RÉSUMÉ
BACKGROUND: Synovial fibrosis is a common complication of knee osteoarthritis (KOA), a pathological process characterized by myofibroblast activation and excessive extracellular matrix (ECM) deposition. Fibroblast-like synoviocytes (FLSs) are implicated in KOA pathogenesis, contributing to synovial fibrosis through diverse mechanisms. Nuclear protein 1 (NUPR1) is a recently identified transcription factor with crucial roles in various fibrotic diseases. However, its molecular determinants in KOA synovial fibrosis remain unknown. This study aims to investigate the role of NUPR1 in KOA synovial fibrosis through in vivo and in vitro experiments. METHODS: We examined NUPR1 expression in the murine synovium and determined the impact of NUPR1 on synovial fibrosis by knockdown models in the destabilization of the medial meniscus (DMM)-induced KOA mouse model. TGF-ß was employed to induce fibrotic response and myofibroblast activation in mouse FLSs, and the role and molecular mechanisms in synovial fibrosis were evaluated under conditions of NUPR1 downexpression. Additionally, the pharmacological effect of NUPR1 inhibitor in synovial fibrosis was assessed using a surgically induced mouse KOA model. RESULTS: We found that NUPR1 expression increased in the murine synovium after DMM surgical operation. The adeno-associated virus (AAV)-NUPR1 shRNA promoted NUPR1 deficiency, attenuating synovial fibrosis, inhibiting synovial hyperplasia, and significantly reducing the expression of pro-fibrotic molecules. Moreover, the lentivirus-mediated NUPR1 deficiency alleviated synoviocyte proliferation and inhibited fibroblast to myofibroblast transition. It also decreased the expression of fibrosis markers α-SMA, COL1A1, CTGF, Vimentin and promoted the activation of the SMAD family member 3 (SMAD3) pathway. Importantly, trifluoperazine (TFP), a NUPR1 inhibitor, attenuated synovial fibrosis in DMM mice. CONCLUSIONS: These findings indicate that NUPR1 is an antifibrotic modulator in KOA, and its effect on anti-synovial fibrosis is partially mediated by SMAD3 signaling. This study reveals a promising target for developing novel antifibrotic treatment.
Sujet(s)
Fibroblastes , Fibrose , Transduction du signal , Protéine Smad-3 , Cellules synoviales , Animaux , Protéine Smad-3/métabolisme , Cellules synoviales/métabolisme , Cellules synoviales/anatomopathologie , Fibroblastes/métabolisme , Fibroblastes/anatomopathologie , Souris de lignée C57BL , Membrane synoviale/anatomopathologie , Membrane synoviale/métabolisme , Mâle , Gonarthrose/anatomopathologie , Gonarthrose/métabolisme , Modèles animaux de maladie humaine , Souris , Facteurs de transcription à motif basique hélice-boucle-hélice/métabolisme , Protéines de liaison à l'ADN , Protéines tumoralesRÉSUMÉ
Degenerative disorders like osteoarthritis (OA) might impair the ability of tissue-resident mesenchymal stem/stromal cells (MSCs) for tissue regeneration. As primary cells with MSC-like properties are exploited for patient-derived stem cell therapies, a detailed evaluation of their in vitro properties is needed. Here, we aimed to compare synovium-derived and bone-derived MSCs in early hip OA with those of patients without OA (non-OA). Tissues from three synovial sites of the hip (paralabral synovium, cotyloid fossa, inner surface of peripheral capsule) were collected along with peripheral trabecular bone from 16 patients undergoing hip arthroscopy (8 early OA and 8 non-OA patients). Primary cells isolated from tissues were compared using detailed in vitro analyses. Gene expression profiling was performed for the skeletal stem cell markers podoplanin (PDPN), CD73, CD164 and CD146 as well as for immune-related molecules to assess their immunomodulatory potential. Synovium-derived and bone-derived MSCs from early OA patients showed comparable clonogenicity, cumulative population doublings, osteogenic, adipogenic and chondrogenic potential, and immunophenotype to those of non-OA patients. High PDPN/low CD146 profile (reminiscent of skeletal stem cells) was identified mainly for non-OA MSCs, while low PDPN/high CD146 mainly defined early OA MSCs. These data suggest that MSCs from early OA patients are not affected by degenerative changes in the hip. Moreover, the synovium represents an alternative source of MSCs for patient-derived stem cell therapies, which is comparable to bone. The expression profile reminiscent of skeletal stem cells suggests the combination of low PDPN and high CD146 as potential biomarkers in early OA.
Sujet(s)
Cellules souches mésenchymateuses , Membrane synoviale , Humains , Cellules souches mésenchymateuses/métabolisme , Membrane synoviale/anatomopathologie , Membrane synoviale/métabolisme , Femelle , Mâle , Adulte d'âge moyen , Différenciation cellulaire , Sujet âgé , Arthrose/anatomopathologie , Arthrose/métabolisme , Os et tissu osseux/anatomopathologie , Os et tissu osseux/métabolisme , Adulte , Marqueurs biologiques/métabolisme , Chondrogenèse , Ostéogenèse , Cellules cultivéesRÉSUMÉ
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease with a complex pathological mechanism involving autoimmune response, local inflammation and bone destruction. Metabolic pathways play an important role in immune-related diseases and their immune responses. The pathogenesis of rheumatoid arthritis may be related to its metabolic dysregulation. Moreover, histological techniques, including genomics, transcriptomics, proteomics and metabolomics, provide powerful tools for comprehensive analysis of molecular changes in biological systems. The present study explores the molecular and metabolic mechanisms of RA, emphasizing the central role of metabolic dysregulation in the RA disease process and highlighting the complexity of metabolic pathways, particularly metabolic remodeling in synovial tissues and its association with cytokine-mediated inflammation. This paper reveals the potential of histological techniques in identifying metabolically relevant therapeutic targets in RA; specifically, we summarize the genetic basis of RA and the dysregulated metabolic pathways, and explore their functional significance in the context of immune cell activation and differentiation. This study demonstrates the critical role of histological techniques in decoding the complex metabolic network of RA and discusses the integration of histological data with other types of biological data.
