-
Arthritis Research & Therapy Aug 2023Rheumatoid arthritis (RA) is a chronic, progressive autoimmune disease. Over-activation of fibroblast-like synoviocytes is responsible for the hyperplasia of synovium...
OBJECTIVE
Rheumatoid arthritis (RA) is a chronic, progressive autoimmune disease. Over-activation of fibroblast-like synoviocytes is responsible for the hyperplasia of synovium and destruction of cartilage and bone and pyroptosis of FLS plays a key role in those pathological processes during RA. This study investigated the detailed mechanisms that SMAD2 regulates the pyroptosis of FLS and secretion of inflammatory factors in rheumatoid arthritis.
METHODS
We collected synovial tissues of RA patients and FLS-RA and cultured FLS for detection of expression of SMAD2. ASC, NLRP3, cleaved-caspase-1, and GSDMD-N were detected by Western blot after overexpression of SMAD2. Besides, flow cytometry, electron microscope, ELISA, HE staining, and Safranin O staining were performed to further demonstrate that SMAD2 can affect the pyroptosis of FLS-RA.
RESULTS
The expression of SMAD2 was down-regulated in synovial tissues of RA patients and FLS-RA. Overexpression of SMAD2 can inhibit the expression of ASC, NLRP3, cleaved-caspase-1, and GSDMD-N. Flow cytometry and electron microscope further demonstrated that SMAD2 attenuated pyroptosis of FLS-RA. In addition, overexpression of SMAD2 also inhibited inflammatory factors such as IL-1β, IL-18, IL-6, and IL-8 secretion and release of LDH. Besides, overexpression of SMAD2 can reverse the decrease of p-SMAD2 and TGF-TGF-β induced by nigericin. In vivo experiments on CIA rats further demonstrated that overexpression of SMAD2 by local intra-articular injection of LV-SMAD2 can effectively alleviate joint redness, swelling, and destruction of cartilage and bones.
CONCLUSION
SMAD2 inhibited FLS-RA pyroptosis by down-regulating of NLRP3 inflammasomes (NLRP3, ASC, and caspase-1 complex) and eased the secretion of inflammatory factors via the TGF-β signaling pathway, thereby improving the symptom of RA. We hope that this study may provide a new research idea for RA and a potential target for the treatment of RA.
Topics: Animals; Rats; Arthritis, Rheumatoid; Caspases; Cell Proliferation; Cells, Cultured; Fibroblasts; NLR Family, Pyrin Domain-Containing 3 Protein; Pyroptosis; Synovial Membrane; Synoviocytes; Transforming Growth Factor beta; Humans; Smad2 Protein
PubMed: 37559090
DOI: 10.1186/s13075-023-03136-1 -
Nature Communications Feb 2024The synovium is an important component of any synovial joint and is the major target tissue of inflammatory arthritis. However, the multi-omics landscape of synovium...
The synovium is an important component of any synovial joint and is the major target tissue of inflammatory arthritis. However, the multi-omics landscape of synovium required for functional inference is absent from large-scale resources. Here we integrate genomics with transcriptomics and chromatin accessibility features of human synovium in up to 245 arthritic patients, to characterize the landscape of genetic regulation on gene expression and the regulatory mechanisms mediating arthritic diseases predisposition. We identify 4765 independent primary and 616 secondary cis-expression quantitative trait loci (cis-eQTLs) in the synovium and find that the eQTLs with multiple independent signals have stronger effects and heritability than single independent eQTLs. Integration of genome-wide association studies (GWASs) and eQTLs identifies 84 arthritis related genes, revealing 38 novel genes which have not been reported by previous studies using eQTL data from the GTEx project or immune cells. We further develop a method called eQTac to identify variants that could affect gene expression by affecting chromatin accessibility and identify 1517 regions with potential regulatory function of chromatin accessibility. Altogether, our study provides a comprehensive synovium multi-omics resource for arthritic diseases and gains new insights into the regulation of gene expression.
