DMY protects the knee joints of rats with collagen-induced arthritis by inhibition of NF-κB signaling and osteoclastic bone resorption

2020 ◽  
Vol 11 (7) ◽  
pp. 6251-6264
Author(s):  
Jing Wu ◽  
Kai-Jian Fan ◽  
Qi-Shan Wang ◽  
Bing-Xin Xu ◽  
Qing Cai ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Animal Model ◽  
Articular Cartilage ◽  
Bone Resorption ◽  
Bone Erosion ◽  
Cartilage Destruction ◽  
Osteoclastic Bone Resorption ◽  
Knee Joints ◽  
Collagen Induced Arthritis

Collagen-induced arthritis (CIA) is a widely used animal model for studying rheumatoid arthritis (RA), which manifests serious joint dysfunction, progressive bone erosion and articular cartilage destruction.

scholarly journals The Role of Collagen Triple Helix Repeat-Containing 1 Protein (CTHRC1) in Rheumatoid Arthritis

2021 ◽  
Vol 22 (5) ◽  
pp. 2426
Author(s):  
Askhat Myngbay ◽  
Limara Manarbek ◽  
Steve Ludbrook ◽  
Jeannette Kunz
Keyword(s):  
Rheumatoid Arthritis ◽  
Drug Targets ◽  
Triple Helix ◽  
Cancer Metastasis ◽  
Bone Erosion ◽  
Cartilage Destruction ◽  
Patient Treatment ◽  
Collagen Triple Helix ◽  
Potential Biomarker

Rheumatoid arthritis (RA) is a chronic autoimmune disease causing inflammation of joints, cartilage destruction and bone erosion. Biomarkers and new drug targets are actively sought and progressed to improve available options for patient treatment. The Collagen Triple Helix Repeat Containing 1 protein (CTHRC1) may have an important role as a biomarker for rheumatoid arthritis, as CTHRC1 protein concentration is significantly elevated in the peripheral blood of rheumatoid arthritis patients compared to osteoarthritis (OA) patients and healthy individuals. CTHRC1 is a secreted glycoprotein that promotes cell migration and has been implicated in arterial tissue-repair processes. Furthermore, high CTHRC1 expression is observed in many types of cancer and is associated with cancer metastasis to the bone and poor patient prognosis. However, the function of CTHRC1 in RA is still largely undefined. The aim of this review is to summarize recent findings on the role of CTHRC1 as a potential biomarker and pathogenic driver of RA progression. We will discuss emerging evidence linking CTHRC1 to the pathogenic behavior of fibroblast-like synoviocytes and to cartilage and bone erosion through modulation of the balance between bone resorption and repair.

scholarly journals Update on the Pathomechanism, Diagnosis, and Treatment Options for Rheumatoid Arthritis

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 880 ◽  
Author(s):  
Yen-Ju Lin ◽  
Martina Anzaghe ◽  
Stefan Schülke
Keyword(s):  
Rheumatoid Arthritis ◽  
Side Effects ◽  
Bone Erosion ◽  
Treatment Options ◽  
Joint Damage ◽  
Cartilage Destruction ◽  
Biologic Dmards ◽  
Clinical Benefits ◽  
Synthetic Dmards ◽  
Inability To Work

Rheumatoid arthritis (RA) is an autoimmune disease that involves multiple joints bilaterally. It is characterized by an inflammation of the tendon (tenosynovitis) resulting in both cartilage destruction and bone erosion. While until the 1990s RA frequently resulted in disability, inability to work, and increased mortality, newer treatment options have made RA a manageable disease. Here, great progress has been made in the development of disease-modifying anti-rheumatic drugs (DMARDs) which target inflammation and thereby prevent further joint damage. The available DMARDs are subdivided into (1) conventional synthetic DMARDs (methotrexate, hydrochloroquine, and sulfadiazine), (2) targeted synthetic DMARDs (pan-JAK- and JAK1/2-inhibitors), and (3) biologic DMARDs (tumor necrosis factor (TNF)-α inhibitors, TNF-receptor (R) inhibitors, IL-6 inhibitors, IL-6R inhibitors, B cell depleting antibodies, and inhibitors of co-stimulatory molecules). While DMARDs have repeatedly demonstrated the potential to greatly improve disease symptoms and prevent disease progression in RA patients, they are associated with considerable side-effects and high financial costs. This review summarizes our current understanding of the underlying pathomechanism, diagnosis of RA, as well as the mode of action, clinical benefits, and side-effects of the currently available DMARDs.

