Systemic characteristics of chronic arthritis induced by transfer of human rheumatoid synovial membrane into SCID mice (human/murine SCID arthritis).

Erosive human/murine (hu/mu) SCID arthritis, caused by unilateral engrafting of human rheumatoid arthritis synovial membrane (RA-SM) in the knee joints of SCID mice, was monitored for up to 18 weeks by scintigraphic, radiological, morphological and immunohistochemical analyses.(99m)Tc-DPD scintigraphy and histology revealed secondary, oligoarticular spreading of arthritis to contralateral knees and hips, but not to forelimb joints. Also, there were no extraarticular manifestations. At 18 weeks, surviving human cells were found within the pannus, but not directly at the cartilage erosion front, where fibroblast-like cells and macrophages of murine origin predominated. The latter cells also predominated in secondarily affected joints, where no human cells were detectable. Preventive depletion of murine NK-cells by anti-asialo-GMI antibodies, to check the influence of NK cells independently of strain and MHC system, combined with application of autologous human PBMN cells, had virtually no effects on the disease process. The completeness of the SCID defect was not critical, i.e. T cells were completely absent in the organs examined, and the presence of a few B cells in the spleen did not correspond to particular disease features. The SCID defect itself had a clear impact, since, in the chronic phase, SCID.bg and RAG-2(-/-)knockout mice developed less consistent pathological/scintigraphic signs of disease than SCID mice. Thus, unilaterally-induced hu/mu SCID arthritis is an oligoarticular disorder of the hindlimbs. Murine macrophages and fibroblast-like cells appear responsible for tissue destruction in engrafted and non-engrafted arthritic joints.     

A novel model of fibroblast-mediated cartilage destruction

In rheumatoid arthritis (RA), fibroblasts have been shown to be crucial for disease progression as well as joint destruction. In the model of human/murine SCID arthritis, synovial explants as well as fibroblasts from human rheumatoid synovial membrane induce destructive arthritis in immunodeficient mice. Hereby, the underlying cartilage destruction is accomplished by murine fibroblasts. Therefore, murine destructive fibroblasts represent a promising tool to investigate destruction of articular cartilage and bone. In this context, a novel destructive murine fibroblast line (LS48) was examined for morphological, ultrastructural, immunological and functional cellular parameters. These cells were injected into knees of SCID mice. Subsequently, the animals were monitored for joint swelling and serological parameters of arthritis by radiological methods. Finally, cartilage destruction was assessed morphologically. Cultured LS48 cells exhibit characteristic features that resemble those of activated synovial fibroblasts in human RA. Expression levels of inducible nitric oxide synthase, interleukin-6, tumour necrosis factor-alpha and matrix metalloproteinases were comparable to those detected in invasive human fibroblasts. The instillation of 5 x 10(5) LS48 cells into the knee joints of SCID mice initiated a rapid progressive process, that caused cartilage destruction within 10 days, and morphological examinations revealed that articular cartilage was infiltrated by the fibroblasts injected previously. In summary, the intra-articular application of LS48 cells represents a rapid and highly reproducible model to investigate the initiation and progression of cartilage destruction in connection with RA therapy and represents an easy-to-handle animal model.     

Synovial fibroblasts of patients with rheumatoid arthritis attach to and invade normal human cartilage when engrafted into SCID mice.

Rheumatoid arthritis (RA) has been thought to be largely a T-cell-mediated disease. To evaluate the role of T-cell-independent pathways in RA, we examined the interaction between isolated RA synovial fibroblasts and normal human cartilage engrafted into SCID mice in the absence of T cells and other human cells. The expression of cartilage-de grading enzymes and adhesion molecules was examined by immunohistochemistry and in situ hybridization techniques. The RA synovial fibroblasts invaded the cartilage and kept their transformed appearing cellular shape. They expressed VCAM-1 and produced the cathepsins L and B at the site of invasion. We conclude that RA synovial fibroblasts maintain their invasive and destructive behavior over longer periods of time in the absence of human T cells, indicating that T-cell-independent pathways play a significant role in rheumatoid joint destruction.     