Sujet(s)
Polyarthrite rhumatoïde , Marqueurs biologiques , Métabolomique , Protéomique , Polyarthrite rhumatoïde/immunologie , Polyarthrite rhumatoïde/métabolisme , Humains , Métabolomique/méthodes , Protéomique/méthodes , Génomique/méthodes , Animaux , Voies et réseaux métaboliques , Membrane synoviale/immunologie , Membrane synoviale/métabolisme , Membrane synoviale/anatomopathologie , Multi-omiqueRÉSUMÉ
Rheumatoid arthritis (RA) is a common autoimmune and inflammatory disease characterized by inflammation and hyperplasia of the synovial tissues. RA pathogenesis involves multiple cell types, genes, transcription factors (TFs) and networks. Yet, little is known about the TFs, and key drivers and networks regulating cell function and disease at the synovial tissue level, which is the site of disease. In the present study, we used available RNA-seq databases generated from synovial tissues and developed a novel approach to elucidate cell type-specific regulatory networks on synovial tissue genes in RA. We leverage established computational methodologies to infer sample-specific gene regulatory networks and applied statistical methods to compare network properties across phenotypic groups (RA versus osteoarthritis). We developed computational approaches to rank TFs based on their contribution to the observed phenotypic differences between RA and controls across different cell types. We identified 18 (fibroblast-like synoviocyte), 16 (T cells), 19 (B cells) and 11 (monocyte) key regulators in RA synovial tissues. Interestingly, fibroblast-like synoviocyte (FLS) and B cells were driven by multiple independent co-regulatory TF clusters that included MITF, HLX, BACH1 (FLS) and KLF13, FOSB, FOSL1 (B cells). However, monocytes were collectively governed by a single cluster of TF drivers, responsible for the main phenotypic differences between RA and controls, which included RFX5, IRF9, CREB5. Among several cell subset and pathway changes, we also detected reduced presence of Natural killer T (NKT) cells and eosinophils in RA synovial tissues. Overall, our novel approach identified new and previously unsuspected Key driver genes (KDG), TF and networks and should help better understanding individual cell regulation and co-regulatory networks in RA pathogenesis, as well as potentially generate new targets for treatment.
Sujet(s)
Polyarthrite rhumatoïde , Réseaux de régulation génique , Membrane synoviale , Humains , Polyarthrite rhumatoïde/génétique , Polyarthrite rhumatoïde/immunologie , Membrane synoviale/métabolisme , Membrane synoviale/immunologie , Membrane synoviale/anatomopathologie , Facteurs de transcription/génétique , Facteurs de transcription/métabolisme , Analyse de profil d'expression de gènes , Biologie informatique/méthodes , Cellules synoviales/métabolisme , Arthrose/génétique , Arthrose/métabolisme , Régulation de l'expression des gènes , Lymphocytes B/immunologie , Lymphocytes B/métabolisme , TranscriptomeRÉSUMÉ
Rheumatoid arthritis (RA) is a common autoimmune condition and chronic inflammatory disease, mostly affecting synovial joints. The complex pathogenesis of RA is supportive of high morbidity, disability, and mortality rates. Pathological changes a common characteristic in RA synovial tissue is attributed to the inadequacy of apoptotic pathways. In that regard, apoptotic pathways have been the center of attention in RA therapeutic approaches. As the regulators in the complex network of apoptosis, microRNAs (miRNAs) are found to be vital modulators in both intrinsic and extrinsic pathways through altering their regulatory genes. Indeed, miRNA, a member of the family of non-coding RNAs, are found to be an important player in not even apoptosis, but proliferation, gene expression, signaling pathways, and angiogenesis. Aberrant expression of miRNAs is implicated in attenuation and/or intensification of various apoptosis routes, resulting in culmination of human diseases including RA. Considering the need for more studies focused on the underlying mechanisms of RA in order to elevate the unsatisfactory clinical treatments, this study is aimed to delineate the importance of apoptosis in the pathophysiology of this disease. As well, this review is focused on the critical role of miRNAs in inducing or inhibiting apoptosis of RA-synovial fibroblasts and fibroblast-like synoviocytes and how this mechanism can be exerted for therapeutic purposes for RA.
