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

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 (10 July 2018) | Viewed by 145770

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 Colleagues,

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. Chih-Hsin Tang
Guest Editor

Manuscript Submission Information

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Keywords

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

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Published Papers (21 papers)

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Editorial

Jump to: Research, Review

4 pages, 175 KiB  
Editorial
Research of Pathogenesis and Novel Therapeutics in Arthritis
by Chih-Hsin Tang
Int. J. Mol. Sci. 2019, 20(7), 1646; https://doi.org/10.3390/ijms20071646 - 02 Apr 2019
Cited by 52 | Viewed by 5018
Abstract
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. The exact etiology of arthritis remains unclear and no cure exists. Anti-inflammatory drugs are commonly used in the [...] Read more.
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. The exact etiology of arthritis remains unclear and no cure exists. Anti-inflammatory drugs are commonly used in the treatment of arthritis, but are associated with significant side effects. Novel modes of therapy and additional prognostic biomarkers are urgently needed for these patients. In this editorial, the twenty articles published in the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis 2019 are summarized and discussed as part of the global picture of the current understanding of arthritis. Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis)

Research

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21 pages, 5277 KiB  
Article
The Micro-RNA Expression Profiles of Autoimmune Arthritis Reveal Novel Biomarkers of the Disease and Therapeutic Response
by Steven Dudics, Shivaprasad H. Venkatesha and Kamal D. Moudgil
Int. J. Mol. Sci. 2018, 19(8), 2293; https://doi.org/10.3390/ijms19082293 - 05 Aug 2018
Cited by 30 | Viewed by 5768
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disease of the joints affecting about 0.3–1% of the population in different countries. About 50–60 percent of RA patients respond to presently used drugs. Moreover, the current biomarkers for RA have inherent limitations. Consequently, there is [...] Read more.
Rheumatoid arthritis (RA) is a chronic autoimmune disease of the joints affecting about 0.3–1% of the population in different countries. About 50–60 percent of RA patients respond to presently used drugs. Moreover, the current biomarkers for RA have inherent limitations. Consequently, there is a need for additional, new biomarkers for monitoring disease activity and responsiveness to therapy of RA patients. We examined the micro-RNA (miRNA) profile of immune (lymphoid) cells of arthritic Lewis rats and arthritic rats treated with celastrol, a natural triterpenoid. Experimental and bioinformatics analyses revealed 8 miRNAs (miR-22, miR-27a, miR-96, miR-142, miR-223, miR-296, miR-298, and miR-451) and their target genes in functional pathways important for RA pathogenesis. Interestingly, 6 of them (miR-22, miR-27a, miR-96, miR-142, miR-223, and miR-296) were further modulated by celastrol treatment. Interestingly, serum levels of miR-142, miR-155, and miR-223 were higher in arthritic versus control rats, whereas miR-212 showed increased expression in celastrol-treated rats compared with arthritic rats or control rats. This is the first study on comprehensive miRNA expression profiling in the adjuvant-induced arthritis (AA) model and it also has revealed new miRNA targets for celastrol in arthritis. We suggest that subsets of the above miRNAs may serve as novel biomarkers of disease activity and therapeutic response in arthritis. Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis)
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14 pages, 1809 KiB  
Article
Arthroprotective Effects of Cf-02 Sharing Structural Similarity with Quercetin
by Feng-Cheng Liu, Jeng-Wei Lu, Chiao-Yun Chien, Hsu-Shan Huang, Chia-Chung Lee, Shiu-Bii Lien, Leou-Chyr Lin, Liv Weichien Chen, Yi-Jung Ho, Min-Chung Shen, Ling-Jun Ho and Jenn-Haung Lai
Int. J. Mol. Sci. 2018, 19(5), 1453; https://doi.org/10.3390/ijms19051453 - 14 May 2018
Cited by 13 | Viewed by 3725
Abstract
In this study, we synthesized hundreds of analogues based on the structure of small-molecule inhibitors (SMIs) that were previously identified in our laboratory with the aim of identifying potent yet safe compounds for arthritis therapeutics. One of the analogues was shown to share [...] Read more.
