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Research of Pathogenesis and Novel Therapeutics in Arthritis 3.0
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Research of Pathogenesis and Novel Therapeutics in Arthritis 3.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 July 2022) | Viewed by 71348

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Prof. Dr. Chih-Hsin Tang

E-Mail Website
Guest Editor
Graduate Institute of Basic Medical Science, China Medical University, Taichung 40402, Taiwan
Interests: arthritis; bone cancer; osteoporosis; metastasis; drug development
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleague，

Arthritis has a high prevalence globally and includes over 100 types, the most common of which are rheumatoid arthritis, osteoarthritis, psoriatic arthritis, and inflammatory arthritis. All types of arthritis share common features of disease, including monocyte infiltration, inflammation, synovial swelling, pannus formation, stiffness in the joints and articular cartilage destruction. The exact etiology of arthritis remains unclear, and no cure exists as of yet. Anti-inflammatory drugs (NSAIDs and corticosteroids) are commonly used in the treatment of arthritis. However, these drugs are associated with significant side effects, such as gastric bleeding and an increased risk for heart attack and other cardiovascular problems. It is therefore crucial that we continue to research the pathogenesis of arthritis and seek to discover novel modes of therapy. We invite researchers to submit original research and review articles covering significant developments in the pathogenesis of arthritis, as well as novel medicines or strategies that hold promise in the prevention and/or treatment of this disease. In particular, we welcome research covering novel signaling pathways, signaling molecules, inflammatory cytokines, or anti-inflammatory drugs.

Prof. Dr. Chih-Hsin Tang
Guest Editor

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Keywords

  • Arthritis
  • Treatment
  • Molecular mechanisms
  • Inflammatory cytokines
  • Prevention

Published Papers (19 papers)

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Editorial

Jump to: Research, Review

4 pages, 191 KiB  
Editorial
Research of Pathogenesis and Novel Therapeutics in Arthritis 3.0
by Chih-Hsin Tang
Int. J. Mol. Sci. 2023, 24(12), 10166; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241210166 - 15 Jun 2023
Cited by 1 | Viewed by 789
Abstract
Arthritis has a high prevalence globally and includes over 100 types, the most common of which are rheumatoid arthritis (RA), osteoarthritis (OA), psoriatic arthritis (PsA), and inflammatory arthritis [...] Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis 3.0)

Research

Jump to: Editorial, Review

12 pages, 1562 KiB  
Article
Mammalian Glycosylation Patterns Protect Citrullinated Chemokine MCP-1/CCL2 from Partial Degradation
by Olexandr Korchynskyi, Ken Yoshida, Nataliia Korchynska, Justyna Czarnik-Kwaśniak, Paul P. Tak, Ger J. M. Pruijn, Takeo Isozaki, Jeffrey H. Ruth, Phillip L. Campbell, M. Asif Amin and Alisa E. Koch
Int. J. Mol. Sci. 2023, 24(3), 1862; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24031862 - 18 Jan 2023
Cited by 1 | Viewed by 1961
Abstract
Monocyte chemoattractant protein-1 (MCP-1/CCL2) is a potent chemotactic agent for monocytes, primarily produced by macrophages and endothelial cells. Significantly elevated levels of MCP-1/CCL2 were found in synovial fluids of patients with rheumatoid arthritis (RA), compared to osteoarthritis or other arthritis patients. Several studies [...] Read more.
Monocyte chemoattractant protein-1 (MCP-1/CCL2) is a potent chemotactic agent for monocytes, primarily produced by macrophages and endothelial cells. Significantly elevated levels of MCP-1/CCL2 were found in synovial fluids of patients with rheumatoid arthritis (RA), compared to osteoarthritis or other arthritis patients. Several studies suggested an important role for MCP-1 in the massive inflammation at the damaged joint, in part due to its chemotactic and angiogenic effects. It is a known fact that the post-translational modifications (PTMs) of proteins have a significant impact on their properties. In mammals, arginine residues within proteins can be converted into citrulline by peptidylarginine deiminase (PAD) enzymes. Anti-citrullinated protein antibodies (ACPA), recognizing these PTMs, have become a hallmark for rheumatoid arthritis (RA) and other autoimmune diseases and are important in diagnostics and prognosis. In previous studies, we found that citrullination converts the neutrophil attracting chemokine neutrophil-activating peptide 78 (ENA-78) into a potent macrophage chemoattractant. Here we report that both commercially available and recombinant bacterially produced MCP-1/CCL2 are rapidly (partially) degraded upon in vitro citrullination. However, properly glycosylated MCP-1/CCL2 produced by mammalian cells is protected against degradation during efficient citrullination. Site-directed mutagenesis of the potential glycosylation site at the asparagine-14 residue within human MCP-1 revealed lower expression levels in mammalian expression systems. The glycosylation-mediated recombinant chemokine stabilization allows the production of citrullinated MCP-1/CCL2, which can be effectively used to calibrate crucial assays, such as modified ELISAs. Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis 3.0)
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Graphical abstract