Sujet(s)
Apoptose , Polyarthrite rhumatoïde , microARN , Polyarthrite rhumatoïde/génétique , Polyarthrite rhumatoïde/métabolisme , Polyarthrite rhumatoïde/anatomopathologie , Humains , microARN/génétique , microARN/métabolisme , Apoptose/génétique , Membrane synoviale/anatomopathologie , Membrane synoviale/métabolisme , Cellules synoviales/métabolisme , Cellules synoviales/anatomopathologie , Transduction du signal , Fibroblastes/métabolisme , Fibroblastes/anatomopathologie , AnimauxRÉSUMÉ
OBJECTIVE: Rheumatoid Arthritis (RA) often exhibits suboptimal treatment response despite early diagnosis and treatment. This study aimed to analyze Early Rheumatoid Arthritis (ERA) synovial biopsies through histology and immunohistochemistry (IHC) to identify predictive factors for treatment response to Methotrexate (MTX). METHODS: 140 ERA patients from the UCLouvain Arthritis Cohort underwent synovial biopsy and were monitored after initiating Disease-Modifying Antirheumatic Drug (DMARD) therapy. Histological features [Synovial Hyperplasia, Fibrinoid Necrosis (FN), Hypervascularization and Inflammatory Infiltrate] and IHC (CD3, CD20, CD138, CD68) were each semi-quantitatively assessed on a 0-3 scale with 7 levels. RESULTS: A strong association was observed between synovial CD68 and Fibrinoid Necrosis scores [r = 0.44 (0.27 - 0.56); p < 0.0001]. CD68 correlated with C-Reactive Protein (CRP), DAS28, SDAI and CDAI. Fibrinoid Necrosis score correlated with CRP and DAS28. Patients were then categorized as CD68NecrosisHIGH (CD68 + Necrosis ≥ 3) and CD68NecrosisLOW (CD68 + Necrosis < 3). CD68NecrosisHIGH exhibited higher pre-treatment disease activity [5.48 (1.6) versus 4.8 (1.7); p = 0.03] and a greater fall in DAS28 [1.99 (2.06) versus 1.1 (2.27), p = 0.03], SDAI [21.45 (IQR 23.3) versus 11.65 (IQR 17.5); p = 0.003] and CDAI [16 [14.9] versus 10.5 (20.1), p = 0.04]. CD68NecrosisHIGH patients had a higher EULAR Moderate/Good Response rate. CD68Necrosis score was incorporated into a probability matrix model together with clinical features (SJC44 and DAS28) to predict achieving a Moderate/Good EULAR Response Criteria at 3 months with a good performance (AUC 0.724). CONCLUSION: FN and CD68 + in ERA synovial biopsies identify patients with higher disease activity and predict a better treatment response at three months. A model including synovial CD68 and fibrinoid necrosis with baseline clinical features predicts EULAR response at 3 months.
Sujet(s)
Antirhumatismaux , Polyarthrite rhumatoïde , Méthotrexate , Nécrose , Membrane synoviale , Humains , Méthotrexate/usage thérapeutique , Polyarthrite rhumatoïde/traitement médicamenteux , Polyarthrite rhumatoïde/anatomopathologie , Femelle , Mâle , Adulte d'âge moyen , Membrane synoviale/anatomopathologie , Membrane synoviale/effets des médicaments et des substances chimiques , Membrane synoviale/métabolisme , Antirhumatismaux/usage thérapeutique , Sujet âgé , Études de cohortes , Adulte , Résultat thérapeutique , ImmunohistochimieRÉSUMÉ
TNF is a potent cytokine known for its involvement in physiology and pathology. In Rheumatoid Arthritis (RA), persistent TNF signals cause aberrant activation of synovial fibroblasts (SFs), the resident cells crucially involved in the inflammatory and destructive responses of the affected synovial membrane. However, the molecular switches that control the pathogenic activation of SFs remain poorly defined. Cyld is a major component of deubiquitination (DUB) machinery regulating the signaling responses towards survival/inflammation and programmed necrosis that induced by cytokines, growth factors and microbial products. Herein, we follow functional genetic approaches to understand how Cyld affects arthritogenic TNF signaling in SFs. We demonstrate that in spontaneous and induced RA models, SF-Cyld DUB deficiency deteriorates arthritic phenotypes due to increased levels of chemokines, adhesion receptors and bone-degrading enzymes generated by mutant SFs. Mechanistically, Cyld serves to restrict the TNF-induced hyperactivation of SFs by limiting Tak1-mediated signaling, and, therefore, leading to supervised NF-κB and JNK activity. However, Cyld is not critically involved in the regulation of TNF-induced death of SFs. Our results identify SF-Cyld as a regulator of TNF-mediated arthritis and inform the signaling landscape underpinning the SF responses.