In this study, we synthesized hundreds of analogues based on the structure of small-molecule inhibitors (SMIs) that were previously identified in our laboratory with the aim of identifying potent yet safe compounds for arthritis therapeutics. One of the analogues was shown to share structural similarity with quercetin, a potent anti-inflammatory flavonoid present in many different fruits and vegetables. We investigated the immunomodulatory effects of this compound, namely 6-(2,4-difluorophenyl)-3-(3-(trifluoromethyl)phenyl)-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (Cf-02), in a side-by-side comparison with quercetin. Chondrocytes were isolated from pig joints or the joints of patients with osteoarthritis that had undergone total knee replacement surgery. Several measures were used to assess the immunomodulatory potency of these compounds in tumor necrosis factor (TNF-α)-stimulated chondrocytes. Characterization included the protein and mRNA levels of molecules associated with arthritis pathogenesis as well as the inducible nitric oxide synthase (iNOS)–nitric oxide (NO) system and matrix metalloproteinases (MMPs) in cultured chondrocytes and proteoglycan, and aggrecan degradation in cartilage explants. We also examined the activation of several important transcription factors, including nuclear factor-kappaB (NF-κB), interferon regulatory factor-1 (IRF-1), signal transducer and activator of transcription-3 (STAT-3), and activator protein-1 (AP-1). Our overall results indicate that the immunomodulatory potency of Cf-02 is fifty-fold more efficient than that of quercetin without any indication of cytotoxicity. When tested in vivo using the induced edema method, Cf-02 was shown to suppress inflammation and cartilage damage. The proposed method shows considerable promise for the identification of candidate disease-modifying immunomodulatory drugs and leads compounds for arthritis therapeutics. Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis)
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15 pages, 17358 KiB  
Article
Therapeutic Potential of Sclareol in Experimental Models of Rheumatoid Arthritis
by Sen-Wei Tsai, Ming-Chia Hsieh, Shiming Li, Shih-Chao Lin, Shun-Ping Wang, Caitlin W. Lehman, Christopher Z. Lien and Chi-Chien Lin
Int. J. Mol. Sci. 2018, 19(5), 1351; https://doi.org/10.3390/ijms19051351 - 03 May 2018
Cited by 30 | Viewed by 6076
Abstract
Previous studies have shown that the natural diterpene compound, sclareol, potentially inhibits inflammation, but it has not yet been determined whether sclareol can alleviate inflammation associated with rheumatoid arthritis (RA). Here, we utilized human synovial cell line, SW982, and an experimental murine model [...] Read more.
Previous studies have shown that the natural diterpene compound, sclareol, potentially inhibits inflammation, but it has not yet been determined whether sclareol can alleviate inflammation associated with rheumatoid arthritis (RA). Here, we utilized human synovial cell line, SW982, and an experimental murine model of rheumatoid arthritis, collagen-induced arthritis (CIA), to evaluate the therapeutic effects of sclareol in RA. Arthritic DBA/1J mice were dosed with 5 and 10 mg/kg sclareol intraperitoneally every other day over 21 days. Arthritic severity was evaluated by levels of anti-collagen II (anti-CII) antibody, inflammatory cytokines, and histopathologic examination of knee joint tissues. Our results reveal that the serum anti-CII antibody, cytokines interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and IL-17, as well as Th17 and Th1 cell population in inguinal lymph nodes, were significantly lower in sclareol-treated mice compared to the control group. Also, the sclareol treatment groups showed reduced swelling in the paws and lower histological arthritic scores, indicating that sclareol potentially mitigates collagen-induced arthritis. Furthermore, IL-1β-stimulated SW982 cells secreted less inflammatory cytokines (TNF-α and IL-6), which is associated with the downregulation of p38-mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), and NF-κB pathways. Overall, we demonstrate that sclareol could relieve arthritic severities by modulating excessive inflammation and our study merits the pharmaceutical development of sclareol as a therapeutic treatment for inflammation associated with RA. Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis)