Treatment with a neutralizing anti-murine interleukin-17 antibody after the onset of collagen-induced arthritis reduces joint inflammation, cartilage destruction, and bone erosion

2004 ◽  
Vol 50 (2) ◽  
pp. 650-659 ◽  
Author(s):  
Erik Lubberts ◽  
Marije I. Koenders ◽  
Birgitte Oppers-Walgreen ◽  
Liduine van den Bersselaar ◽  
Christina J. J. Coenen-de Roo ◽  
...  
Keyword(s):  
Bone Erosion ◽  
Joint Inflammation ◽  
Cartilage Destruction ◽  
Interleukin 17 ◽  
Collagen Induced Arthritis

Histomorphological Basis of Articular Cartilage Destruction in Rheumatoid Arthritis

1983 ◽  
Vol 3 (2) ◽  
pp. 141-155 ◽  
Author(s):  
Hans Georg Fassbender
Keyword(s):  
Rheumatoid Arthritis ◽  
Articular Cartilage ◽  
Cartilage Destruction

scholarly journals PTEN Methylation Promotes Inflammation and Activation of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiao-Feng Li ◽  
Sha Wu ◽  
Qi Yan ◽  
Yuan-Yuan Wu ◽  
He Chen ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Articular Cartilage ◽  
Dna Methyltransferase ◽  
Underlying Mechanism ◽  
Cartilage Destruction ◽  
Specific Pcr ◽  
Methylation Inhibitor ◽  
Fibroblast Like Synoviocytes

Rheumatoid arthritis (RA) is characterized by a tumor-like expansion of the synovium and subsequent destruction of adjacent articular cartilage and bone. In our previous work we showed that phosphatase and tension homolog deleted on chromosome 10 (PTEN) contributes to the activation of fibroblast-like synoviocytes (FLS) in adjuvant-induced arthritis (AIA), but the underlying mechanism is not unknown. In this study, we show that PTEN is downregulated while DNA methyltransferase (DNMT)1 is upregulated in FLS from RA patients and a rat model of AIA. DNA methylation of PTEN was increased by administration of tumor necrosis factor (TNF)-α in FLS of RA patients, as determined by chromatin immunoprecipitation and methylation-specific PCR. Treatment with the methylation inhibitor 5-azacytidine suppressed cytokine and chemokine release and FLS activation in vitro and alleviated paw swelling in vivo. PTEN overexpression reduced inflammation and activation of FLS via protein kinase B (AKT) signaling in RA, and intra-articular injection of PTEN-expressing adenovirus into the knee of AIA rats markedly reduced inflammation and paw swelling. Thus, PTEN methylation promotes the inflammation and activation of FLS in the pathogenesis of RA. These findings provide insight into the molecular basis of articular cartilage destruction in RA, and indicate that therapeutic strategies that prevent PTEN methylation may an effective treatment.

scholarly journals Propionibacterium freudenreichii Inhibits RANKL-Induced Osteoclast Differentiation and Ameliorates Rheumatoid Arthritis in Collagen-Induced Arthritis Mice

2021 ◽  
Vol 10 (1) ◽  
pp. 48
Author(s):  
Jiah Yeom ◽  
Dong Joon Yim ◽  
Seongho Ma ◽  
Young-Hee Lim
Keyword(s):  
Rheumatoid Arthritis ◽  
Mouse Model ◽  
Bone Erosion ◽  
Osteoclast Differentiation ◽  
Joint Damage ◽  
Bone Destruction ◽  
In Vivo Studies ◽  
Propionibacterium Freudenreichii ◽  
Limited Information ◽  
Collagen Induced Arthritis