Sujet(s)
Polyarthrite rhumatoïde , Deubiquitinating enzyme CYLD , Fibroblastes , I-kappa B Kinase , MAP Kinase Kinase Kinases , Transduction du signal , Membrane synoviale , Fibroblastes/métabolisme , Fibroblastes/anatomopathologie , Deubiquitinating enzyme CYLD/métabolisme , Deubiquitinating enzyme CYLD/génétique , MAP Kinase Kinase Kinases/métabolisme , MAP Kinase Kinase Kinases/génétique , Animaux , Membrane synoviale/métabolisme , Membrane synoviale/anatomopathologie , Souris , I-kappa B Kinase/métabolisme , I-kappa B Kinase/génétique , Polyarthrite rhumatoïde/métabolisme , Polyarthrite rhumatoïde/anatomopathologie , Polyarthrite rhumatoïde/génétique , Facteur de nécrose tumorale alpha/métabolisme , Facteur de nécrose tumorale alpha/pharmacologie , Humains , Facteur de transcription NF-kappa B/métabolisme , Souris de lignée C57BL , Souris knockoutRÉSUMÉ
Rheumatoid arthritis (RA) and arthrofibrosis (AF) are both chronic synovial hyperplasia diseases that result in joint stiffness and contractures. They shared similar symptoms and many common features in pathogenesis. Our study aims to perform a comprehensive analysis between RA and AF and identify novel drugs for clinical use. Based on the text mining approaches, we performed a correlation analysis of 12 common joint diseases including arthrofibrosis, gouty arthritis, infectious arthritis, juvenile idiopathic arthritis, osteoarthritis, post infectious arthropathies, post traumatic osteoarthritis, psoriatic arthritis, reactive arthritis, rheumatoid arthritis, septic arthritis, and transient arthritis. 5 bulk sequencing datasets and 4 single-cell sequencing datasets of RA and AF were integrated and analyzed. A novel drug repositioning method was found for drug screening, and text mining approaches were used to verify the identified drugs. RA and AF performed the highest gene similarity (0.77) and functional ontology similarity (0.84) among all 12 joint diseases. We figured out that they share the same key pathogenic cell including CD34 + sublining fibroblasts (CD34-SLF) and DKK3 + sublining fibroblasts (DKK3-SLF). Potential therapeutic target database (PTTD) was established with the differential expressed genes (DEGs) of these key pathogenic cells. Based on the PTTD, 15 potential drugs for AF and 16 potential drugs for RA were identified. This work provides a new perspective on AF and RA study which enhances our understanding of their pathogenesis. It also shed light on their underlying mechanism and open new avenues for drug repositioning studies.
Sujet(s)
Polyarthrite rhumatoïde , Fibrose , Membrane synoviale , Humains , Polyarthrite rhumatoïde/anatomopathologie , Polyarthrite rhumatoïde/traitement médicamenteux , Polyarthrite rhumatoïde/génétique , Polyarthrite rhumatoïde/métabolisme , Membrane synoviale/anatomopathologie , Membrane synoviale/métabolisme , Fibroblastes/métabolisme , Fibroblastes/effets des médicaments et des substances chimiques , Repositionnement des médicaments , Microenvironnement cellulaire/effets des médicaments et des substances chimiques , Fouille de donnéesRÉSUMÉ
PURPOSE: This study aimed to investigate the efficacy and safety of ultrasound-guided percutaneous radiofrequency ablation (RFA) for the treatment of synovial hyperplasia in the knee joints of antigen-induced arthritis (AIA) model rabbits. METHODS: Forty Japanese large-eared white rabbits were divided into AIA and control groups. After successful induction of the AIA model, the knee joints were randomly assigned to RFA and non-RFA groups. The RFA group underwent ultrasound-guided RFA to treat synovial hyperplasia in the knee joint. Dynamic observation of various detection indices was conducted to evaluate the safety and effectiveness of the RFA procedure. RESULTS: Successful synovial ablation was achieved in the RFA group, with no intraoperative or perioperative mortality. Postoperative the circumference of the knee joint reached a peak before decreasing in the third week after surgery. The incidence and diameter of postoperative skin ulcers were not significantly different compared to the non-RFA group (p > .05). Anatomical examination revealed an intact intermuscular fascia around the ablated area in the RFA group. The ablated synovial tissue initially presented as a white mass, which subsequently liquefied into a milky white viscous fluid. Gross articular cartilage was observed, along with liquefied necrosis of the synovium on pathological histology and infiltration of inflammatory cells in the surrounding soft tissue. CONCLUSION: The experimental results demonstrated that ultrasound-guided RFA of the knee in the treatment of synovial hyperplasia in AIA model animals was both effective and safe.
Sujet(s)
Hyperplasie , Ablation par radiofréquence , Animaux , Lapins , Ablation par radiofréquence/méthodes , Hyperplasie/chirurgie , Hyperplasie/anatomopathologie , Membrane synoviale/anatomopathologie , Membrane synoviale/imagerie diagnostique , Échographie/méthodes , Mâle , Échographie interventionnelle/méthodesRÉSUMÉ
OBJECTIVES: The imbalance between apoptosis and proliferation in fibroblast-like synoviocytes (FLSs) plays a key role in the pathogenesis of rheumatoid arthritis (RA). This study aims to investigate the potential of all-trans retinoic acid (ATRA) as a supplementary therapeutic agent alongside methotrexate (MTX) for RA, by examining its ability to inhibit synovial cell proliferation and enhance apoptosis through the ROS-JNK signalling pathway. METHODS: The viability, apoptosis, and autophagy levels of human rheumatoid arthritis fibroblast-like synovial cells (HFLS-RA) were evaluated, while ROS generation was measured through the DCFH-DA fluorescence microplate assay. Western blotting was used to analyse the expression levels of JNK signalling pathway-related proteins. To assess therapeutic potential in vivo, a collagen-induced arthritis (CIA) model was established in Wistar rats. RESULTS: Small doses of MTX did not significantly affect the viability of HFLS-RAs or induce apoptosis. However, when ATRA was added to the treatment, the therapy markedly inhibited cell proliferation and induced apoptosis and excessive autophagy. Mechanistically, ATRA activated the ROS/JNK signalling pathway in HFLS-RAs. ROS scavengers and JNK inhibitors significantly attenuated ATRA-induced apoptosis and autophagy. In vivo, the combination therapy demonstrated a remarkable enhancement of the anti-arthritic efficacy in CIA rats. CONCLUSIONS: The ability of ATRA to inhibit proliferation in RA FLSs through autophagy and apoptosis underscores its potential as a supplementary therapeutic agent alongside MTX for RA, particularly when compared to the limited impact of MTX on these processes. This combined strategy holds promise for enhancing therapeutic outcomes and warrants further investigation in the management of RA.