12 pages, 1671 KiB  
Article
Short Peptides of Innate Immunity Protein Tag7 Inhibit the Production of Cytokines in CFA-Induced Arthritis
by Georgii B. Telegin, Aleksandr S. Chernov, Alexey N. Minakov, Irina P. Balmasova, Elena A. Romanova, Tatiana N. Sharapova, Lidia P. Sashchenko and Denis V. Yashin
Int. J. Mol. Sci. 2022, 23(20), 12435; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232012435 - 17 Oct 2022
Cited by 4 | Viewed by 1672
Abstract
The pathogenesis of autoimmune arthritis is a hot topic in current research. The main focus of this work was to study cytokines released in CFA-induced arthritis in ICR mice as well as the regulation of blood levels of cytokines by two peptides of [...] Read more.
The pathogenesis of autoimmune arthritis is a hot topic in current research. The main focus of this work was to study cytokines released in CFA-induced arthritis in ICR mice as well as the regulation of blood levels of cytokines by two peptides of the innate immunity protein Tag7 (PGLYRP1) capable of blocking the activation of the TNFR1 receptor. Arthritis was induced by local periarticular single-dose injections of 40 µL of complete Freund’s adjuvant (CFA) into the left ankle joints of mice. The levels of chemokines and cytokines in plasma were measured using a Bio-Plex Pro Mouse Cytokine Kit at 3, 10, and 21 days after arthritis induction. Tag7 peptides were shown to decrease the blood levels of the pro-inflammatory cytokines IL-6, TNF, and IL-1β. Administration of peptides also decreased the levels of chemokines MGSA/CXCL1, MIP-2α/CXCL2, ENA78/CXCL5, MIG/CXCL9, IP-10/CXCL10, MCP-1/CCL2, and RANTES/CCL5. Furthermore, a decrease in the levels of cytokines IL7, G-CSF, and M-CSF was demonstrated. Addition of the studied peptides strongly affected IFN-γ concentration. We believe that a decrease in the levels of cytokine IFN-γ was associated with a therapeutic effect of Tag7 peptides manifested in alleviation of the destruction of cartilage and bone tissues in the CFA-induced arthritis. Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis 3.0)
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17 pages, 1548 KiB  
Article
Development of Two Innovative Performance-Based Objective Measures in Feline Osteoarthritis: Their Reliability and Responsiveness to Firocoxib Analgesic Treatment
by Aliénor Delsart, Maxim Moreau, Colombe Otis, Marilyn Frezier, Marlene Drag, Jean-Pierre Pelletier, Johanne Martel-Pelletier, Bertrand Lussier, Jérôme del Castillo and Eric Troncy
Int. J. Mol. Sci. 2022, 23(19), 11780; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911780 - 04 Oct 2022
Cited by 2 | Viewed by 1448
Abstract
The metrological properties of two performance-based outcome measures of feline osteoarthritis (OA), namely Effort Path (Path) and Stairs Assay Compliance (Stairs), were tested. Cats naturally affected by OA (n = 32) were randomly distributed into four groups (A: 0.40, B: 0.25, C: [...] Read more.
The metrological properties of two performance-based outcome measures of feline osteoarthritis (OA), namely Effort Path (Path) and Stairs Assay Compliance (Stairs), were tested. Cats naturally affected by OA (n = 32) were randomly distributed into four groups (A: 0.40, B: 0.25, C: 0.15, or D: 0.00 mg firocoxib/kg bodyweight) and assessed during baseline, treatment, and recovery periods. For Path, from an elevated walking platform, the cats landed on a pressure-sensitive mattress and jumped up onto a second elevated platform. Analysis included velocity, time to completion, peak vertical force (PVF), and vertical impulse. For Stairs, the number of steps and time to completion were recorded for 16 steps up and down in a 4 min period. Reliability was moderate to very good for Path and poor to good for Stairs. Different normalization methods are described in the manuscript. The placebo group remained stable within-time in Path, whereas treated cats trotted faster on the ramp (p < 0.0001), improved their PVF (p < 0.018) and completed the task quicker (p = 0.003). The percentage of cats completing the Stairs finish line was higher under treatment (p < 0.036), with huge effect size, the placebo group results being stable within-time. Both are promising performance-based outcome measures to better diagnose and manage feline OA pain. Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis 3.0)
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18 pages, 2635 KiB  
Article
Inhibition of TREM-2 Markedly Suppresses Joint Inflammation and Damage in Experimental Arthritis
by Alexander B. Sigalov
Int. J. Mol. Sci. 2022, 23(16), 8857; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23168857 - 09 Aug 2022
Cited by 2 | Viewed by 2898
Abstract
The triggering receptors expressed on myeloid cells (TREMs) are a family of activating immune receptors that regulate the inflammatory response. TREM-1, which is expressed on monocytes and/or macrophages and neutrophils, functions as an inflammation amplifier and plays a role in the pathogenesis of [...] Read more.