Modulation of hu/mu severe combined immunodeficient (SCID) mouse arthritis by local application of human recombinant IL-1β, IL-2 and IL-6

The contribution of interleukins produced by most inflammatory cells to chronic arthritis is not well understood. Therefore, we investigated the influence of several human recombinant interleukins (IL-1β, IL-2 and IL-6) on joint swelling, on the inflammatory process, and on serological parameters in a novel animal model of arthritis, the human/murine SCID arthritis. In this model an arthritis is induced by implanting human synovial tissue from patients with rheumatoid arthritis (RA) into the knee joint of mice with SCID. These mice tolerate the xenogeneic implant and develop a mixed human/murine pannus tissue. The interleukins were injected daily for 7 or 14 days after implantation. IL-1β led to a significant increase in joint swelling. It intensified the inflammatory process accompanied by enhanced migration of murine inflammatory cells into the knee joint. The production of human IL-6 in the transplanted tissue was stimulated through the application of IL-1β, and the serum level of human IL-6 was thus significantly higher than in controls. We could not observe a significant influence of IL-1β on the production of human IgG or IgM by the implant. The application of human IL-2 had a weak effect similar to that of IL-1β, but without statistical significance. Although IL-6 is a good marker for inflammation in RA, the application of recombined human IL-6 had no influence on the inflammatory process in this model.     

E2F decoy oligodeoxynucleotide ameliorates cartilage invasion by infiltrating synovium derived from rheumatoid arthritis

This study examined the ability of E2F decoy oligodeoxynucleotides (ODN) to inhibit proliferation of synovial fibroblasts derived from patients with rheumatoid arthritis (RA). The effect of E2F decoy ODN on cartilage invasion by RA synovium in a murine model of human RA was also investigated. E2F decoy ODN were introduced into synovial tissue and synovial fibroblasts derived from patients with RA using hemagglutinating virus of Japan (HVJ)-liposomes. The effect of E2F decoy ODN on synovial fibroblast proliferation was evaluated by MTT assay and by RT-PCR for the cell cycle regulatory genes proliferating-cell nuclear antigen (PCNA) and cyclin-dependent kinase 2 (cdk2). Changes in production of inflammatory mediators by RA synovial tissue following transfection with E2F decoy ODN were assessed by ELISA. Human cartilage and RA synovial tissue transfected with E2F decoy ODN were co-transplanted in severe combined immunodeficient (SCID) mice. After 4 weeks, the mice were sacrificed and the implants histologically examined for inhibition of cartilage damage by E2F decoy ODN. E2F decoy ODN resulted in significant inhibition of synovial fibroblast proliferation, corresponding with reduced expression of PCNA and cdk2 mRNA in synovial fibroblasts. The production of interleukin-1beta (IL-1beta), IL-6 and matrix metalloproteinase (MMP)-1 by synovial tissue was also significantly inhibited by the introduction of E2F decoy ODN. Further, in an in vivo model, cartilage that was co-implanted with RA synovial tissue transfected with E2F decoy ODN exhibited no invasive and progressive cartilage degradation. These data demonstrate that transfection of E2F decoy ODN prevents cartilage destruction by inhibition of synovial cell proliferation, and suggest that transfection of E2F decoy ODN may provide a useful therapeutic approach for the treatment of joint destruction in arthritis.     

Successful induction of severe destructive arthritis by the transfer of in vitro-activated synovial fluid T cells from patients with rheumatoid arthritis (RA) in severe combined immunodeficient (SCID) mice

In order to investigate the role of pathogenic T cells in RA, the establishment of an RA model using patients’ T cells is thought to be essential. In this study, multiple and severe destructive arthritis was established by transferring in vitro-stimulated synovial fluid T (SFT) cells from patients with RA through simultaneous injection into knee joint and peritoneal cavity of SCID mice without causing xenogeneic graft-versus--host disease (GVHD). Neither the transfer of unstimulated SFT cells nor sole i.p. injection was sufficient to induce severe arthritis. Interestingly, in contrast with SFT cells, in vitro-activated peripheral blood lymphocytes from RA patients failed to trigger such arthritis, suggesting that pathogenic T cells might be concentrated in synovial fluid of RA patients. This, the first severe arthritis model mimicking RA induced by RA patients’ T cells, is expected to provide important information about RA pathogenesis and a possible therapeutic approach.     