Sujet(s)
Apoptose , Arthrite expérimentale , Polyarthrite rhumatoïde , Autophagie , Prolifération cellulaire , Méthotrexate , Rat Wistar , Espèces réactives de l'oxygène , Cellules synoviales , Trétinoïne , Trétinoïne/pharmacologie , Apoptose/effets des médicaments et des substances chimiques , Polyarthrite rhumatoïde/traitement médicamenteux , Polyarthrite rhumatoïde/anatomopathologie , Polyarthrite rhumatoïde/métabolisme , Méthotrexate/pharmacologie , Autophagie/effets des médicaments et des substances chimiques , Animaux , Humains , Arthrite expérimentale/traitement médicamenteux , Arthrite expérimentale/anatomopathologie , Arthrite expérimentale/métabolisme , Espèces réactives de l'oxygène/métabolisme , Cellules synoviales/effets des médicaments et des substances chimiques , Cellules synoviales/anatomopathologie , Cellules synoviales/métabolisme , Prolifération cellulaire/effets des médicaments et des substances chimiques , Association de médicaments , Antirhumatismaux/pharmacologie , Membrane synoviale/effets des médicaments et des substances chimiques , Membrane synoviale/anatomopathologie , Membrane synoviale/métabolisme , Mâle , Système de signalisation des MAP kinases/effets des médicaments et des substances chimiques , Rats , Lignée cellulaireRÉSUMÉ
BACKGROUND: Synovial hemangiomas are rare benign vascular anomalies surrounded by a synovial lining and were first described by Bouchut in 1856. These neoplasms can develop in the intra-articular region, resulting in effusions and knee pain. However, their cause remains unknown. Prompt diagnosis and intervention are critical to prevent chondral damage. Histopathological examination is used to achieve the diagnosis, which is often delayed because of a lack of specific clinical signs. This report describes a unique case in which a painful infrapatellar mass was diagnosed as a synovial hemangioma. The absence of typical magnetic resonance imaging (MRI) findings highlights the importance of arthroscopic excision for diagnosis and symptom relief. CASE PRESENTATION: A 20-year-old woman presented with persistent anterior left knee pain that became exacerbated when she climbed stairs. Despite previous pain management and physical therapy, she developed a painful lump beneath her patella that worsened over time. She had also undergone arthrocentesis, but this did not relieve her pain. Physical examination revealed a palpable, immobile 5-cm mass along the patellar tendon with limited knee flexion and extension and normal ligament stability. T1-weighted fat-saturated MRI of the left knee with gadolinium-based contrast revealed a lobulated intra-articular mass in Hoffa's fat pad that resembled a soft tissue chondroma. A biopsy of the mass was performed to provide histopathological evidence, confirming the benign nature of the mass. The subsequent excisional arthroscopy, combined with incision enlargement for mass removal, confirmed the histopathologic diagnosis of synovial hemangioma based on the presence of numerous dilated blood vessels and venous proliferation within sections of the synovium. Recovery was complete, and no residual tumor was detected on follow-up MRI after 1 year. CONCLUSION: This case study emphasizes the importance of arthroscopic excision over open surgery for patients with synovial hemangioma. The minimally invasive nature of arthroscopy combined with the well-encapsulated nature and location of the mass facilitates complete resection.
Sujet(s)
Hémangiome , Articulation du genou , Imagerie par résonance magnétique , Membrane synoviale , Humains , Femelle , Hémangiome/chirurgie , Hémangiome/complications , Hémangiome/imagerie diagnostique , Hémangiome/diagnostic , Hémangiome/anatomopathologie , Jeune adulte , Membrane synoviale/anatomopathologie , Membrane synoviale/imagerie diagnostique , Articulation du genou/chirurgie , Articulation du genou/anatomopathologie , Articulation du genou/imagerie diagnostique , Arthroscopie , Douleur chronique/étiologie , Tumeurs des tissus mous/chirurgie , Tumeurs des tissus mous/anatomopathologie , Tumeurs des tissus mous/diagnostic , Tumeurs des tissus mous/complications , Tumeurs des tissus mous/imagerie diagnostique , Patella/anatomopathologie , Patella/chirurgie , Patella/imagerie diagnostique , Arthralgie/étiologieRÉSUMÉ
Intra-articular injection of mesenchymal stem cells (MSCs) is envisioned as a solution for knee osteoarthritis (OA). Although synovial MSCs (SyMSCs) are promising for cartilage regeneration, the clinical choice is usually adipose MSCs (AdMSCs). However, the similarities/differences in the mode of action between SyMSCs and AdMSCs remain unclear. Here, we compared factors secreted by human SyMSCs and AdMSCs after injection into OA knees. Human SyMSCs or AdMSCs were injected into the knees of rat partial meniscectomy models. The next day, the knee joints were collected to analyze the distribution of injected MSCs and transcriptome changes in the human MSCs and rat synovium. Non-injected MSCs were mixed with rat synovium as a control. After injection, no difference was apparent in intra-articular distribution of the SyMSCs or AdMSCs. RNA sequencing demonstrated an enrichment of cytokine-cytokine receptor interaction-related genes in both human SyMSCs and AdMSCs after injection. Differentially expressed genes (DEGs) specific to SyMSCs were associated with cartilage matrix synthesis and homeostasis. PCR analysis of the matrisome-related DEGs showed significantly higher expression of PRG4 in SyMSCs than in AdMSCs after injection. Immunostaining also confirmed a significantly greater expression of lubricin by SyMSCs than by AdMSCs. These findings indicate that SyMSCs will be a more promising treatment for OA.