The triggering receptors expressed on myeloid cells (TREMs) are a family of activating immune receptors that regulate the inflammatory response. TREM-1, which is expressed on monocytes and/or macrophages and neutrophils, functions as an inflammation amplifier and plays a role in the pathogenesis of rheumatoid arthritis (RA). Unlike TREM-1, the role in RA of TREM-2, which is expressed on macrophages, immature monocyte-derived dendritic cells, osteoclasts, and microglia, remains unclear and controversial. TREM-2 ligands are still unknown, adding further uncertainty to our understanding of TREM-2 function. Previously, we demonstrated that TREM-1 blockade, using a ligand-independent TREM-1 inhibitory peptide sequence GF9 rationally designed by our signaling chain homooligomerization (SCHOOL) model of cell signaling, ameliorates collagen-induced arthritis (CIA) severity in mice. Here, we designed a TREM-2 inhibitory peptide sequence IA9 and tested it in the therapeutic CIA model, either as a free 9-mer peptide IA9, or as a part of a 31-mer peptide IA31 incorporated into lipopeptide complexes (IA31-LPC), for targeted delivery. We demonstrated that administration of IA9, but not a control peptide, after induction of arthritis diminished release of proinflammatory cytokines and dramatically suppressed joint inflammation and damage, suggesting that targeting TREM-2 may be a promising approach for the treatment of RA. Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis 3.0)
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14 pages, 3262 KiB  
Article
IL-17 Facilitates VCAM-1 Production and Monocyte Adhesion in Osteoarthritis Synovial Fibroblasts by Suppressing miR-5701 Synthesis
by Tsung-Ju Wu, Sunny Li-Yun Chang, Chih-Yang Lin, Chao-Yang Lai, Xiu-Yuan He, Chun-Hao Tsai, Chih-Yuan Ko, Yi-Chin Fong, Chen-Ming Su and Chih-Hsin Tang
Int. J. Mol. Sci. 2022, 23(12), 6804; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23126804 - 18 Jun 2022
Cited by 10 | Viewed by 2369
Abstract
Osteoarthritis (OA) is characterized by the infiltration and adhesion of monocytes into the inflamed joint synovium. Interleukin (IL)-17 is a critical inflammatory mediator that participates in the progression of OA, although the mechanisms linking IL-17 and monocyte infiltration are not well understood. Our [...] Read more.
Osteoarthritis (OA) is characterized by the infiltration and adhesion of monocytes into the inflamed joint synovium. Interleukin (IL)-17 is a critical inflammatory mediator that participates in the progression of OA, although the mechanisms linking IL-17 and monocyte infiltration are not well understood. Our analysis of synovial tissue samples retrieved from the Gene Expression Omnibus (GEO) dataset exhibited higher monocyte marker (CD11b) and vascular cell adhesion molecule 1 (VCAM-1) levels in OA samples than in normal, healthy samples. The stimulation of human OA synovial fibroblasts (OASFs) with IL-17 increased VCAM-1 production and subsequently enhanced monocyte adhesion. IL-17 affected VCAM-1-dependent monocyte adhesion by reducing miR-5701 expression through the protein kinase C (PKC)-α and c-Jun N-terminal kinase (JNK) signaling cascades. Our findings improve our understanding about the effect of IL-17 on OA progression and, in particular, VCAM-1 production and monocyte adhesion, which may help with the design of more effective OA treatments. Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis 3.0)
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17 pages, 3642 KiB  
Article
Anti-Inflammatory Effects of Endogenously Released Adenosine in Synovial Cells of Osteoarthritis and Rheumatoid Arthritis Patients
by Rebecca Sohn, Marius Junker, Andrea Meurer, Frank Zaucke, Rainer H. Straub and Zsuzsa Jenei-Lanzl
Int. J. Mol. Sci. 2021, 22(16), 8956; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168956 - 19 Aug 2021
Cited by 9 | Viewed by 2690
Abstract
Exogenous adenosine and its metabolite inosine exert anti-inflammatory effects in synoviocytes of osteoarthritis (OA) and rheumatoid arthritis (RA) patients. We analyzed whether these cells are able to synthesize adenosine/inosine and which adenosine receptors (ARs) contribute to anti-inflammatory effects. The functionality of synthesizing enzymes [...] Read more.
Exogenous adenosine and its metabolite inosine exert anti-inflammatory effects in synoviocytes of osteoarthritis (OA) and rheumatoid arthritis (RA) patients. We analyzed whether these cells are able to synthesize adenosine/inosine and which adenosine receptors (ARs) contribute to anti-inflammatory effects. The functionality of synthesizing enzymes and ARs was tested using agonists/antagonists. Both OA and RA cells expressed CD39 (converts ATP to AMP), CD73 (converts AMP to adenosine), ADA (converts adenosine to inosine), ENT1/2 (adenosine transporters), all AR subtypes (A1, A2A, A2B and A3) and synthesized predominantly adenosine. The CD73 inhibitor AMPCP significantly increased IL-6 and decreased IL-10 in both cell types, while TNF only increased in RA cells. The ADA inhibitor DAA significantly reduced IL-6 and induced IL-10 in both OA and RA cells. The A2AAR agonist CGS 21680 significantly inhibited IL-6 and induced TNF and IL-10 only in RA, while the A2BAR agonist BAY 60-6583 had the same effect in both OA and RA. Taken together, OA and RA synoviocytes express the complete enzymatic machinery to synthesize adenosine/inosine; however, mainly adenosine is responsible for the anti- (IL-6 and IL-10) or pro-inflammatory (TNF) effects mediated by A2A- and A2BAR. Stimulating CD39/CD73 with simultaneous ADA blockage in addition to TNF inhibition might represent a promising therapeutic strategy. Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis 3.0)
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15 pages, 2809 KiB  
Article
Hyperbilirubinemia Maintained by Chronic Supplementation of Unconjugated Bilirubin Improves the Clinical Course of Experimental Autoimmune Arthritis
by Tomas Sykora, Pavel Babal, Kristina Mikus-Kuracinova, Frantisek Drafi, Silvester Ponist, Monika Dvorakova, Pavol Janega and Katarina Bauerova
Int. J. Mol. Sci. 2021, 22(16), 8662; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168662 - 12 Aug 2021
Cited by 5 | Viewed by 2704
Abstract