Topics: Humans; Genome-Wide Association Study; Genetic Predisposition to Disease; Gene Expression Regulation; Chromatin; Synovial Membrane; Arthritis; Polymorphism, Single Nucleotide
PubMed: 38360850
DOI: 10.1038/s41467-024-45652-x -
Nature Communications Jan 2024Mast cells are phenotypically and functionally heterogeneous, and their state is possibly controlled by local microenvironment. Therefore, specific analyses are needed...
Mast cells are phenotypically and functionally heterogeneous, and their state is possibly controlled by local microenvironment. Therefore, specific analyses are needed to understand whether mast cells function as powerful participants or dispensable bystanders in specific diseases. Here, we show that degranulation of mast cells in inflammatory synovial tissues of patients with rheumatoid arthritis (RA) is induced via MAS-related G protein-coupled receptor X2 (MRGPRX2), and the expression of MHC class II and costimulatory molecules on mast cells are upregulated. Collagen-induced arthritis mice treated with a combination of anti-IL-17A and cromolyn sodium, a mast cell membrane stabilizer, show significantly reduced clinical severity and decreased bone erosion. The findings of the present study suggest that synovial microenvironment-influenced mast cells contribute to disease progression and may provide a further mast cell-targeting therapy for RA.
Topics: Humans; Mice; Animals; Mast Cells; Arthritis, Rheumatoid; Synoviocytes; Synovial Membrane; Receptors, G-Protein-Coupled; Nerve Tissue Proteins; Receptors, Neuropeptide
PubMed: 38168103
DOI: 10.1038/s41467-023-44304-w -
Protein & Cell May 2024The synovium, a thin layer of tissue that is adjacent to the joints and secretes synovial fluid, undergoes changes in aging that contribute to intense shoulder pain and...
The synovium, a thin layer of tissue that is adjacent to the joints and secretes synovial fluid, undergoes changes in aging that contribute to intense shoulder pain and other joint diseases. However, the mechanism underlying human synovial aging remains poorly characterized. Here, we generated a comprehensive transcriptomic profile of synovial cells present in the subacromial synovium from young and aged individuals. By delineating aging-related transcriptomic changes across different cell types and their associated regulatory networks, we identified two subsets of mesenchymal stromal cells (MSCs) in human synovium, which are lining and sublining MSCs, and found that angiogenesis and fibrosis-associated genes were upregulated whereas genes associated with cell adhesion and cartilage development were downregulated in aged MSCs. Moreover, the specific cell-cell communications in aged synovium mirrors that of aging-related inflammation and tissue remodeling, including vascular hyperplasia and tissue fibrosis. In particular, we identified forkhead box O1 (FOXO1) as one of the major regulons for aging differentially expressed genes (DEGs) in synovial MSCs, and validated its downregulation in both lining and sublining MSC populations of the aged synovium. In human FOXO1-depleted MSCs derived from human embryonic stem cells, we recapitulated the senescent phenotype observed in the subacromial synovium of aged donors. These data indicate an important role of FOXO1 in the regulation of human synovial aging. Overall, our study improves our understanding of synovial aging during joint degeneration, thereby informing the development of novel intervention strategies aimed at rejuvenating the aged joint.
Topics: Humans; Forkhead Box Protein O1; Synovial Membrane; Mesenchymal Stem Cells; Gene Expression Profiling; Transcriptome; Aged; Aging; Adult; Cellular Senescence; Male; Middle Aged; Female
PubMed: 38092362
DOI: 10.1093/procel/pwad060 -
Journal of ISAKOS : Joint Disorders &... Feb 2024Stiff elbow is a complex condition whose diagnosis and management are sometimes quite a challenge. Compared to the other joints, the elbow is disproportionately affected...