Osteoclast differentiation is crucial for bone absorption, and osteoclasts are involved in bone destruction in rheumatoid arthritis (RA). Dairy Propionibacterium freudenreichii is used as a cheese starter and possesses prebiotic and postbiotic properties. It is known to stimulate the growth of bifidobacteria and produces valuable metabolites, such as vitamin B12 and propionic acid. However, limited information is available on the beneficial effects of P. freudenreichii on human disease. Herein, we aimed to investigate the inhibitory effect of P. freudenreichii MJ2 (MJ2) isolated from raw milk on osteoclast differentiation and evaluate the improvement in RA. The murine macrophage cell line, RAW 264.7, and a collagen-induced arthritis (CIA) mouse model were used to perform in vitro and in vivo studies, respectively. Heat-killed P. freudenreichii MJ2 (hkMJ2)-treated cells significantly inhibited RANKL-induced osteoclast differentiation and TRAP activity. HkMJ2-treated cells exhibited significantly decreased expression of genes and proteins related to RANKL-induced osteoclast differentiation. MJ2 administration decreased the arthritic score in the CIA mouse model. Live and dead MJ2 inhibited bone loss and afforded protection against bone erosion and joint damage in CIA mice. MJ2 decreased the levels of collagen-specific antibodies and inflammatory cytokines and the expression of osteoclast differentiation-related genes and proteins in CIA mice. Interestingly, live and dead MJ2 showed similar RA improvement effects in CIA mice. In conclusion, P. freudenreichii MJ2 inhibited osteoclast differentiation by inhibiting the NF-κB signaling pathway and ameliorated CIA.

scholarly journals Knockdown adiponectin receptor 1 expression in synovial tissue alleviate the progression of collagen-induced arthritis

2019 ◽  
Author(s):  
Yani Wang ◽  
Rui Liu ◽  
Pengfei Zhao ◽  
Qian Zhang ◽  
Yingheng Huang ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Synovial Tissue ◽  
Bone Erosion ◽  
Adiponectin Receptor ◽  
Inflammatory Factors ◽  
Nuclear Factor ◽  
Collagen Induced Arthritis ◽  
Adiponectin Receptor 1 ◽  
Receptor Activator

Abstract Background: Previous studies have shown that adiponectin (APN) is involved in the pathogenesis of rheumatoid arthritis (RA). The proinflammatory effect of APN is mainly mediated adiponectin receptor 1 (AdipoR1). The high expression of AdipoR1 have been suggested in RA synovial tissue. This study was aimed to investigate the effects of AdipoR1 in inflammation and bone erosion in collagen-induced arthritis (CIA) mice, and to further explore the underlying mechanisms. Methods: The expression of APN and AdipoR1 in synovial tissue of RA and osteoarthritis (OA) patient was tested by qPCR and western blot. RA synovial fibroblasts (RASFs) were stimulated with APN, IL-6 or TNF-α respectively. The expression of AdipoR1 on RASFs were tested by flow cytometry. To prove the pathogenic role, AdipoR1 was silenced in a human rheumatoid arthritis synovial fibroblast cell line (MH7A) and local joint of CIA mice by specific short hairpin RNAs (shRNAs) using a lentiviral delivery system. The levels of proliferation, apoptosis and inflammatory factors on MH7A were assessed in vitro. Local AdipoR1 knockdown on CIA mice were further estimated by arthritis clinical scores, inflammatory cytokine expression, micro-CT, H&E staining and receptor activator of nuclear factor к B ligand (RANKL) / osteoprotegerin (OPG) in vivo. Results: We found that the levels of APN and AdipoR1 expression were significantly higher in RASFs and the expression of AdipoR1 was upregulated by APN in RASFs. Silencing AdipoR1 could effectively reduce lipopolysaccharides (LPS) induced proliferation of MH7A cells, promote their apoptosis, and reduce the release of inflammatory factors. In CIA mice, local silencing AdipoR1 in arthritis markedly reduced joint inflammation and alleviated bone erosion and osteoporosis in vivo. Furthermore, local silencing AdipoR1 inhibited receptor activator of nuclear factor к B ligand (RANKL) expression and decreased RANKL / osteoprotegerin (OPG) ratio in knees and ankles of CIA mice. Conclusions: This study suggests that AdipoR1 plays a key role in the development of RA and silencing AdipoR1 might be a new target for the clinical treatment of RA.

scholarly journals TAK1 inhibition effectively suppresses NLRP3 inflammasome-mediated inflammation and osteoclastic bone resorption in rheumatoid arthritis

Bone Reports ◽  
2020 ◽  
Vol 13 ◽  
pp. 100635
Author(s):  
Hirofumi Tenshin ◽  
Jumpei Teramachi ◽  
Masahiro Hiasa ◽  
Asuka Oda ◽  
Takeshi Harada ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Bone Resorption ◽  
Nlrp3 Inflammasome ◽  
Osteoclastic Bone Resorption

scholarly journals A Computational Modeling Framework to Analyze Synovial-Tissue Based Drug Targets and Diagnostic Biomarkers in Rheumatoid Arthritis