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14 pages, 3186 KiB  
Article
Fraxinellone Attenuates Rheumatoid Inflammation in Mice
by Seung Min Jung, Jaeseon Lee, Seung Ye Baek, Juhyun Lee, Se Gwang Jang, Seung-Min Hong, Jin-Sil Park, Mi-La Cho, Sung-Hwan Park and Seung-Ki Kwok
Int. J. Mol. Sci. 2018, 19(3), 829; https://doi.org/10.3390/ijms19030829 - 13 Mar 2018
Cited by 11 | Viewed by 3727
Abstract
This study aimed to evaluate the therapeutic effect of fraxinellone on inflammatory arthritis and identify the underlying mechanisms. Fraxinellone (7.5 mg/kg) or a vehicle control was injected into mice with collagen-induced arthritis (CIA). The severity of arthritis was evaluated clinically and histologically. The [...] Read more.
This study aimed to evaluate the therapeutic effect of fraxinellone on inflammatory arthritis and identify the underlying mechanisms. Fraxinellone (7.5 mg/kg) or a vehicle control was injected into mice with collagen-induced arthritis (CIA). The severity of arthritis was evaluated clinically and histologically. The differentiation of CD4+ T cells and CD19+ B cells was investigated in the presence of fraxinellone. Osteoclastogenesis after fraxinellone treatment was evaluated by staining with tartrate-resistant acid phosphatase (TRAP) and by measuring the mRNA levels of osteoclastogenesis-related genes. Fraxinellone attenuated the clinical and histologic features of inflammatory arthritis in CIA mice. Fraxinellone suppressed the production of interleukin-17 and the expression of RAR-related orphan receptor γ t and phospho-signal transducer and activator of transcription 3 in CD4+ T cells. CD19+ B cells showed lower expression of activation-induced cytidine deaminase and B lymphocyte-induced maturation protein-1 after treatment with fraxinellone. The formation of TRAP-positive cells and the expression of osteoclastogenesis-related markers were reduced in the presence of fraxinellone. Inhibition of interleukin-17 and osteoclastogenesis was also observed in experiments using human peripheral mononuclear cells. Fraxinellone alleviated synovial inflammation and osteoclastogenesis in mice. The therapeutic effect of fraxinellone was associated with the inhibition of cellular differentiation and activation. The data suggests that fraxinellone could be a novel treatment for inflammatory arthritis, including rheumatoid arthritis. Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis)
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10 pages, 2233 KiB  
Article
Visfatin Promotes IL-6 and TNF-α Production in Human Synovial Fibroblasts by Repressing miR-199a-5p through ERK, p38 and JNK Signaling Pathways
by Min-Huan Wu, Chun-Hao Tsai, Yuan-Li Huang, Yi-Chin Fong and Chih-Hsin Tang
Int. J. Mol. Sci. 2018, 19(1), 190; https://doi.org/10.3390/ijms19010190 - 08 Jan 2018
Cited by 66 | Viewed by 7178
Abstract
Osteoarthritis (OA), an inflammatory form of arthritis, is characterized by synovial inflammation and cartilage destruction largely influenced by two key proinflammatory cytokines—interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α). Notably, levels of visfatin (a proinflammatory adipokine) are elevated in patients with OA, although [...] Read more.
Osteoarthritis (OA), an inflammatory form of arthritis, is characterized by synovial inflammation and cartilage destruction largely influenced by two key proinflammatory cytokines—interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α). Notably, levels of visfatin (a proinflammatory adipokine) are elevated in patients with OA, although the relationship of visfatin to IL-6 and TNF-α expression in OA pathogenesis has been unclear. In this study, visfatin enhanced the expression of IL-6 and TNF-α in human OA synovial fibroblasts (OASFs) in a concentration-dependent manner and stimulation of OASFs with visfatin promoted phosphorylation of extracellular-signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK), while ERK, p38, and JNK inhibitors or siRNAs all abolished visfatin-induced increases in IL-6 and TNF-α production. Moreover, transfection with miR-199a-5p mimics reversed visfatin-induced increases in IL-6 and TNF-α production. Furthermore, we also found that visfatin-promoted IL-6 and TNF-α production is mediated via the inhibition of miR-199a-5p expression through the ERK, p38, and JNK signaling pathways. Visfatin may therefore be an appropriate target for drug intervention in OA treatment. Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis)