Stiff elbow is a complex condition whose diagnosis and management are sometimes quite a challenge. Compared to the other joints, the elbow is disproportionately affected by loss of motion following trauma or surgery. It is unclear why the elbow tends to develop stiffness; its anatomical complexity, namely the presence of three highly congruent joints in the same capsule and synovial space, the tautness of the lateral and medial collateral ligaments through the whole range of motion, and the very close relationship among tendons, muscles, and skin 2 may account for this characteristic. In a stiff elbow, it is critical to assess the possible involvement of articular and periarticular tissues, particularly the degree of preservation of the articular surfaces and joint congruency. Morrey et al have classified post-traumatic stiff elbow into three types: 1) extrinsic contracture, which involves the soft tissue around the joint (capsule, ligaments, muscles) and heterotopic ossification across the joint, 2) intrinsic contracture, secondary to intra-articular fractures that have altered the anatomy of the articular surface, and 3) mixed contracture, combining intrinsic and extrinsic contracture. In the preoperative clinical assessment, we assume capsule contracture to be present in all patients with a stiff elbow. Two main associated lesions can affect prognosis and surgical management: heterotopic ossification and an altered bone joint anatomy. According to Morrey et al, most activities of daily living can be accomplished within an arc of motion from 30° to 130° in extension and flexion and of 50° in pronation and supination. The elbow arc of motion is not compensated for by the wrist and shoulder, thus loss of extension impairs the use of the hand in the space around the body and loss of flexion limits its use for grooming and self-care. The elbow should carefully be tested for deformity of the axial bone alignment (varus and valgus deformity) and rotational stability. Several treatment options are available for stiff elbow, from conservative management with a dedicated rehabilitation program to surgical treatment and from arthroscopic capsulectomy to joint replacement.
Topics: Animals; Humans; Elbow; Activities of Daily Living; Retrospective Studies; Contracture; Ossification, Heterotopic
PubMed: 37696358
DOI: 10.1016/j.jisako.2023.09.002 -
Arthritis & Rheumatology (Hoboken, N.J.) Dec 2023We sought to develop computer vision methods to quantify aggregates of cells in synovial tissue and compare these with clinical and gene expression parameters.
OBJECTIVE
We sought to develop computer vision methods to quantify aggregates of cells in synovial tissue and compare these with clinical and gene expression parameters.
METHODS
We assembled a computer vision pipeline to quantify five features encompassing synovial cell density and aggregates and compared these with pathologist scores, disease classification, autoantibody status, and RNA expression in a cohort of 156 patients with rheumatoid arthritis (RA) and 149 patients with osteoarthritis (OA).
RESULTS
All five features were associated with pathologist scores of synovial lymphocytic inflammation (P < 0.0001). Three features that related to the cells per unit of tissue were significantly increased in patients with both seronegative and seropositive RA compared with those with OA; on the other hand, aggregate features (number and diameter) were significantly increased in seropositive, but not seronegative, RA compared with OA. Aggregate diameter was associated with the gene expression of immunoglobulin heavy-chain genes in the synovial tissue. Compared with blood, synovial immunoglobulin isotypes were skewed from IGHM and IGHD to IGHG3 and IGHG1. Further, patients with RA with high levels of lymphocytic infiltrates in the synovium demonstrated parallel skewing in their blood with a relative decrease in IGHGM (P < 0.002) and IGHD (P < 0.03) and an increase in class-switched immunoglobulin genes IGHG3 (P < 0.03) and IGHG1 (P < 0.002).
CONCLUSION
High-resolution automated identification and quantification of synovial immune cell aggregates uncovered skewing in the synovium from naïve IGHD and IGHM to memory IGHG3 and IGHG1 and revealed that this process is reflected in the blood of patients with high inflammatory synovium.