Rheumatoid arthritis (RA) is a chronic multisystem disease, therapy of which remains a challenge for basic research. The present work examined the effect of unconjugated bilirubin (UCB) administration in adjuvant-induced arthritis (AIA)—an experimental model, in which oxidative stress (OS), inflammation and inadequate immune [...] Read more.
Rheumatoid arthritis (RA) is a chronic multisystem disease, therapy of which remains a challenge for basic research. The present work examined the effect of unconjugated bilirubin (UCB) administration in adjuvant-induced arthritis (AIA)—an experimental model, in which oxidative stress (OS), inflammation and inadequate immune response are often similar to RA. Male Lewis rats were randomized into groups: CO—control, AIA—untreated adjuvant-induced arthritis, AIA-BIL—adjuvant-induced arthritis administrated UCB, CO-BIL—control with administrated UCB. UCB was administered intraperitoneally 200 mg/kg of body weight daily from 14th day of the experiment, when clinical signs of the disease are fully manifested, to 28th day, the end of the experiment. AIA was induced by a single intradermal immunization at the base of the tail with suspension of Mycobacterium butyricum in incomplete Freund’s adjuvant. Clinical, hematologic, biochemical and histologic examinations were performed. UCB administration to animals with AIA lead to a significant decrease in hind paws volume, plasma levels of C-reactive protein (CRP) and ceruloplasmin, drop of leukocytes, lymphocytes, erythrocytes, hemoglobin and an increase in platelet count. UCB administration caused significantly lowered oxidative damage to DNA in arthritic animals, whereas in healthy controls it induced considerable oxidative damage to DNA. UCB administration also induced atrophy of the spleen and thymus in AIA and CO animals comparing to untreated animals. Histological signs of joint damage assessed by neutrophils infiltration and deposition of fibrin were significantly reduced by UCB administration. The effects of exogenously administered UCB to the animals with adjuvant-induced arthritis might be identified as therapeutic, in contrast to the effects of UCB administration in healthy animals rather classified as toxic. Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis 3.0)
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15 pages, 4360 KiB  
Article
Immunofluorescence Analysis of NF-kB and iNOS Expression in Different Cell Populations during Early and Advanced Knee Osteoarthritis
by Marko Ostojic, Ante Zevrnja, Katarina Vukojevic and Violeta Soljic
Int. J. Mol. Sci. 2021, 22(12), 6461; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126461 - 16 Jun 2021
Cited by 19 | Viewed by 3125
Abstract
Synovitis of the knee synovium is proven to be a precursor of knee osteoarthritis (OA), leading to a radiologically advanced stage of the disease. This study was conducted to elucidate the expression pattern of different inflammatory factors—NF-kB, iNOS, and MMP-9 in a subpopulation [...] Read more.
Synovitis of the knee synovium is proven to be a precursor of knee osteoarthritis (OA), leading to a radiologically advanced stage of the disease. This study was conducted to elucidate the expression pattern of different inflammatory factors—NF-kB, iNOS, and MMP-9 in a subpopulation of synovial cells. Thirty synovial membrane intra-operative biopsies of patients (ten controls, ten with early OA, and ten with advanced OA, according to the Kellgren–Lawrence radiological score) were immunohistochemically stained for NF-kB, iNOS, and MMP9, and for different cell markers for macrophages, fibroblasts, leukocytes, lymphocytes, blood vessel endothelial cells, and blood vessel smooth muscle cells. The total number of CD68+/NF-kB+ cells/mm2 in the intima of early OA patients (median = 2359) was significantly higher compared to the total number of vimentin+/Nf-kB+ cells/mm2 (median = 1321) and LCA+/NF-kB+ cells/mm2 (median = 64) (p < 0.001 and p < 0.0001, respectively). The total number of LCA+/NF-kB+ cells/mm2 in the subintima of advanced OA patients (median = 2123) was significantly higher compared to the total number of vimentin+/NF-kB+ cells/mm2 (median = 14) and CD68+/NF-kB+ cells/mm2 (median = 29) (p < 0.0001). The total number of CD68+/iNOS+ cells/mm2 in the intima of both early and advanced OA patients was significantly higher compared to the total number of vimentin+/iNOS+ cells/mm2 and LCA+/iNOS+ cells/mm2 (p < 0.0001 and p < 0.001, respectively). The total number of CD68+/MMP-9+ cells/mm2 in the intima of both early and advanced OA patients was significantly higher compared to the total number of vimentin+/MMP-9+ cells/mm2 and CD5+/MMP-9+ cells/mm2 (p < 0.0001). Macrophages may have a leading role in OA progression through the NF-kB production of inflammatory factors (iNOS and MMP-9) in the intima, except in advanced OA, where leukocytes could have a dominant role through NF-kB production in subintima. The blocking of macrophageal and leukocyte NF-kB expression is a possible therapeutic target as a disease modifying drug. Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis 3.0)
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16 pages, 15833 KiB  
Article
Kurarinone Attenuates Collagen-Induced Arthritis in Mice by Inhibiting Th1/Th17 Cell Responses and Oxidative Stress
by Kuo-Tung Tang, Chi-Chien Lin, Shih-Chao Lin, Jou-Hsuan Wang and Sen-Wei Tsai
Int. J. Mol. Sci. 2021, 22(8), 4002; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22084002 - 13 Apr 2021
Cited by 20 | Viewed by 3436
Abstract
Kurarinone is a flavanone, extracted from Sophora flavescens Aiton, with multiple biological effects. Here, we determine the therapeutic potential of kurarinone and elucidate the interplay between kurarinone and the autoimmune disease rheumatoid arthritis (RA). Arthritis was recapitulated by induction of bovine collagen II [...] Read more.