Sujet(s)
Tissu adipeux , Transplantation de cellules souches mésenchymateuses , Cellules souches mésenchymateuses , Gonarthrose , Membrane synoviale , Animaux , Cellules souches mésenchymateuses/métabolisme , Humains , Gonarthrose/métabolisme , Gonarthrose/thérapie , Gonarthrose/anatomopathologie , Gonarthrose/génétique , Rats , Membrane synoviale/métabolisme , Membrane synoviale/anatomopathologie , Transplantation de cellules souches mésenchymateuses/méthodes , Tissu adipeux/métabolisme , Tissu adipeux/cytologie , Injections articulaires , Mâle , Rat Sprague-Dawley , Glycoprotéines/métabolisme , Glycoprotéines/génétique , Cellules cultivées , Protéoglycanes/métabolisme , Protéoglycanes/génétiqueRÉSUMÉ
Fibroblast-like synoviocytes (FLS) plays an important role in synovial inflammation and joint damage in rheumatoid arthritis (RA). As the most abundant mRNA modification, N6-methyladenosine (m6A) is involved in the development of various diseases; however, its role in RA remains to be defined. In this study, we reported the elevated expression of the m6A demethylase fat mass and obesity-associated protein (FTO) in FLS and synovium from RA patients. Functionally, FTO knockdown or treatment with FB23-2, an inhibitor of the mRNA m6A demethylase FTO, inhibited the migration, invasion and inflammatory response of RA FLS, however, FTO-overexpressed RA FLS exhibited increased migration, invasion and inflammatory response. We further demonstrated that FTO promoted ADAMTS15 mRNA stability in an m6A-IGF2BP1 dependent manner. Notably, the severity of arthritis was significantly reduced in CIA mice with FB23-2 administration or CIA rats with intra-articular injection of FTO shRNA. Our results illustrate the contribution of FTO-mediated m6A modification to joint damage and inflammation in RA and suggest that FTO might be a potential therapeutic target in RA.
Sujet(s)
Adénosine , Alpha-ketoglutarate-dependent dioxygenase FTO , Polyarthrite rhumatoïde , Inflammation , , Animaux , Humains , Souris , Rats , Adénosine/analogues et dérivés , Adénosine/métabolisme , Alpha-ketoglutarate-dependent dioxygenase FTO/métabolisme , Alpha-ketoglutarate-dependent dioxygenase FTO/génétique , Arthrite expérimentale/métabolisme , Arthrite expérimentale/anatomopathologie , Arthrite expérimentale/génétique , Polyarthrite rhumatoïde/métabolisme , Polyarthrite rhumatoïde/anatomopathologie , Polyarthrite rhumatoïde/génétique , Inflammation/métabolisme , Inflammation/anatomopathologie , Inflammation/génétique , Stabilité de l'ARN , ARN messager/génétique , ARN messager/métabolisme , Membrane synoviale/métabolisme , Membrane synoviale/anatomopathologie , Cellules synoviales/métabolisme , Cellules synoviales/anatomopathologieRÉSUMÉ
With the rise in longevity within the population, medicine continues to encounter fresh hurdles necessitating prompt actions, among which are those associated with hip joint aging. Age-related arthropathies encompass damage to bones' articulating extremities and their supporting structures, such as articular cartilage, and alterations in the quantity and quality of synovial fluid. This study aims to summarize the biomolecular methods of hip joint evaluation focused on its vascularization, using data correlated with biomolecular research on other joints and tissues, in order to reach an objective opinion of the study prospects in this field. Following a retrospective study on most modern biomolecular research methods on the synovium, the capsule, and the articular cartilage of the hip joint, we have hereby concretized certain future research directions in this field that will improve the qualitative and morphofunctional management of the hip joint at an advanced age, even within population categories at risk of developing various degenerative joint pathologies.
Sujet(s)
Cartilage articulaire , Articulation de la hanche , Humains , Articulation de la hanche/anatomopathologie , Cartilage articulaire/anatomopathologie , Cartilage articulaire/métabolisme , Membrane synoviale/anatomopathologie , Membrane synoviale/métabolisme , Conflit fémoro-acétabulaire/anatomopathologieRÉSUMÉ
BACKGROUND: This study aimed to validate alterations in the gene expression of DNA methylation-related enzymes and global methylation in the peripheral blood mononuclear cell (PBMC) and synovial tissues of animal hip osteoarthritis (OA) models. METHODS: Animals were assigned to the control (no treatment), sham (25 µL of sterile saline), and OA (25 µL of sterile saline and 2 mg of monoiodoacetate) groups. Microcomputed tomography scan, histopathological assessment and pain threshold measurement were performed after induction. The mRNA expression of the DNA methylation machinery genes and global DNA methylation in the PBMC and hip synovial tissue were evaluated. RESULTS: The OA group presented with hip joint OA histopathologically and radiologically and decreased pain threshold. The mRNA expression of DNA methyltransferase (Dnmt 3a), ten-eleven translocation (Tet) 1 and Tet 3 in the synovial tissue of the OA group was significantly upregulated. Global DNA methylation in the synovial tissue of the OA group was significantly higher than that of the control and sham groups. CONCLUSIONS: The intra-articular administration of monoiodoacetate induced hip joint OA and decreased pain threshold. The DNA methylation machinery in the synovial tissues of hip OA was altered.