Topics: Humans; Arthritis, Rheumatoid; Synovial Membrane; Osteoarthritis; Autoantibodies; Inflammation
PubMed: 37463182
DOI: 10.1002/art.42653 -
Clinical Rheumatology May 2024
Topics: Humans; Calcinosis; Osteoarthritis; Fingers; Joint Capsule
PubMed: 38502410
DOI: 10.1007/s10067-024-06941-4 -
Clinical and Experimental Rheumatology May 2024Inflammation-induced bone destruction is the main cause of progressive joint damage in rheumatoid arthritis (RA) and osteoarthritis (OA). In addition, depending on the... (Review)
Review
Inflammation-induced bone destruction is the main cause of progressive joint damage in rheumatoid arthritis (RA) and osteoarthritis (OA). In addition, depending on the tissue microenvironment stimulators, the synovium transforms into a hyperplastic invasive tissue. The synovium includes two specific subsets of fibroblasts surrounding the joints: lining and sublining synovial fibroblasts (SFs). These SFs grow and interact with immune cells invading the bone and cartilage; specifically, SFs, which are the major mesenchymal cells in the joints, develop an aggressive phenotype, thereby producing cytokines and proteases involved in arthritis pathogeneses. Transcriptomic differences in the heterogeneity of SFs reflect the joint-specific origins of the SFs interacting with immune cells. To understand the subsets of SFs that lead to joint damage in arthritis, clarifying the distinct phenotypes and properties of SFs and understanding how they influence bone cells, such as osteoclasts and chondrocytes, is crucial. This review provides an overview of the advancements in the understanding of SF subsets and features, which may aid in identifying newer therapeutic targets.
Topics: Humans; Fibroblasts; Synovial Membrane; Cartilage, Articular; Arthritis, Rheumatoid; Osteoarthritis; Phenotype; Animals; Signal Transduction
PubMed: 37706287
DOI: 10.55563/clinexprheumatol/txl9rm -
Cellular & Molecular Immunology Jan 2024A novel rheumatoid arthritis (RA) synovial fluid protein, Syntenin-1, and its receptor, Syndecan-1 (SDC-1), are colocalized on RA synovial tissue endothelial cells and...
A novel rheumatoid arthritis (RA) synovial fluid protein, Syntenin-1, and its receptor, Syndecan-1 (SDC-1), are colocalized on RA synovial tissue endothelial cells and fibroblast-like synoviocytes (FLS). Syntenin-1 exacerbates the inflammatory landscape of endothelial cells and RA FLS by upregulating transcription of IRF1/5/7/9, IL-1β, IL-6, and CCL2 through SDC-1 ligation and HIF1α, or mTOR activation. Mechanistically, Syntenin-1 orchestrates RA FLS and endothelial cell invasion via SDC-1 and/or mTOR signaling. In Syntenin-1 reprogrammed endothelial cells, the dynamic expression of metabolic intermediates coincides with escalated glycolysis along with unchanged oxidative factors, AMPK, PGC-1α, citrate, and inactive oxidative phosphorylation. Conversely, RA FLS rewired by Syntenin-1 displayed a modest glycolytic-ATP accompanied by a robust mitochondrial-ATP capacity. The enriched mitochondrial-ATP detected in Syntenin-1 reprogrammed RA FLS was coupled with mitochondrial fusion and fission recapitulated by escalated Mitofusin-2 and DRP1 expression. We found that VEGFR1/2 and Notch1 networks are responsible for the crosstalk between Syntenin-1 rewired endothelial cells and RA FLS, which are also represented in RA explants. Similar to RA explants, morphological and transcriptome studies authenticated the importance of VEGFR1/2, Notch1, RAPTOR, and HIF1α pathways in Syntenin-1 arthritic mice and their obstruction in SDC-1 deficient animals. Consistently, dysregulation of SDC-1, mTOR, and HIF1α negated Syntenin-1 inflammatory phenotype in RA explants, while inhibition of HIF1α impaired synovial angiogenic imprint amplified by Syntenin-1. In conclusion, since the current therapies are ineffective on Syntenin-1 and SDC-1 expression in RA synovial tissue and blood, targeting this pathway and its interconnected metabolic intermediates may provide a novel therapeutic strategy.
Topics: Animals; Mice; Adenosine Triphosphate; Angiogenesis; Arthritis, Rheumatoid; Cells, Cultured; Endothelial Cells; Fibroblasts; Inflammation; Metabolic Reprogramming; Synovial Membrane; Synoviocytes; Syntenins; TOR Serine-Threonine Kinases
PubMed: 38105293
DOI: 10.1038/s41423-023-01108-8