Th17 lymphocyte-dependent degradation of joint cartilage by synovial fibroblasts in a humanized mouse model of arthritis and reversal by secukinumab

How T-helper (Th) lymphocyte subpopulations identified in synovial fluid from patients with juvenile idiopathic arthritis (JIA) (Th17, classic Th1, or nonclassic Th1) drive joint damage is of great interest for the possible use of biological drugs that inhibit the specific cytokines. Our objective was to clarify the role of such Th subpopulations in the pathogenesis of articular cartilage destruction by synovial fibroblasts (SFbs), and the effect of Th17 blockage in an animal model. SFbs were isolated from healthy subjects and patients with JIA, and peripheral blood Th lymphocytes subsets were obtained from healthy subjects. Fragments of human cartilage from healthy subjects in a collagen matrix containing JIA or normal SFbs grafted underskin in SCID mice were used to measure cartilage degradation under the effects of Th supernatants. JIA SFbs overexpress MMP9 and MMP2 and Th17 induce both MMPs in normal SFbs, while nonclassic Th1 upregulate urokinase plasminogen activator (uPA) activity. In vitro invasive phenotype of normal SFbs is stimulated with conditioned medium of Th17 and nonclassic-Th1. In the in vivo “inverse wrap” model, normal SFbs stimulated with supernatants of Th17-lymphocytes and nonclassic Th1 produced a cartilage invasion and degradation similar to JIA SFbs. Secukinumab inhibits the cartilage damage triggered by factors produced by Th17.     

Synovial fibroblasts and synovial macrophages from patients with rheumatoid arthritis and other inflammatory joint diseases show chromosomal aberrations

Chromosomal aberrations were investigated in nuclei extracted from synovial tissue and first-passage synovial fibroblasts (P-1 SFB, 98% enrichment) or macrophages (P-1 Mphi) from patients with rheumatoid arthritis (n=10). The findings were compared with those in other rheumatic diseases (osteoarthritis, n=14; reactive arthritis, n=1), as well as with those in chronic obstructive pulmonary disease (n=8). Controls were paired peripheral blood lymphocytes from arthritic patients, synovial tissue or SFB/Mphi from joint trauma/normals (n=9), and peripheral blood monocytes from normal donors (n=10). GTG banding of metaphase chromosomes and interphase fluorescence in situ hybridization with centromere-specific probes were used. Comparable chromosomal aberrations were observed in synovial tissue and P-1 SFB of patients with rheumatoid arthritis, osteoarthritis, and reactive arthritis (polysomy 7 and aneusomies of chromosomes 4, 8, 9, 12, and 18). Notably, aneusomies of chromosomes 4, 6, 7, 8, 9, 11, 12, and/or X were also detected in P-1 synovial Mphi from rheumatoid arthritis (90% of the cases), osteoarthritis (93%), and reactive arthritis (1/1), as well as bronchial Mphi from chronic obstructive pulmonary disease (25%). No aberrations were detected in paired peripheral blood lymphocytes (except for one osteoarthritis case with a karyotype 45,X[10]/46,XX[17]), or in peripheral blood monocytes and synovial tissue of normals/joint trauma. Because Mphi aberrations were common to chronic joint and pulmonary disease, chronic inflammatory stress may induce chromosomal aberrations with potential functional relevance in local mesenchymal cells and infiltrating leukocytes in an organ-independent fashion.     

Expression of interleukin-1 and interleukin-1 receptor antagonist by human rheumatoid synovial tissue macrophages.

Interleukin-1 (IL-1) has protean effects in the pathogenesis of rheumatoid arthritis (RA). These effects include production of prostaglandins and collagenase from rheumatoid fibroblasts as well as upregulation of adhesion molecule expression on these cells. IL-1 can activate monocytes and neutrophils, as well as promote the growth of fibroblasts and endothelial cells. Recently, a novel interleukin-1 receptor antagonist protein (IRAP) has been isolated, purified, cloned, and expressed, which may modulate the effects of IL-1. In this study, we present data demonstrating that macrophages isolated from human RA synovial tissues express both IL-1 and IRAP genes. In addition, RA synovial tissue macrophages and lining cells display IL-1 and IRAP antigenic expression by immunohistochemistry. In contrast, osteoarthritis synovial tissues, as compared to RA, have fewer IL-1 and IRAP-positive macrophages. Thus, the production of IL-1 balanced by IRAP may affect the joint destruction found in these diseases.     

