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

2020 ◽  
Author(s):  
Askhat Myngbay ◽  
Limara Manarbek ◽  
Steve B. 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 this is associated with cancer metastasis to the bone and poor 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 that may be linked to the pathogenic behavior of fibroblast-like synoviocytes, cartilage destruction, and bone erosion.

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.

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.

Novel Insights into the Ontogenetic and Functional Heterogeneity of Macrophages in Synovial Tissue and Bone

2021 ◽  
Vol 30 (04) ◽  
pp. 292-298
Author(s):  
Gulce Itir Percin ◽  
Anika Grüneboom ◽  
Claudia Waskow ◽  
Stephan Culemann
Keyword(s):  
Immune System ◽  
Synovial Tissue ◽  
Single Cell Analysis ◽  
Bone Erosion ◽  
Imaging Techniques ◽  
Cartilage Destruction ◽  
Innate Immune ◽  
Cell Analysis ◽  
Functional Heterogeneity ◽  
Advanced Imaging

AbstractInflammatory joint diseases like rheumatoid arthritis (RA) belong to the most prevalent autoimmune disorders. RA is characterized by a massive infiltration of immune cells into synovial tissue, cartilage destruction and bone erosion. The perpetuating inflammatory and destructive milieu is associated with severe pain and culminates in complete disability of synovial joints. The events initiating RA are still not fully understood and the treatments are mainly confined to strategies that modify and inhibit the body’s immune system. Macrophages and osteoclasts (OC) are myeloid cells of the innate immune system and are considered to play a central role in the inflammatory and destructive events of arthritis by production of inflammatory cytokines and mediating pathological bone resorption. In recent years, the use of novel fate mapping strategies identifying the origin and cellular development (ontogeny) of OC and macrophages in conjunction with new genetically modified mouse models, single cell analysis and advanced imaging techniques substantially changed our understanding on the ontogenetic and functional heterogeneity of these cells.

scholarly journals Correction to: Adiponectin aggravates bone erosion by promoting osteopontin production in synovial tissue of rheumatoid arthritis

2018 ◽  
Vol 20 (1) ◽  
Author(s):  
Jie Qian ◽  
Lingxiao Xu ◽  
Xiaoxuan Sun ◽  
Yani Wang ◽  
Wenhua Xuan ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Synovial Tissue ◽  
Bone Erosion

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 Identification and Analysis of Novel Synovial Tissue-based Biomarkers and Interacting Pathways for Rheumatoid Arthritis

2021 ◽  
Author(s):  
Paridhi Latawa
Keyword(s):  
Rheumatoid Arthritis ◽  
Synovial Tissue ◽  
Inflammatory Disorder ◽  
Target Tissue ◽  
Hematopoietic Stem ◽  
Stem Cell Migration ◽  
Current Medication ◽  
Number Of Patients ◽  
Gene Expression Studies ◽  
Synovial Tissues

Rheumatoid arthritis (RA) is an inflammatory disorder with autoimmune pathogenesis characterized by the immune system attacking the synovium. It is a clinically heterogeneous disease that affects approximately 1.2 million Americans and 20 million people worldwide. It is advantageous to diagnose RA before extensive erosion as treatments are more effective at early stages. RA treatments have made notable progresses, yet a significant number of patients still fail to respond to current medication and most of these come with harmful side effects. While the mechanistic reason for such failure rates remains unknown, the cellular and molecular signatures in the synovial tissues of patients with RA are likely to play a role in the variable treatment response and heterogeneous clinical evolution. While blood-based criteria are currently employed for diagnostics and treatments. such serologic parameters do not necessarily reflect biological actions in the target tissue of the patient and are relatively nonspecific to RA. Synovial tissue-based biomarkers are especially attractive as they can provide a confirmed diagnosis for RA. The shortage of accurate synovial tissue-based identifiers for RA diagnosis encouraged this research. This study analyzed data from several gene expression studies for differentially expressed genes in donor synovial tissue. Bioinformatics tools were used to construct and analyse protein interaction networks. Analysis deduced that regulating hematopoietic stem cell migration could serve as a potential RA diagnostic. VAV1, CD3G, LCK, PTPN6, ITGB2, CXCL13, CD4, and IL7R are found to be previously unclassified, potential biomarkers.

scholarly journals Combined Cornus Officinalis and Paeonia Lactiflora Pall Therapy Alleviates Rheumatoid Arthritis by Regulating Synovial Apoptosis via AMPK-Mediated Mitochondrial Fission

2021 ◽  
Vol 12 ◽  
Author(s):  
Lichuang Huang ◽  
Shaoqi Hu ◽  
Meiyu Shao ◽  
Xin Wu ◽  
Jida Zhang ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Bone Erosion ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Cartilage Destruction ◽  
Paeonia Lactiflora ◽  
Active Components ◽  
Cornus Officinalis ◽  
Medicinal Value ◽  
Underlying Mechanisms

Rheumatoid arthritis (RA) is a chronic autoimmune disease that leads to cartilage destruction and bone erosion. In-depth exploration of the pathogenesis of RA and the development of effective therapeutic drugs are of important clinical and social value. Herein, we explored the medicinal value of Cornus officinalis Sieb. and Paeonia lactiflora Pall. in RA treatment using a rat model of collagen-induced arthritis (CIA). We compared the therapeutic effect of Cornus officinalis and Paeonia lactiflora with that of their main active compounds, ursolic acid and paeoniflorin, respectively. We demonstrated that the combination of Cornus officinalis and Paeonia lactiflora effectively inhibited the release of factors associated with oxidative stress and inflammation during RA, therein ameliorating the symptoms and suppressing the progression of RA. We further showed that the underlying mechanisms may be related to the regulation of apoptosis in synovial tissues, and we investigated the potential involvement of AMPK-mediated mitochondrial dynamics in the therapeutic action of the two drugs and their active components.

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