclinic.


Assuntos
Osteoartrite , Membrana Sinovial , Animais , Macrófagos , Compostos de Manganês , Camundongos , Mitocôndrias/metabolismo , Osteoartrite/metabolismo , Óxidos/farmacologia , Membrana Sinovial/metabolismo
19.
J Immunol ; 208(11): 2482-2496, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35500934

RESUMO

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial hyperplasia and inflammation. The finding of autoantibodies in seropositive RA suggests that complement system activation might play a pathophysiologic role due to the local presence of immune complexes in the joints. Our first objective was to explore the Pathobiology of Early Arthritis Cohort (PEAC) mRNA sequencing data for correlations between clinical disease severity as measured by DAS28-ESR (disease activity score in 28 joints for erythrocyte sedimentation rate) and complement system gene expression, both in the synovium and in blood. Our second objective was to determine the biodistribution using multiplex immunohistochemical staining of specific complement activation proteins and inhibitors from subjects in the Accelerating Medicines Partnership (AMP) RA/SLE study. In the PEAC study, there were significant positive correlations between specific complement gene mRNA expression levels in the synovium and DAS28-ESR for the following complement genes: C2, FCN1, FCN3, CFB, CFP, C3AR1, C5AR1, and CR1 Additionally, there were significant negative correlations between DAS28-ESR and Colec12, C5, C6, MASP-1, CFH, and MCP In the synovium there were also significant positive correlations between DAS28-ESR and FcγR1A, FcγR1B, FcγR2A, and FcγR3A Notably, CFHR4 synovial expression was positively correlated following treatment with the DAS28-ESR at 6 mo, suggesting a role in worse therapeutic responses. The inverse correlation of C5 RNA expression in the synovium may underlie the failure of significant benefit from C5/C5aR inhibitors in clinical trials performed in patients with RA. Multiplex immunohistochemical analyses of early RA synovium reveal significant evidence of regional alterations of activation and inhibitory factors that likely promote local complement activation.


Assuntos
Artrite Reumatoide , Membrana Sinovial , Artrite Reumatoide/tratamento farmacológico , Proteínas do Sistema Complemento/metabolismo , Expressão Gênica , Humanos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Índice de Gravidade de Doença , Membrana Sinovial/metabolismo , Distribuição Tecidual
20.
Cell Rep ; 39(5): 110766, 2022 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-35508128

RESUMO

Ectopic lymphoid structures (ELS) can develop in rheumatoid arthritis (RA) synovial tissue, but the precise pathways of B cell activation and selection are not well understood. Here, we identify a synovial B cell population characterized by co-expression of a family of orphan nuclear receptors (NR4A1-3), which is highly enriched in RA synovial tissue. A transcriptomic profile of NR4A synovial B cells significantly overlaps with germinal center light zone B cells and an accrual of somatic hypermutation that correlates with loss of naive B cell state. NR4A B cells co-express lymphotoxins α and ß and IL-6, supporting functions in ELS promotion. Expanded and shared clones between synovial NR4A B cells and plasma cells and the rapid upregulation with BCR stimulation point to in situ differentiation. Together, we identify a dynamic progression of B cell activation in RA synovial ELS, with NR4A transcription factors having an important role in local adaptive immune responses.


Assuntos
Artrite Reumatoide , Membrana Sinovial , Linfócitos B , Humanos , Plasmócitos/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Membrana Sinovial/metabolismo
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