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.

scholarly journals Susceptibility of cyclin-dependent kinase inhibitor 1-deficient mice to rheumatoid arthritis arising from interleukin-1β-induced inflammation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yoshinori Takashima ◽  
Shinya Hayashi ◽  
Koji Fukuda ◽  
Toshihisa Maeda ◽  
Masanori Tsubosaka ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Cartilage Destruction ◽  
Cyclin Dependent Kinase ◽  
In Vivo Models ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Tnf Α ◽  
Safranin O ◽  
And Cartilage

AbstractWe recently reported that cyclin-dependent kinase inhibitor 1 (p21) deficiency induces osteoarthritis susceptibility. Here, we determined the mechanism underlying the effect of p21 in synovial and cartilage tissues in RA. The knee joints of p21-knockout (p21−/−) (n = 16) and wild type C57BL/6 (p21+/+) mice (n = 16) served as in vivo models of collagen antibody-induced arthritis (CAIA). Arthritis severity was evaluated by immunological and histological analyses. The response of p21 small-interfering RNA (siRNA)-treated human RA FLSs (n = 5 per group) to interleukin (IL)-1β stimulation was determined in vitro. Arthritis scores were higher in p21−/− mice than in p21+/+ mice. More severe synovitis, earlier loss of Safranin-O staining, and cartilage destruction were observed in p21−/− mice compared to p21+/+ mice. p21−/− mice expressed higher levels of IL-1β, TNF-α, F4/80, CD86, p-IKKα/β, and matrix metalloproteinases (MMPs) in cartilage and synovial tissues via IL-1β-induced NF-kB signaling. IL-1β stimulation significantly increased IL-6, IL-8, and MMP expression, and enhanced IKKα/β and IκBα phosphorylation in human FLSs. p21-deficient CAIA mice are susceptible to RA phenotype alterations, including joint cartilage destruction and severe synovitis. Therefore, p21 may have a regulatory role in inflammatory cytokine production including IL-1β, IL-6, and TNF-α.

scholarly journals The loss of α2β1 integrin suppresses joint inflammation and cartilage destruction in mouse models of rheumatoid arthritis

2012 ◽  
Vol 64 (5) ◽  
pp. 1359-1368 ◽  
Author(s):  
Marvin A. Peters ◽  
Doreen Wendholt ◽  
Simon Strietholt ◽  
Svetlana Frank ◽  
Noreen Pundt ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Mouse Models ◽  
Joint Inflammation ◽  
Cartilage Destruction ◽  
Α2β1 Integrin ◽  
And Cartilage

scholarly journals Managing Osteoporosis and Joint Damage in Patients with Rheumatoid Arthritis: An Overview

2021 ◽  
Vol 10 (6) ◽  
pp. 1241
Author(s):  
Yoshiya Tanaka
Keyword(s):  
Rheumatoid Arthritis ◽  
Structural Damage ◽  
Kinase Inhibitors ◽  
Joint Destruction ◽  
Joint Damage ◽  
Nuclear Factor Κb ◽  
Cartilage Destruction ◽  
Janus Kinase ◽  
Systemic Autoimmune Disease ◽  
And Cartilage

In rheumatoid arthritis, a representative systemic autoimmune disease, immune abnormality and accompanying persistent synovitis cause bone and cartilage destruction and systemic osteoporosis. Biologics targeting tumor necrosis factor, which plays a central role in the inflammatory process, and Janus kinase inhibitors have been introduced in the treatment of rheumatoid arthritis, making clinical remission a realistic treatment goal. These drugs can prevent structural damage to bone and cartilage. In addition, osteoporosis, caused by factors such as menopause, aging, immobility, and glucocorticoid use, can be treated with bisphosphonates and the anti-receptor activator of the nuclear factor-κB ligand antibody. An imbalance in the immune system in rheumatoid arthritis induces an imbalance in bone metabolism. However, osteoporosis and bone and cartilage destruction occur through totally different mechanisms. Understanding the mechanisms underlying osteoporosis and joint destruction in rheumatoid arthritis leads to improved care and the development of new treatments.