Sujet(s)
Méthylation de l'ADN , Modèles animaux de maladie humaine , Coxarthrose , Animaux , Coxarthrose/génétique , Coxarthrose/métabolisme , Coxarthrose/anatomopathologie , Mâle , Rats , Acide iodo-acétique , Membrane synoviale/métabolisme , Membrane synoviale/anatomopathologie , Agranulocytes/métabolisme , Rat Sprague-Dawley , DNA methyltransferase 3A/génétique , DNA methyltransferase 3A/métabolisme , Seuil nociceptifRÉSUMÉ
Introduction: Pathological changes in the articular cartilage (AC) and synovium are major manifestations of osteoarthritis (OA) and are strongly associated with pain and functional limitations. Exosome-derived microRNAs (miRNAs) are crucial regulatory factors in intercellular communication and can influence the progression of OA by participating in the degradation of chondrocytes and the phenotypic transformation in the polarization of synovial macrophages. However, the specific relationships and pathways of action of exosomal miRNAs in the pathological progression of OA in both cartilage and synovium remain unclear. Methods: This study evaluates the effects of fibroblast-like synoviocyte (FLS)-derived exosomes (FLS-Exos), influenced by miR-146a, on AC degradation and synovial macrophage polarization. We investigated the targeted relationship between miR-146a and TRAF6, both in vivo and in vitro, along with the involvement of the NF-κB signaling pathway. Results: The expression of miR-146a in the synovial exosomes of OA rats was significantly higher than in healthy rats. In vitro, the upregulation of miR-146a reduced chondrocyte apoptosis, whereas its downregulation had the opposite effect. In vivo, exosomes derived from miR-146a-overexpressing FLSs (miR-146a-FLS-Exos) reduced AC injury and chondrocyte apoptosis in OA. Furthermore, synovial proliferation was reduced, and the polarization of synovial macrophages shifted from M1 to M2. Mechanistically, the expression of TRAF6 was inhibited by targeting miR-146a, thereby modulating the Toll-like receptor 4/TRAF6/NF-κB pathway in the innate immune response. Discussion: These findings suggest that miR-146a, mediated through FLS-Exos, may alleviate OA progression by modulating cartilage degradation and macrophage polarization, implicating the NF-κB pathway in the innate immune response. These insights highlight the therapeutic potential of miR-146a as a protective agent in OA, underscoring the importance of exosomal miRNAs in the pathogenesis and potential treatment of the disease.
Sujet(s)
Exosomes , Macrophages , microARN , Arthrose , Cellules synoviales , Facteur-6 associé aux récepteurs de TNF , microARN/génétique , Animaux , Exosomes/métabolisme , Arthrose/métabolisme , Arthrose/anatomopathologie , Arthrose/immunologie , Rats , Macrophages/immunologie , Macrophages/métabolisme , Cellules synoviales/métabolisme , Cellules synoviales/anatomopathologie , Mâle , Facteur-6 associé aux récepteurs de TNF/métabolisme , Facteur-6 associé aux récepteurs de TNF/génétique , Cartilage articulaire/métabolisme , Cartilage articulaire/anatomopathologie , Chondrocytes/métabolisme , Facteur de transcription NF-kappa B/métabolisme , Transduction du signal , Rat Sprague-Dawley , Fibroblastes/métabolisme , Membrane synoviale/métabolisme , Membrane synoviale/anatomopathologie , Membrane synoviale/immunologie , Cellules cultivées , Apoptose , Récepteur de type Toll-4/métabolisme , Récepteur de type Toll-4/génétique , Activation des macrophagesRÉSUMÉ
OBJECTIVES: To assess the presence and anatomical distribution of activated fibroblasts in the joints and entheses of patients with psoriasis with arthralgia and to test how fibroblast activation visualised by 68gallium-labelled fibroblast activation protein inhibitor-04 (68Ga-FAPI-04)-positron emission tomography (PET)/CT correlates with clinical tenderness, musculoskeletal ultrasound findings and progression to psoriatic arthritis (PsA). METHODS: We conducted a prospective cohort study in patients with psoriasis and arthralgia who underwent clinical and ultrasound evaluation and whole-body PET/CT imaging with 68Ga-FAPI-04. 68Ga-FAPI-04 uptake at synovial and entheseal sites was assessed by maximal standardised uptake values (SUVmax) and PET/CT Joint Index (JI); logistic regression models were used to investigate its correlation with clinical and ultrasound findings. Survival analyses were performed on patients with at least 6 months of follow-up. RESULTS: 36 patients with psoriasis were enrolled. 68Ga-FAPI-04 uptake was found in 318 (7.9%) joints and 369 (7.3%) entheses in 29 (80.6%) participants, with a mean SUVmax (SD) of 3.2 (1.8) for joints and 2.9 (1.6) for entheses. Large joints and the lower limbs were predominantly affected. A significant positive relationship was found between 68Ga-FAPI-04-PET/CT signal intensity and the 68 tender joint count (SUVmax: p<0.001; PET/CT-JI: p<0.001) and tender entheses count (SUVmax: p<0.001; PET/CT-JI: p=0.002). No correlations were found with ultrasound findings (SUVmax: p=0.969; PET/CT-JI: p=0.720). Patients with relevant synovio-entheseal 68Ga-FAPI-04 uptake showed a statistically significant higher risk of developing PsA (p=0.02), independent of ultrasound findings. CONCLUSIONS: Patients with psoriasis presenting with arthralgia show localised signs of resident tissue activation in joints and entheses, which are associated with higher risk of developing PsA.