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1280 KiB  
Article
Clodronate as a Therapeutic Strategy against Osteoarthritis
by Maria Teresa Valenti, Monica Mottes, Alessandro Biotti, Massimiliano Perduca, Arianna Pisani, Michele Bovi, Michela Deiana, Samuele Cheri and Luca Dalle Carbonare
Int. J. Mol. Sci. 2017, 18(12), 2696; https://doi.org/10.3390/ijms18122696 - 13 Dec 2017
Cited by 20 | Viewed by 5236
Abstract
Osteoarthritis (OA), the most prevalent musculoskeletal pathology, is mainly characterized by the progressive degradation of articular cartilage due to an imbalance between anabolic and catabolic processes. Consequently, OA has been associated with defects in the chondrocitic differentiation of progenitor stem cells (PSCs). In [...] Read more.
Osteoarthritis (OA), the most prevalent musculoskeletal pathology, is mainly characterized by the progressive degradation of articular cartilage due to an imbalance between anabolic and catabolic processes. Consequently, OA has been associated with defects in the chondrocitic differentiation of progenitor stem cells (PSCs). In addition, SOX9 is the transcription factor responsible for PSCs chondrogenic commitment. To evaluate the effects of the non-amino bisphosphonate clodronate in OA patients we investigated SOX9 gene expression in circulating progenitor cells (CPCs) and in an in vitro OA model. We evaluated pain intensity, mental and physical performance in OA patients, as well as serum biomarkers related to bone metabolism. In addition, in order to improve therapeutic strategies, we assayed nanoparticle-embedded clodronate (NPs-clo) in an in vitro model of chondrogenic differentiation. Our data showed upregulation of SOX9 gene expression upon treatment, suggesting an increase in chondrocytic commitment. Clodronate also reduced osteoarticular pain and improved mental and physical performance in patients. Furthermore, NPs-clo stimulated SOX9 expression more efficaciously than clodronate alone. Clodronate may therefore be considered a good therapeutic tool against OA; its formulation in nanoparticles may represent a promising challenge to counteract cartilage degeneration. Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis)
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6084 KiB  
Article
Nitric Oxide Mediates Crosstalk between Interleukin 1β and WNT Signaling in Primary Human Chondrocytes by Reducing DKK1 and FRZB Expression
by Leilei Zhong, Stefano Schivo, Xiaobin Huang, Jeroen Leijten, Marcel Karperien and Janine N. Post
Int. J. Mol. Sci. 2017, 18(11), 2491; https://doi.org/10.3390/ijms18112491 - 22 Nov 2017
Cited by 28 | Viewed by 5536
Abstract
Interleukin 1 beta (IL1β) and Wingless-Type MMTV Integration Site Family (WNT) signaling are major players in Osteoarthritis (OA) pathogenesis. Despite having a large functional overlap in OA onset and development, the mechanism of IL1β and WNT crosstalk has remained largely unknown. In this [...] Read more.
Interleukin 1 beta (IL1β) and Wingless-Type MMTV Integration Site Family (WNT) signaling are major players in Osteoarthritis (OA) pathogenesis. Despite having a large functional overlap in OA onset and development, the mechanism of IL1β and WNT crosstalk has remained largely unknown. In this study, we have used a combination of computational modeling and molecular biology to reveal direct or indirect crosstalk between these pathways. Specifically, we revealed a mechanism by which IL1β upregulates WNT signaling via downregulating WNT antagonists, DKK1 and FRZB. In human chondrocytes, IL1β decreased the expression of Dickkopf-1 (DKK1) and Frizzled related protein (FRZB) through upregulation of nitric oxide synthase (iNOS), thereby activating the transcription of WNT target genes. This effect could be reversed by iNOS inhibitor 1400W, which restored DKK1 and FRZB expression and their inhibitory effect on WNT signaling. In addition, 1400W also inhibited both the matrix metalloproteinase (MMP) expression and cytokine-induced apoptosis. We concluded that iNOS/NO play a pivotal role in the inflammatory response of human OA through indirect upregulation of WNT signaling. Blocking NO production may inhibit the loss of the articular phenotype in OA by preventing downregulation of the expression of DKK1 and FRZB. Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis)
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2346 KiB  
Article