scholarly journals Prostaglandins and Rheumatoid Arthritis

Arthritis ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Mohammad Javad Fattahi ◽  
Abbas Mirshafiey
Keyword(s):  
Rheumatoid Arthritis ◽  
Arachidonic Acid ◽  
Immune Responses ◽  
Cartilage Destruction ◽  
Heterogeneous Population ◽  
Therapeutic Protocol ◽  
Site Of Action ◽  
And Cartilage ◽  
Homeostatic Mechanisms

Rheumatoid arthritis (RA) is a chronic, autoimmune, and complex inflammatory disease leading to bone and cartilage destruction, whose cause remains obscure. Accumulation of genetic susceptibility, environmental factors, and dysregulated immune responses are necessary for mounting this self-reacting disease. Inflamed joints are infiltrated by a heterogeneous population of cellular and soluble mediators of the immune system, such as T cells, B cells, macrophages, cytokines, and prostaglandins (PGs). Prostaglandins are lipid inflammatory mediators derived from the arachidonic acid by multienzymatic reactions. They both sustain homeostatic mechanisms and mediate pathogenic processes, including the inflammatory reaction. They play both beneficial and harmful roles during inflammation, according to their site of action and the etiology of the inflammatory response. With respect to the role of PGs in inflammation, they can be effective mediators in the pathophysiology of RA. Thus the use of agonists or antagonists of PG receptors may be considered as a new therapeutic protocol in RA. In this paper, we try to elucidate the role of PGs in the immunopathology of RA.

A MULTIMODAL IMAGING MODALITY FOR UNDERSTANDING BONE AND CARTILAGE DESTRUCTION AND REPAIR IN RHEUMATOID ARTHRITIS

2008 ◽  
Vol 41 ◽  
pp. S189
Author(s):  
Kathryn Stok ◽  
Danièle Noël ◽  
Florence Apparailly ◽  
David Gould ◽  
Yuti Chernajovsky ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Multimodal Imaging ◽  
Imaging Modality ◽  
Cartilage Destruction ◽  
And Cartilage

scholarly journals The Janus kinase inhibitor (baricitinib) suppresses the rheumatoid arthritis active marker gliostatin/thymidine phosphorylase in human fibroblast-like synoviocytes

2022 ◽  
Author(s):  
Yuji Joyo ◽  
Yohei Kawaguchi ◽  
Hiroki Yonezu ◽  
Hiroya Senda ◽  
Sanshiro Yasuma ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Thymidine Phosphorylase ◽  
Kinase Inhibitor ◽  
Cartilage Destruction ◽  
Janus Kinase ◽  
Enzyme Linked Immunosorbent Assay ◽  
Stat Proteins ◽  
Protein Levels ◽  
Stat Signaling ◽  
Fibroblast Like Synoviocytes

AbstractGliostatin/thymidine phosphorylase (GLS/TP) is known to have angiogenic and arthritogenic activities in the pathogenesis of rheumatoid arthritis (RA). The novel oral Janus kinase (JAK) inhibitor baricitinib has demonstrated high efficacy in RA. However, the effect of baricitinib on fibroblast-like synoviocytes (FLSs), a key component of invasive synovitis, has not been still elucidated. This study investigated whether GLS/TP production could be regulated by JAK/signal transducers and activators of transcription (STAT) signaling in FLSs derived from patients with RA. FLSs were cultured and stimulated by interferon (IFN)γ in the presence of baricitinib. Expression levels of GLS/TP were determined using reverse transcription-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and immunocytochemistry. Phosphorylation of STAT proteins was investigated by Western blot. In cultured FLSs, GLS/TP mRNA and protein levels were significantly induced by treatment with IFNγ and these inductions were suppressed by baricitinib treatment. Baricitinib inhibited IFNγ-induced STAT1 phosphorylation, while JAK/STAT activation played a pivotal role in IFNγ-mediated GLS/TP upregulation in RA. These results suggested that baricitinib suppressed IFNγ-induced GLS/TP expression by inhibiting JAK/STAT signaling, resulting in the attenuation of neovascularization, synovial inflammation, and cartilage destruction.

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.

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