2021 ◽  
Author(s):  
Paridhi Latawa ◽  
Brianna Chrisman
Keyword(s):  
Rheumatoid Arthritis ◽  
Synovial Tissue ◽  
Drug Targets ◽  
Bone Erosion ◽  
Cartilage Destruction ◽  
Modeling Framework ◽  
Diagnostic Biomarkers ◽  
Number Of Patients ◽  
Targeted Treatments ◽  
Inflammatory Autoimmune Disease

Rheumatoid Arthritis (RA) is an inflammatory autoimmune disease that affects 23 million people worldwide. It is a clinically heterogeneous disorder characterized by the attack of inflammatory chemicals on the synovial tissue that lines joints. It is advantageous to develop effective, targeted treatments and identify specific diagnostic biomarkers for RA before extensive joint degradation, bone erosion, and cartilage destruction. Current modes of RA treatments have alleviated and notably halted the progression of RA. Despite this, not many patients reach low disease activity status after treatment, and a significant number of patients fail to respond to medication due to drug non-specificity. While the reasons for these rates remain unknown, the cellular and molecular signatures present in the synovial tissue for RA patients likely play a role in the varied treatment response. Thus, a drug that particularly targets specific genes and networks may have a significant effect in halting the progression of RA. This study evaluates and proposes potential drug targets through in silico mathematical modeling of various pathways of interest in RA. To understand how drugs interact with genes, we built a mathematical model with 30 two-gene and three-gene network interactions and analyzed the effect of 92 different perturbations to rate constants. We determined that inhibition of the LCK-CD4, VAV1-CD4, and MLT-ROR pathways could potentially serve as drug targets. We also found that increased activity of the DEC2-IL1β and the NF-κB-interleukin pathway and the decreased activity of the TNF-α-REV-ERB pathway could serve as diagnostic biomarkers.

scholarly journals Susceptibility of Cyclin-dependent Kinase Inhibitor-1–deficient Mice to Rheumatoid Arthritis From IL-1β–induced Inflammation

2020 ◽  
Author(s):  
Yoshinori Takashima ◽  
Shinya Hayashi ◽  
Koji Fukuda ◽  
Toshihisa Maeda ◽  
Masanori Tsubosaka ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Monoclonal Antibodies ◽  
Kinase Inhibitor ◽  
Joint Inflammation ◽  
Type Ii Collagen ◽  
Cartilage Destruction ◽  
Knee Joints ◽  
Inflammatory Disorder ◽  
Cyclin Dependent Kinase ◽  
And Cartilage

Abstract Background: Rheumatoid arthritis (RA) is a chronic and systemic inflammatory disorder whose progression is modulated by fibroblast-like synoviocytes (FLSs). Cyclin-dependent kinase (CDK) inhibitor 1 (p21) regulates the activation of other CDKs, and we recently reported that p21 deficiency induces susceptibility to osteoarthritis. Here, we focused on joint inflammation to determine the mechanisms associated with p21 function in synovial and cartilage tissues in RA.Methods: p21-knockout (p21-/-) mice and wild-type C57BL/6 (WT p21+/+) mice were used to establish a collagen antibody-induced arthritis (CAIA) model. The severity of arthritis was evaluated visually, and histological and immunohistological analyses performed 7, 14, and 28 days after injection with a cocktail of five monoclonal antibodies that recognize conserved epitopes on various species of type II collagen. The response of p21 siRNA-treated human RA FLSs to IL-1β stimulation was also determined.Results: Arthritis scores were higher in p21-/- mice than those in p21+/+ mice. More severe and prolonged synovitis of the knee joints and earlier loss of staining and cartilage destruction were observed in p21-/- mice than in p21+/+ mice. p21-/- mice expressed higher levels of IL-1β, F4/80, p-IKKα/β, and MMPs in cartilage and synovial tissues at each time point, except for before injection of the monoclonal antibodies, via IL-1β-induced NF-kB signaling. IL-1β stimulation significantly increased MMP expression and enhanced IKKα/β phosphorylation in human FLSs.Conclusion: p21-deficient CAIA mice are susceptible to alterations in the RA phenotype, including joint cartilage destruction and severe synovitis, via IL-1β-induced inflammation. Therefore, p21 regulation may constitute a possible strategy for RA treatment.

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