IRAK4 inhibition: a promising strategy for treating RA joint inflammation and bone erosion

Flares of joint inflammation and resistance to currently available biologic therapeutics in rheumatoid arthritis (RA) patients could reflect activation of innate immune mechanisms. Herein, we show that a TLR7 GU-rich endogenous ligand, miR-Let7b, potentiates synovitis by amplifying RA monocyte and fibroblast (FLS) trafficking. miR-Let7b ligation to TLR7 in macrophages (MΦs) and FLSs expanded the synovial inflammatory response. Moreover, secretion of M1 monokines triggered by miR-Let7b enhanced Th1/Th17 cell differentiation. We showed that IRAK4 inhibitor (i) therapy attenuated RA disease activity by blocking TLR7-induced M1 MΦ or FLS activation, as well as monokine-modulated Th1/Th17 cell polarization. IRAK4i therapy also disrupted RA osteoclastogenesis, which was amplified by miR-Let7b ligation to joint myeloid TLR7. Hence, the effectiveness of IRAK4i was compared with that of a TNF inhibitor (i) or anti-IL-6R treatment in collagen-induced arthritis (CIA) and miR-Let7b-mediated arthritis. We found that TNF or IL-6R blocking therapies mitigated CIA by reducing the infiltration of joint F480⁺iNOS⁺ MΦs, the expression of certain monokines, and Th1 cell differentiation. Unexpectedly, these biologic therapies were unable to alleviate miR-Let7b-induced arthritis. The superior efficacy of IRAK4i over anti-TNF or anti-IL-6R therapy in miR-Let7b-induced arthritis or CIA was due to the ability of IRAK4i therapy to restrain the migration of joint F480⁺iNOS⁺ MΦs, vimentin⁺ fibroblasts, and CD3⁺ T cells, in addition to negating the expression of a wide range of monokines, including IL-12, MIP2, and IRF5 and Th1/Th17 lymphokines. In conclusion, IRAK4i therapy may provide a promising strategy for RA therapy by disconnecting critical links between inflammatory joint cells.     

Intra-articular tissue factor/factor VII complex induces chronic arthritis

OBJECTIVE: Fibrin accumulation in the joint cavity is a common feature of chronic arthritides, such as rheumatoid arthritis (RA). Complex formation between tissue factor (TF) and factor VII (FVII) is the initial step in such a fibrin formation. METHODS: To assess the role of the TF/FVII complex in the pathogenesis of joint inflammation, 1) the levels of TF/FVII complex were measured in synovial fluid of RA patients; 2) the complex was injected to healthy mice intra-articularly. RESULTS: Morphological analysis of the joints 4 days after TF/FVII injection revealed influx of CD4-Mac1+ mononuclear leukocytes into synovial tissue followed by cartilage and bone destruction. Inflammation induced by TF/FVII complex was more profound than that caused by each of the proteins separately, both with respect to frequency, severity and duration of arthritis. Interaction between macrophages and lymphocytes in sustaining joint inflammation was proved by the requirement of the combined lymphocyte/ monocyte depletion to abolish TF/FVII induced arthritis. Induction of monocyte attracting chemokines (MIP-1 alpha and RANTES) was shown to be one of the potential mechanisms for TF/FVII complex triggered inflammatory cell influx. Interestingly, TF/FVII complexes were detected in synovial fluid of 20/40 patients with RA. CONCLUSIONS: Altogether these findings indicate that TF/FVII complexes, frequently found intra-articularly in joints of RA patients, may be an important component in both induction and progression of chronic destructive arthritis.     

Rheumatoid arthritis and interleukin-32]

Inflammatory cytokine cascade plays a pivotal role in the pathogenesis of rheumatoid arthritis. Recently, a novel human cytokine, interleukin-32, was reported to induce TNF-alpha. Interleukin-32 is expressed mainly in lymphoid tissues and leukocytes, but also in stimulated epithelial cells and synovial fibroblasts. Although the interleukin-32 receptor has not been reported, interleukin-32 can induce other inflammatory cytokines, such as TNF-alpha, interleukin-1beta, and interleukin-6 from monocytes/macrophages in vitro and in vivo, and synergizes with signals from pattern-recognition receptors. Notably, in the inflamed synovial tissues from rheumatoid arthritis patients, interleukin-32 is prominently expressed and correlates with the severity of arthritis and the expression of other cytokines, including TNF-alpha and interleukin-1. In experimental mice models of arthritis, joint injection of interleukin-32 induces joint inflammation, and overexpression of interleukin-32beta in haematopoietic cells exacerbates collagen-induced arthritis. Herein, interleukin-32 plays an important role in the pathogenesis of rheumatoid arthritis.     

Transfer of type II collagen-induced arthritis from DBA/1 to severe combined immunodeficiency mice can be prevented by blockade of Mac-1.