Deduction of Novel Genes Potentially Involved in Osteoblasts of Rheumatoid Arthritis Using Next-Generation Sequencing and Bioinformatic Approaches
by Yi-Jen Chen, Wei-An Chang, Ya-Ling Hsu, Chia-Hsin Chen and Po-Lin Kuo
Int. J. Mol. Sci. 2017, 18(11), 2396; https://doi.org/10.3390/ijms18112396 - 11 Nov 2017
Cited by 21 | Viewed by 6137
Abstract
The role of osteoblasts in peri-articular bone loss and bone erosion in rheumatoid arthritis (RA) has gained much attention, and microRNAs are hypothesized to play critical roles in the regulation of osteoblast function in RA. The aim of this study is to explore [...] Read more.
The role of osteoblasts in peri-articular bone loss and bone erosion in rheumatoid arthritis (RA) has gained much attention, and microRNAs are hypothesized to play critical roles in the regulation of osteoblast function in RA. The aim of this study is to explore novel microRNAs differentially expressed in RA osteoblasts and to identify genes potentially involved in the dysregulated bone homeostasis in RA. RNAs were extracted from cultured normal and RA osteoblasts for sequencing. Using the next generation sequencing and bioinformatics approaches, we identified 35 differentially expressed microRNAs and 13 differentially expressed genes with potential microRNA–mRNA interactions in RA osteoblasts. The 13 candidate genes were involved mainly in cell–matrix adhesion, as classified by the Gene Ontology. Two genes of interest identified from RA osteoblasts, A-kinase anchoring protein 12 (AKAP12) and leucin rich repeat containing 15 (LRRC15), were found to express more consistently in the related RA synovial tissue arrays in the Gene Expression Omnibus database, with the predicted interactions with miR-183-5p and miR-146a-5p, respectively. The Ingenuity Pathway Analysis identified AKAP12 as one of the genes involved in protein kinase A signaling and the function of chemotaxis, interconnecting with molecules related to neovascularization. The findings indicate new candidate genes as the potential indicators in evaluating therapies targeting chemotaxis and neovascularization to control joint destruction in RA. Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis)
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2901 KiB  
Article
The Immunogenicity of Branded and Biosimilar Infliximab in Rheumatoid Arthritis According to Th9-Related Responses
by Rossella Talotta, Angela Berzi, Andrea Doria, Alberto Batticciotto, Maria Chiara Ditto, Fabiola Atzeni, Piercarlo Sarzi-Puttini and Daria Trabattoni
Int. J. Mol. Sci. 2017, 18(10), 2127; https://doi.org/10.3390/ijms18102127 - 12 Oct 2017
Cited by 8 | Viewed by 4277
Abstract
Our objective was to evaluate the immunogenicity of branded and biosimilar infliximab by detecting changes in T-helper-9 (Th9) percentages induced by an in vitro stimulation test. Methods: Peripheral blood mononuclear cells collected from 55 consecutive rheumatoid arthritis (RA) outpatients (15 drug free, 20 [...] Read more.
Our objective was to evaluate the immunogenicity of branded and biosimilar infliximab by detecting changes in T-helper-9 (Th9) percentages induced by an in vitro stimulation test. Methods: Peripheral blood mononuclear cells collected from 55 consecutive rheumatoid arthritis (RA) outpatients (15 drug free, 20 successfully treated with branded infliximab, 20 branded infliximab inadequate responders) and 10 healthy controls were cultured, with or without 50 μg/mL of infliximab originator (Remicade®) or 50 μg/mL of infliximab biosimilar (Remsima®) for 18 h. Th9 lymphocytes were identified by means of flow cytometry as PU.1 and IRF4-expressing, IL-9-secreting CD4+ T cells. Furthermore, the markers CCR7 and CD45RA were used to distinguish naïve from memory IL-9 producer cells. Results: Under unstimulated conditions, the drug-free RA patients had the highest percentages of Th9 lymphocytes. Following stimulation with branded infliximab, the percentages of PU.1 and IRF4-expressing Th9 cells, CCR7+, CD45RA− (central memory) and CCR7−, CD45RA− (effector memory) cells significantly increased in the group of inadequate responders, but no significant variation was observed after exposure to the biosimilar of infliximab. Conclusions: Th9 cells seem to be involved in the immune response to the epitopes of branded, but not biosimilar, infliximab, and this may depend on the recall and stimulation of both central and effector memory cells. Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis)
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Review