Kurarinone is a flavanone, extracted from Sophora flavescens Aiton, with multiple biological effects. Here, we determine the therapeutic potential of kurarinone and elucidate the interplay between kurarinone and the autoimmune disease rheumatoid arthritis (RA). Arthritis was recapitulated by induction of bovine collagen II (CII) in DBA/1 mice as a collagen-induced arthritis (CIA) model. After the establishment of the CIA, kurarinone was given orally from day 21 to 42 (100 mg/kg/day) followed by determination of the severity based on a symptom scoring scale and with histopathology. Levels of cytokines, anti-CII antibodies, and the proliferation and lineages of T cells from the draining lymph nodes were measured using ELISA and flow cytometry, respectively. The expressional changes, including STAT1, STAT3, Nrf2, KEAP-1, and heme oxygenase-1 (HO-1) changes in the paw tissues, were evaluated by Western blot assay. Oxidative stress featured with malondiadehyde (MDA) and hydrogen peroxide (H2O2) activities in paw tissues were also evaluated. Results showed that kurarinone treatment reduced arthritis severity of CIA mice, as well as their levels of proinflammatory cytokines, TNF-α, IL-6, IFN-γ, and IL-17A, in the serum and paw tissues. T cell proliferation was also reduced by kurarinone even under the stimulation of CII and anti-CD3 antibody. In addition, kurarinone reduced STAT1 and STAT3 phosphorylation and the proportions of Th1 and Th17 cells in lymph nodes. Moreover, kurarinone suppressed the production of MDA and H2O2. All while promoting enzymatic activities of key antioxidant enzymes, SOD and GSH-Px. In the paw tissues, upregulation of Nrf-2 and HO-1, and downregulation of KEAP-1 were observed. Overall, kurarinone showed an anti-inflammatory effect by inhibiting Th1 and Th17 cell differentiation and an antioxidant effect exerted in part through activating the Nrf-2/KEAP-1 pathway. These beneficial effects in CIA mice contributed to the amelioration of their arthritis, indicating that kurarinone might be an adjunct treatment option for rheumatoid arthritis. Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis 3.0)
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17 pages, 3254 KiB  
Article
Berberine Delays Onset of Collagen-Induced Arthritis through T Cell Suppression
by Alexandra A. Vita, Hend Aljobaily, David O. Lyons and Nicholas A. Pullen
Int. J. Mol. Sci. 2021, 22(7), 3522; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073522 - 29 Mar 2021
Cited by 16 | Viewed by 3736
Abstract
There is evidence that berberine (BBR), a clinically relevant plant compound, ameliorates clinically apparent collagen-induced arthritis (CIA) in vivo. However, to date, there are no studies involving the use of BBR which explore its prophylactic potential in this model of rheumatoid arthritis (RA). [...] Read more.
There is evidence that berberine (BBR), a clinically relevant plant compound, ameliorates clinically apparent collagen-induced arthritis (CIA) in vivo. However, to date, there are no studies involving the use of BBR which explore its prophylactic potential in this model of rheumatoid arthritis (RA). The aim of this study was to determine if prophylactic BBR use during the preclinical phase of collagen-induced arthritis would delay arthritic symptom onset, and to characterize the cellular mechanism underlying such an effect. DBA/1J mice were injected with an emulsion of bovine type II collagen (CII) and complete Freund’s adjuvant (day 0) and a booster injection of CII in incomplete Freund’s adjuvant (day 18) to induce arthritis. Mice were then given i.p. injections of 1 mg/kg/day of BBR or PBS (vehicle with 0.01% DMSO) from days 0 to 28, were left untreated (CIA control), or were in a non-arthritic control group (n = 15 per group). Incidence of arthritis in BBR-treated mice was 50%, compared to 90% in both the CIA and PBS controls. Populations of B and T cells from the spleens and draining lymph nodes of mice were examined on day 14 (n = 5 per group) and day 28 (n = 10 per group). BBR-treated mice had significantly reduced populations of CD4+Th and CD4+CXCR5+ Tfh cells, and an increased proportion of Foxp3+ Treg at days 14 and 28, as well as reduced expression of co-stimulatory molecules CD28 and CD154 at both endpoints. The effect seen on T cell populations and co-stimulatory molecule expression in BBR-treated mice was not mirrored in CD19+ B cells. Additionally, BBR-treated mice experienced reduced anti-CII IgG2a and anti-CII total IgG serum concentrations. These results indicate a potential role for BBR as a prophylactic supplement for RA, and that its effect may be mediated specifically through T cell suppression. However, the cellular effector involved raises concern for BBR prophylactic use in the context of vaccine efficacy and other primary adaptive immune responses. Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis 3.0)
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15 pages, 2323 KiB  
Article
Increased Serum Levels of Brain-Derived Neurotrophic Factor Contribute to Inflammatory Responses in Patients with Rheumatoid Arthritis
by Ning-Sheng Lai, Hui-Chun Yu, Hsien-Yu Huang Tseng, Chia-Wen Hsu, Hsien-Bin Huang and Ming-Chi Lu
Int. J. Mol. Sci. 2021, 22(4), 1841; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041841 - 12 Feb 2021
Cited by 17 | Viewed by 2771
Abstract
The aim of this study is to investigate the role of brain-derived neurotrophic factor (BDNF) in the inflammatory responses in patients with rheumatoid arthritis (RA). Serum levels of BDNF and the precursor form of BDNF (proBDNF) from 625 RA patients and 40 controls [...] Read more.