Collagen-induced arthritis in susceptible mice is widely accepted as an experimental model for human rheumatoid arthritis (RA). We have investigated the role of the Mac-1 integrin beta 2 in the development and maintenance of arthritis by means of in vivo administration of 5C6 monoclonal antibody (mAb) to block this receptor. Injection of a single dose of 5C6 mAb (0.5 mg, intraperitoneally) prior to the expected onset of collagen-induced arthritis in DBA/1 mice diminished the severity of subsequent disease in these animals, as assessed both clinically and histologically (P < 0.01, chi 2). In the DBA/1 to severe combined immunodeficiency (SCID) transfer model of arthritis, the incidence of clinical arthritis was significantly reduced in SCID mice receiving maintained 5C6 treatment commencing the day prior to administration of donor splenocytes. Histological evaluation of joints from animals without clinically evident arthritis confirmed the absence of an inflammatory infiltrate in 22/27 joints examined. In a minority of these joints, however, synovial hyperplasia was apparent. In contrast, delaying antibody administration until 10 days after donor spleen cell transfer failed to protect three of five SCID recipients. These results confirm a functional role for Mac-1 in the generation of collagen-induced arthritis in mice. Since mAb 5C6 is non-cytotoxic, its action must be by blockade of the interactions between Mac-1 and its natural ligand(s). Our findings support the hypothesis that cells expressing Mac-1 play an important role in the induction and maintenance of joint damage in collagen-induced arthritis.     

Differential expression and response to anti-TNFalpha treatment of infiltrating versus resident tissue macrophage subsets in autoimmune arthritis

Synovial macrophages play a pivotal role in the pathogenesis of chronic autoimmune arthritis by contributing to local inflammation and tissue damage and are therefore a primary target for therapeutic intervention. The aim of the present study was to investigate in more detail the relative contribution of different synovial macrophage subsets with potentially different inflammatory or anti-inflammatory functions by analysing the two most frequent forms of human autoimmune arthritis, spondyloarthropathy (SpA) and rheumatoid arthritis (RA). Both infiltrating macrophages from peripheral blood expressing myeloid-related proteins (MRP) 8 and 14, and resident tissue macrophages expressing CD163 were abundant in inflamed synovium. Whereas the global number of synovial macrophages was similar in both diseases, infiltrating macrophages were increased in the RA lining layer in contrast with resident tissue macrophages, which were more frequently observed in SpA. Soluble MRP8/MRP14 complexes, which were secreted locally in the joint during the infiltration process, were increased in the serum of arthritis patients and, in contrast with soluble CD163 shed from resident tissue macrophages, correlated well with global inflammatory parameters. Treatment in vivo with anti-TNFalpha had a rapid and pronounced effect on the infiltration of MRP-positive macrophages into tissues, as evidenced by histopathological analysis and serum MRP8/MRP14 levels. Taken together, these data support an important role for infiltrating versus resident tissue macrophages in human autoimmune synovitis and indicate that macrophage products such as soluble MRP8/MRP14 complexes are valuable biomarkers for the experimental and clinical monitoring of specific disease mechanisms in vivo.     

The SCID mouse model: novel therapeutic targets - lessons from gene transfer

The hallmark of rheumatoid arthritis (RA) is progressive destruction of the joints, preceded and accompanied by synovial hyperplasia and chronic inflammation. Spontaneous and induced animal models of RA reflect predominantly the inflammatory aspects of the disease. To reproduce the destruction of cartilage and bone mediated by an activated synovium, it was desirable to develop models that allow the dissection of cellular and molecular components derived from human tissue. The SCID mouse co-implantation model of human RA focuses on RA synovial fibroblasts (RA-SF) and their role in cartilage destruction. The model has provided the best evidence that RA-SF contribute significantly to matrix degradation, even in the absence of human lymphocytes and macrophages, since highly purified RA-SF invade the co-implanted normal human cartilage. Moreover, it became clear that they maintained their aggressive phenotype over long periods of time, particularly at sites of invasion into the co-implanted human cartilage. Targeting different signaling molecules, cytokines and matrix-degrading enzymes by soluble receptors, antagonists or negative mutants in the SCID mouse model of RA has implicated many of them in the mechanisms leading to cartilage destruction. However, since inhibition of a single molecule or pathway is not sufficient to inhibit the aggressive behavior of RA-SF it appears necessary to co-express in the synoviocytes genes for two or even more antagonists of e.g. cytokines, matrix-degrading enzymes or molecules interfering specifically with signaling pathways involved in the apoptosis of RA-SF. Based on the recent observation that the L1 (line-1) endogenous retroviral element appears responsible for the cytokine- independent activation via the MAPK p38delta, the current understanding of disease pathogenesis suggests that both the cytokine-dependent as well as the cytokine-independent pathways of joint destruction must be inhibited. Modulation of both pathways by gene transfer approaches in the SCID mouse model is a feasible method aimed at identifying novel targets for the prevention of cartilage destruction in RA.     