Jump to: Editorial, Research

17 pages, 821 KiB  
Review
Associations between Adipokines in Arthritic Disease and Implications for Obesity
by Iona J. MᵃᶜDonald, Shan-Chi Liu, Chien-Chung Huang, Shu-Jui Kuo, Chun-Hao Tsai and Chih-Hsin Tang
Int. J. Mol. Sci. 2019, 20(6), 1505; https://doi.org/10.3390/ijms20061505 - 26 Mar 2019
Cited by 51 | Viewed by 7042
Abstract
Secretion from adipose tissue of adipokines or adipocytokines, comprising of bioactive peptides or proteins, immune molecules and inflammatory mediators, exert critical roles in inflammatory arthritis and obesity. This review considers the evidence generated over the last decade regarding the effects of several adipokines [...] Read more.
Secretion from adipose tissue of adipokines or adipocytokines, comprising of bioactive peptides or proteins, immune molecules and inflammatory mediators, exert critical roles in inflammatory arthritis and obesity. This review considers the evidence generated over the last decade regarding the effects of several adipokines including leptin, adiponectin, visfatin, resistin, chemerin and apelin, in cartilage and bone homeostasis in the pathogenesis of rheumatoid arthritis and osteoarthritis, which has important implications for obesity. Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis)
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23 pages, 301 KiB  
Review
Immunopathogenic Mechanisms and Novel Immune-Modulated Therapies in Rheumatoid Arthritis
by Shyi-Jou Chen, Gu-Jiun Lin, Jing-Wun Chen, Kai-Chen Wang, Chiung-Hsi Tien, Chih-Fen Hu, Chia-Ning Chang, Wan-Fu Hsu, Hueng-Chuen Fan and Huey-Kang Sytwu
Int. J. Mol. Sci. 2019, 20(6), 1332; https://doi.org/10.3390/ijms20061332 - 16 Mar 2019
Cited by 48 | Viewed by 6381
Abstract
Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease of unknown etiology. It is characterized by the presence of rheumatoid factor and anticitrullinated peptide antibodies. The orchestra of the inflammatory process among various immune cells, cytokines, chemokines, proteases, matrix metalloproteinases (MMPs), and reactive [...] Read more.
Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease of unknown etiology. It is characterized by the presence of rheumatoid factor and anticitrullinated peptide antibodies. The orchestra of the inflammatory process among various immune cells, cytokines, chemokines, proteases, matrix metalloproteinases (MMPs), and reactive oxidative stress play critical immunopathologic roles in the inflammatory cascade of the joint environment, leading to clinical impairment and RA. With the growing understanding of the immunopathogenic mechanisms, increasingly novel marked and potential biologic agents have merged for the treatment of RA in recent years. In this review, we focus on the current understanding of pathogenic mechanisms, highlight novel biologic disease-modifying antirheumatic drugs (DMRADs), targeted synthetic DMRADs, and immune-modulating agents, and identify the applicable immune-mediated therapeutic strategies of the near future. In conclusion, new therapeutic approaches are emerging through a better understanding of the immunopathophysiology of RA, which is improving disease outcomes better than ever. Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis)
21 pages, 1291 KiB  
Review
The Biological Enhancement of Spinal Fusion for Spinal Degenerative Disease
by Takahiro Makino, Hiroyuki Tsukazaki, Yuichiro Ukon, Daisuke Tateiwa, Hideki Yoshikawa and Takashi Kaito
Int. J. Mol. Sci. 2018, 19(8), 2430; https://doi.org/10.3390/ijms19082430 - 17 Aug 2018
Cited by 32 | Viewed by 4808
Abstract
In this era of aging societies, the number of elderly individuals who undergo spinal arthrodesis for various degenerative diseases is increasing. Poor bone quality and osteogenic ability in older patients, due to osteoporosis, often interfere with achieving bone fusion after spinal arthrodesis. Enhancement [...] Read more.
In this era of aging societies, the number of elderly individuals who undergo spinal arthrodesis for various degenerative diseases is increasing. Poor bone quality and osteogenic ability in older patients, due to osteoporosis, often interfere with achieving bone fusion after spinal arthrodesis. Enhancement of bone fusion requires shifting bone homeostasis toward increased bone formation and reduced resorption. Several biological enhancement strategies of bone formation have been conducted in animal models of spinal arthrodesis and human clinical trials. Pharmacological agents for osteoporosis have also been shown to be effective in enhancing bone fusion. Cytokines, which activate bone formation, such as bone morphogenetic proteins, have already been clinically used to enhance bone fusion for spinal arthrodesis. Recently, stem cells have attracted considerable attention as a cell source of osteoblasts, promising effects in enhancing bone fusion. Drug delivery systems will also need to be further developed to assure the safe delivery of bone-enhancing agents to the site of spinal arthrodesis. Our aim in this review is to appraise the current state of knowledge and evidence regarding bone enhancement strategies for spinal fusion for degenerative spinal disorders, and to identify future directions for biological bone enhancement strategies, including pharmacological, cell and gene therapy approaches. Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis)