The aim of this study is to investigate the role of brain-derived neurotrophic factor (BDNF) in the inflammatory responses in patients with rheumatoid arthritis (RA). Serum levels of BDNF and the precursor form of BDNF (proBDNF) from 625 RA patients and 40 controls were analyzed using enzyme-linked immunosorbent assay. Effects of BDNF on the mitogen-activated protein kinase pathway were analyzed by Western blotting. Microarray analysis was conducted to search BDNF regulated gene expression in Jurkat cells, and the differentially expressed genes were validated using T cells from patients with RA and controls. Serum BDNF levels were significantly elevated in patients with RA compared with the controls. Low serum BDNF levels were found in RA patients with anxiety or receiving biologics treatment. BDNF (20 ng/mL) enhanced the phosphorylation of ERK, JNK, and c-Jun, but suppressed the phosphorylation of p38, whereas BDNF (200 ng/mL) enhanced the phosphorylation of ERK and p38. After validation, the expression of CAMK2A, MASP2, GNG13, and MUC5AC, regulated by BDNF and one of its receptors, NGFR, was increased in RA T cells. BDNF increased the IL-2, IL-17, and IFN-γ expression in Jurkat cells and IL-2 and IFN-γ secretion in activated peripheral blood mononuclear cells. Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis 3.0)
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15 pages, 3417 KiB  
Article
Expression Pattern of iNOS, BCL-2 and MMP-9 in the Hip Synovium Tissue of Patients with Osteoarthritis
by Davor Caric, Sandra Zekic Tomas, Natalija Filipovic, Violeta Soljic, Benjamin Benzon, Sandro Glumac, Ivan Rakovac and Katarina Vukojevic
Int. J. Mol. Sci. 2021, 22(3), 1489; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031489 - 02 Feb 2021
Cited by 6 | Viewed by 3374
Abstract
Hip osteoarthritis (HOA) is characterized by degradation of the cartilage and synovitis. However, the pathohistological effects of synovial tissue inflammation on HOA are not clear. The aim of this study was to evaluate the expression of iNOS, BCL-2 and MMP-9 markers in different [...] Read more.
Hip osteoarthritis (HOA) is characterized by degradation of the cartilage and synovitis. However, the pathohistological effects of synovial tissue inflammation on HOA are not clear. The aim of this study was to evaluate the expression of iNOS, BCL-2 and MMP-9 markers in different synovial cell populations. A total of 32 patients were evaluated retrospectively. Age, sex, height, weight, body mass index were recorded and lymphocyte, fibrocytes and macrophages were analysed in tissue sections. Osteoarthritis cartilage histopathology assessment system (OARSI), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Krenn score, Harris Hip Score (HHS) and Kellgren–Lawrence (K-L) grading of the hip joints were performed. Total hip arthroplasty was performed on 32 patients and controls. Patients were divided into two groups according to their disease severity. The tissues were immunohistochemically analysed. K-L grade and Krenn score differ between all three groups, but also between moderate and severe OA. Synovial lining cell layer, resident cells in stroma and especially inflammatory infiltration were increasing with severity of OA. iNOS expression in both intima and subintima was positively correlated with Krenn score in moderate and severe osteoarthritis (OA) groups. Expression of BCL-2 in intima of severe OA patients was positively correlated with Krenn score. In conclusion, iNOS, BCL-2 and MMP-9 are involved in the regulation of HOA. Our study indicates a relationship between the pathohistological features, the synovial inflammation and the cartilage condition at the time of hip replacement due to OA or femoral neck fracture. Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis 3.0)
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14 pages, 4922 KiB  
Article
Anti-Rheumatic Effect of Antisense Oligonucleotide Cytos-11 Targeting TNF-α Expression
by Tatyana P. Makalish, Ilya O. Golovkin, Volodymyr V. Oberemok, Kateryna V. Laikova, Zenure Z. Temirova, Olesya A. Serdyukova, Ilya A. Novikov, Roman A. Rosovskyi, Andrey I. Gordienko, Evgeniya Yu. Zyablitskaya, Elvina A. Gafarova, Kseniya A. Yurchenko, Iryna I. Fomochkina and Anatoly V. Kubyshkin
Int. J. Mol. Sci. 2021, 22(3), 1022; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031022 - 20 Jan 2021
Cited by 9 | Viewed by 3043
Abstract
The urgency of the search for inexpensive and effective drugs with localized action for the treatment of rheumatoid arthritis continues unabated. In this study, for the first time we investigated the Cytos-11 antisense oligonucleotide suppression of TNF-α gene expression in a rat model [...] Read more.
The urgency of the search for inexpensive and effective drugs with localized action for the treatment of rheumatoid arthritis continues unabated. In this study, for the first time we investigated the Cytos-11 antisense oligonucleotide suppression of TNF-α gene expression in a rat model of rheumatoid arthritis induced by complete Freund’s adjuvant. Cytos-11 has been shown to effectively reduce peripheral blood concentrations of TNF-α, reduce joint inflammation, and reduce pannus development. The results achieved following treatment with the antisense oligonucleotide Cytos-11 were similar to those of adalimumab (Humira®); they also compared favorably with those results, which provides evidence of the promise of drugs based on antisense technologies in the treatment of this disease. Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis 3.0)
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Review