Synovial biology and T cells in rheumatoid arthritis.

Events that occur in rheumatoid arthritis synovial tissues are responsible for the signs and symptoms of joint inflammation and for the eventual destruction of articular and periarticular structures that lead to joint dysfunction and disability. The three most abundant cell populations in RA synovium are synovial macrophages (type A synoviocytes), synovial fibroblasts (type B synoviocytes) and infiltrating T lymphocytes. Other important cell populations include B lymphocytes, dendritic cells, plasma cells, mast cells and osteoclasts. Our current understanding of rheumatoid arthritis is moving beyond previous concepts that view this disease as the consequence of a specific and focused humoral or cellular autoimmune response to a single autoantigen. Rather, a new view of rheumatoid arthritis is emerging, which seeks to understand this disease as the product of pathologic cell-cell interactions occurring within a unique and defined environment, the synovium. T lymphocytes in rheumatoid arthritis synovium interact closely with dendritic cells, the most potent antigen-presenting cell population in the immune system. T cells also interact with monocytes and macrophages and cytokine-activated T cells may be, especially, suited to trigger production of the important cytokine TNFalpha by synovial macrophages. Recent evidence also suggests a potent bidirectional interaction between synovial T cells and synovial fibroblasts, which can lead to activation of both cell types. An important role for synovial B lymphocytes has been emphasized recently, both by experimental data and by results of clinical interventions. B cells in synovium can interact with fibroblasts as well as with other cells of the immune system and their potential role as antigen-presenting cells in the joint is as yet underexplored. Rheumatoid arthritis synovium may be one of the most striking examples of pathologic, organ-specific interactions between immune system cells and resident tissue cell populations. This view of rheumatoid arthritis also leads to the prediction that novel approaches to treatment will more logically target the intercellular communication systems that maintain such interactions, rather than attempt to ablate a single cell population.     

Loss of microRNA-147 function alleviates synovial inflammation through ZNF148 in rheumatoid and experimental arthritis

MicroRNA-147 (miR-147) had been previously found induced in synoviocytes by inflammatory stimuli derived from T cells in experimental arthritis. This study was designed to verify whether loss of its function might alleviate inflammatory events in joints of experimental and rheumatoid arthritis (RA). Dark Agouti (DA) rats were injected intradermally with pristane to induce arthritis, and rno-miR-147 antagomir was locally administrated into individual ankle compared with negative control or rno-miR-155-5p antagomir (potential positive control). Arthritis onset, macroscopic severity, and pathological changes were monitored. While in vitro, gain or loss function of hsa-miR-147b-3p/hsa-miR-155-5p and ZNF148 was achieved in human synovial fibroblast cell line SW982 and RA synovial fibroblasts (RASF). The expression of miRNAs and mRNAs was detected by using RT-quantitative PCR, and protein expression was detected by using Western blotting. Anti-miR-147 therapy could alleviate the severity, especially for the synovitis and joint destruction in experimental arthritis. Gain of hsa-miR-147b-3p/hsa-miR-155-5p function in TNF-α stimulated SW982 and RASF cells could upregulate, in contrast, loss of hsa-miR-147b-3p/hsa-miR-155-5p function could downregulate the gene expression of TNF-α, IL-6, MMP3, and MMP13. Hence, such alteration could participate in synovial inflammation and joint destruction. RNAi of ZNF148, a miR-147's target, increased gene expression of TNF-α, IL-6, MMP3, and MMP13 in SW982 and RASF cells. Also, mRNA sequencing data showed that hsa-miR-147b-3p mimic and ZNF148 siRNA commonly regulated the gene expression of CCL3 and DEPTOR as well as some arthritis and inflammation-related pathways. Taken together, miR-147b-3p contributes to synovial inflammation through repressing ZNF148 in RA and experimental arthritis.