Sujet(s)
Arthrite psoriasique , Fibroblastes , Tomographie par émission de positons couplée à la tomodensitométrie , Psoriasis , Humains , Arthrite psoriasique/anatomopathologie , Arthrite psoriasique/imagerie diagnostique , Mâle , Femelle , Adulte d'âge moyen , Psoriasis/anatomopathologie , Adulte , Études prospectives , Fibroblastes/métabolisme , Membrane synoviale/anatomopathologie , Membrane synoviale/imagerie diagnostique , Sujet âgé , Échographie , Évolution de la maladieRÉSUMÉ
Osteoarthritis (OA) is the most common form of arthritis, characterized by osteophyte formation, cartilage degradation, and structural and cellular alterations of the synovial membrane. Activated fibroblast-like synoviocytes (FLS) of the synovial membrane have been identified as key drivers, secreting humoral mediators that maintain inflammatory processes, proteases that cause cartilage and bone destruction, and factors that drive fibrotic processes. In normal tissue repair, fibrotic processes are terminated after the damage has been repaired. In fibrosis, tissue remodeling and wound healing are exaggerated and prolonged. Various stressors, including aging, joint instability, and inflammation, lead to structural damage of the joint and micro lesions within the synovial tissue. One result is the reduced production of synovial fluid (lubricants), which reduces the lubricity of the cartilage areas, leading to cartilage damage. In the synovial tissue, a wound-healing cascade is initiated by activating macrophages, Th2 cells, and FLS. The latter can be divided into two major populations. The destructive thymocyte differentiation antigen (THY)1â phenotype is restricted to the synovial lining layer. In contrast, the THY1+ phenotype of the sublining layer is classified as an invasive one with immune effector function driving synovitis. The exact mechanisms involved in the transition of fibroblasts into a myofibroblast-like phenotype that drives fibrosis remain unclear. The review provides an overview of the phenotypes and spatial distribution of FLS in the synovial membrane of OA, describes the mechanisms of fibroblast into myofibroblast activation, and the metabolic alterations of myofibroblast-like cells.
Sujet(s)
Fibroblastes , Fibrose , Arthrose , Phénotype , Cellules synoviales , Humains , Arthrose/anatomopathologie , Arthrose/immunologie , Arthrose/métabolisme , Fibroblastes/métabolisme , Fibroblastes/anatomopathologie , Fibroblastes/immunologie , Animaux , Cellules synoviales/métabolisme , Cellules synoviales/anatomopathologie , Cellules synoviales/immunologie , Membrane synoviale/anatomopathologie , Membrane synoviale/immunologie , Membrane synoviale/métabolismeRÉSUMÉ
Rheumatoid arthritis (RA) is a chronic inflammatory joint disease characterised by the formation of a hyperplastic pannus, as well as cartilage and bone damage. The pathogenesis of RA is complex and involves broad interactions between various cells present in the inflamed synovium, including fibroblast-like synoviocytes (FLSs), macrophages, and T cells, among others. Under inflammatory conditions, these cells are activated, further enhancing inflammatory responses and angiogenesis and promoting bone and cartilage degradation. Novel treatment methods for RA are greatly needed, and mesenchymal stromal cells (MSCs) have been suggested as a promising new regenerative and immunomodulatory treatment. In this paper, we present the interactions between MSCs and RA-FLSs, and macrophages and T cells, and summarise studies examining the use of MSCs in preclinical and clinical RA studies.
Sujet(s)
Polyarthrite rhumatoïde , Transplantation de cellules souches mésenchymateuses , Cellules souches mésenchymateuses , Humains , Polyarthrite rhumatoïde/anatomopathologie , Polyarthrite rhumatoïde/thérapie , Cellules souches mésenchymateuses/métabolisme , Animaux , Macrophages/métabolisme , Lymphocytes T/immunologie , Membrane synoviale/anatomopathologie , Cellules synoviales/métabolisme , Cellules synoviales/anatomopathologieRÉSUMÉ
Osteoarthritis (OA) is the most common musculoskeletal disease, without any curative treatment. Obesity being the main modifiable risk factor for OA, much attention focused on the role of adipose tissues (AT). In addition to the involvement of visceral and subcutaneous AT via systemic ways, many arguments also highlight the involvement of local AT, present in joint tissues. Local AT include intra-articular AT (IAAT), which border the synovium, and bone marrow AT (BMAT) localized within marrow cavities in the bones. This review describes the known features and involvement of IAAT and BMAT in joint homeostasis and OA. Recent findings evidence that alteration in magnetic resonance imaging signal intensity of infrapatellar fat pad can be predictive of the development and progression of knee OA. IAAT and synovium are partners of the same functional unit; IAAT playing an early and pivotal role in synovial inflammation and fibrosis and OA pain. BMAT, whose functions have only recently begun to be studied, is in close functional interaction with its microenvironment. The volume and molecular profile of BMAT change according to the pathophysiological context, enabling fine regulation of haematopoiesis and bone metabolism. Although its role in OA has not yet been studied, the localization of BMAT, its functions and the importance of the bone remodelling processes that occur in OA argue in favour of a role for BMAT in OA.