Jump to: Editorial, Research

23 pages, 1587 KiB  
Review
A 2022 Systematic Review and Meta-Analysis of Enriched Therapeutic Diets and Nutraceuticals in Canine and Feline Osteoarthritis
by Maude Barbeau-Grégoire, Colombe Otis, Antoine Cournoyer, Maxim Moreau, Bertrand Lussier and Eric Troncy
Int. J. Mol. Sci. 2022, 23(18), 10384; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231810384 - 08 Sep 2022
Cited by 10 | Viewed by 14422
Abstract
With osteoarthritis being the most common degenerative disease in pet animals, a very broad panel of natural health products is available on the market for its management. The aim of this systematic review and meta-analysis, registered on PROSPERO (CRD42021279368), was to test for [...] Read more.
With osteoarthritis being the most common degenerative disease in pet animals, a very broad panel of natural health products is available on the market for its management. The aim of this systematic review and meta-analysis, registered on PROSPERO (CRD42021279368), was to test for the evidence of clinical analgesia efficacy of fortified foods and nutraceuticals administered in dogs and cats affected by osteoarthritis. In four electronic bibliographic databases, 1578 publications were retrieved plus 20 additional publications from internal sources. Fifty-seven articles were included, comprising 72 trials divided into nine different categories of natural health compound. The efficacy assessment, associated to the level of quality of each trial, presented an evident clinical analgesic efficacy for omega-3-enriched diets, omega-3 supplements and cannabidiol (to a lesser degree). Our analyses showed a weak efficacy of collagen and a very marked non-effect of chondroitin-glucosamine nutraceuticals, which leads us to recommend that the latter products should no longer be recommended for pain management in canine and feline osteoarthritis. Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis 3.0)
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18 pages, 1572 KiB  
Review
Mechanisms of Action and Efficacy of Hyaluronic Acid, Corticosteroids and Platelet-Rich Plasma in the Treatment of Temporomandibular Joint Osteoarthritis—A Systematic Review
by Marcin Derwich, Maria Mitus-Kenig and Elzbieta Pawlowska
Int. J. Mol. Sci. 2021, 22(14), 7405; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147405 - 09 Jul 2021
Cited by 38 | Viewed by 6543
Abstract
Temporomandibular joint osteoarthritis (TMJ OA) is a low-inflammatory disorder with multifactorial etiology. The aim of this review was to present the current state of knowledge regarding the mechanisms of action and the efficacy of hyaluronic acid (HA), corticosteroids (CS) and platelet-rich plasma (PRP) [...] Read more.
Temporomandibular joint osteoarthritis (TMJ OA) is a low-inflammatory disorder with multifactorial etiology. The aim of this review was to present the current state of knowledge regarding the mechanisms of action and the efficacy of hyaluronic acid (HA), corticosteroids (CS) and platelet-rich plasma (PRP) in the treatment of TMJ OA.: The PubMed database was analyzed with the keywords: “(temporomandibular joint) AND ((osteoarthritis) OR (dysfunction) OR (disorders) OR (pain)) AND ((treatment) OR (arthrocentesis) OR (arthroscopy) OR (injection)) AND ((hyaluronic acid) OR (corticosteroid) OR (platelet rich plasma))”. After screening of 363 results, 16 studies were included in this review. Arthrocentesis alone effectively reduces pain and improves jaw function in patients diagnosed with TMJ OA. Additional injections of HA, either low-molecular-weight (LMW) HA or high-molecular-weight (HMW) HA, or CS at the end of the arthrocentesis do not improve the final clinical outcomes. CS present several negative effects on the articular cartilage. Results related to additional PRP injections are not consistent and are rather questionable. Further studies should be multicenter, based on a larger group of patients and should answer the question of whether other methods of TMJ OA treatment are more beneficial for the patients than simple arthrocentesis. Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis 3.0)
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20 pages, 4826 KiB  
Review
Ultra-Low Dose Cytokines in Rheumatoid Arthritis, Three Birds with One Stone as the Rationale of the 2LARTH® Micro-Immunotherapy Treatment
by Camille Jacques, Ilaria Floris and Béatrice Lejeune
Int. J. Mol. Sci. 2021, 22(13), 6717; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22136717 - 23 Jun 2021
Cited by 15 | Viewed by 3895
Abstract
Tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) are two cytokines involved in the perpetuation of the chronic inflammation state characterizing rheumatoid arthritis (RA). Significant advances in the treatment of this pathology have been made over the past ten years, partially through the development [...] Read more.
Tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) are two cytokines involved in the perpetuation of the chronic inflammation state characterizing rheumatoid arthritis (RA). Significant advances in the treatment of this pathology have been made over the past ten years, partially through the development of anti-TNF and anti-IL-1 therapies. However, major side effects still persist and new alternative therapies should be considered. The formulation of the micro-immunotherapy medicine (MIM) 2LARTH® uses ultra-low doses (ULD) of TNF-α, IL-1β, and IL-2, in association with other immune factors, to gently restore the body’s homeostasis. The first part of this review aims at delineating the pivotal roles played by IL-1β and TNF-α in RA physiopathology, leading to the development of anti-TNF and anti-IL-1 therapeutic agents. In a second part, an emphasis will be made on explaining the rationale of using multiple therapeutic targets, including both IL-1β and TNF-α in 2LARTH® medicine. Particular attention will be paid to the ULD of those two main pro-inflammatory factors in order to counteract their overexpression through the lens of their molecular implication in RA pathogenesis. Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis 3.0)
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17 pages, 507 KiB  
Review
Vascular Endothelial Growth Factor Biology and Its Potential as a Therapeutic Target in Rheumatic Diseases
by Thi Hong Van Le and Sang-Mo Kwon
Int. J. Mol. Sci. 2021, 22(10), 5387; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22105387 - 20 May 2021
Cited by 17 | Viewed by 4319
Abstract
Rheumatic diseases constitute a diversified group of diseases distinguished by arthritis and often involve other organs. The affected individual has low quality of life, productivity even life-threatening in some severe conditions. Moreover, they impose significant economic and social burdens. In recent years, the [...] Read more.
Rheumatic diseases constitute a diversified group of diseases distinguished by arthritis and often involve other organs. The affected individual has low quality of life, productivity even life-threatening in some severe conditions. Moreover, they impose significant economic and social burdens. In recent years, the patient outcome has been improved significantly due to clearer comprehension of the pathology of rheumatic diseases and the effectiveness of “treat to target” therapies. However, the high cost and the adverse effects are the concerns and full remissions are not often observed. One of the main processes that contributes to the pathogenesis of rheumatic diseases is angiogenesis. Vascular endothelial growth factor (VEGF), a central mediator that regulates angiogenesis, has different isoforms and functions in various physiological processes. Increasing evidence suggests an association between the VEGF system and rheumatic diseases. Anti-VEGF and VEGF receptor (VEGFR) therapies have been used to treat several cancers and eye diseases. This review summarizes the current understanding of VEGF biology and its role in the context of rheumatic diseases, the contribution of VEGF bioavailability in the pathogenesis of rheumatic diseases, and the potential implications of therapeutic approaches targeting VEGF for these diseases. Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis 3.0)
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13 pages, 703 KiB  
Review
Targeting CCN Proteins in Rheumatoid Arthritis and Osteoarthritis
by Iona J. MacDonald, Chien-Chung Huang, Shan-Chi Liu, Yen-You Lin and Chih-Hsin Tang
Int. J. Mol. Sci. 2021, 22(9), 4340; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094340 - 21 Apr 2021
Cited by 22 | Viewed by 4058
Abstract
The CCN family of matricellular proteins (CYR61/CCN1, CTGF/CCN2, NOV/CCN3 and WISP1-2-3/CCN4-5-6) are essential players in the key pathophysiological processes of angiogenesis, wound healing and inflammation. These proteins are well recognized for their important roles in many cellular processes, including cell proliferation, adhesion, migration [...] Read more.
The CCN family of matricellular proteins (CYR61/CCN1, CTGF/CCN2, NOV/CCN3 and WISP1-2-3/CCN4-5-6) are essential players in the key pathophysiological processes of angiogenesis, wound healing and inflammation. These proteins are well recognized for their important roles in many cellular processes, including cell proliferation, adhesion, migration and differentiation, as well as the regulation of extracellular matrix differentiation. Substantial evidence implicates four of the proteins (CCN1, CCN2, CCN3 and CCN4) in the inflammatory pathologies of rheumatoid arthritis (RA) and osteoarthritis (OA). A smaller evidence base supports the involvement of CCN5 and CCN6 in the development of these diseases. This review focuses on evidence providing insights into the involvement of the CCN family in RA and OA, as well as the potential of the CCN proteins as therapeutic targets in these diseases. Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis 3.0)
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