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34 pages, 2940 KiB  
Review
Onset and Progression of Human Osteoarthritis—Can Growth Factors, Inflammatory Cytokines, or Differential miRNA Expression Concomitantly Induce Proliferation, ECM Degradation, and Inflammation in Articular Cartilage?
by Karen A. Boehme and Bernd Rolauffs
Int. J. Mol. Sci. 2018, 19(8), 2282; https://doi.org/10.3390/ijms19082282 - 03 Aug 2018
Cited by 72 | Viewed by 7968
Abstract
Osteoarthritis (OA) is a degenerative whole joint disease, for which no preventative or therapeutic biological interventions are available. This is likely due to the fact that OA pathogenesis includes several signaling pathways, whose interactions remain unclear, especially at disease onset. Early OA is [...] Read more.
Osteoarthritis (OA) is a degenerative whole joint disease, for which no preventative or therapeutic biological interventions are available. This is likely due to the fact that OA pathogenesis includes several signaling pathways, whose interactions remain unclear, especially at disease onset. Early OA is characterized by three key events: a rarely considered early phase of proliferation of cartilage-resident cells, in contrast to well-established increased synthesis, and degradation of extracellular matrix components and inflammation, associated with OA progression. We focused on the question, which of these key events are regulated by growth factors, inflammatory cytokines, and/or miRNA abundance. Collectively, we elucidated a specific sequence of the OA key events that are described best as a very early phase of proliferation of human articular cartilage (AC) cells and concomitant anabolic/catabolic effects that are accompanied by incipient pro-inflammatory effects. Many of the reviewed factors appeared able to induce one or two key events. Only one factor, fibroblast growth factor 2 (FGF2), is capable of concomitantly inducing all key events. Moreover, AC cell proliferation cannot be induced and, in fact, is suppressed by inflammatory signaling, suggesting that inflammatory signaling cannot be the sole inductor of all early OA key events, especially at disease onset. Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis)
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18 pages, 924 KiB  
Review
Implications of Angiogenesis Involvement in Arthritis
by Iona J. MacDonald, Shan-Chi Liu, Chen-Ming Su, Yu-Han Wang, Chun-Hao Tsai and Chih-Hsin Tang
Int. J. Mol. Sci. 2018, 19(7), 2012; https://doi.org/10.3390/ijms19072012 - 10 Jul 2018
Cited by 139 | Viewed by 9014
Abstract
Angiogenesis, the growth of new blood vessels, is essential in the pathogenesis of joint inflammatory disorders such as rheumatoid arthritis (RA) and osteoarthritis (OA), facilitating the invasion of inflammatory cells and increase in local pain receptors that contribute to structural damage and pain. [...] Read more.
Angiogenesis, the growth of new blood vessels, is essential in the pathogenesis of joint inflammatory disorders such as rheumatoid arthritis (RA) and osteoarthritis (OA), facilitating the invasion of inflammatory cells and increase in local pain receptors that contribute to structural damage and pain. The angiogenic process is perpetuated by various mediators such as growth factors, primarily vascular endothelial growth factor (VEGF) and hypoxia-inducible factors (HIFs), as well as proinflammatory cytokines, various chemokines, matrix components, cell adhesion molecules, proteases, and others. Despite the development of potent, well-tolerated nonbiologic (conventional) and biologic disease-modifying agents that have greatly improved outcomes for patients with RA, many remain resistant to these therapies, are only partial responders, or cannot tolerate biologics. The only approved therapies for OA include symptom-modifying agents, such as analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), steroids, and hyaluronic acid. None of the available treatments slow the disease progression, restore the original structure or enable a return to function of the damaged joint. Moreover, a number of safety concerns surround current therapies for RA and OA. New treatments are needed that not only target inflamed joints and control articular inflammation in RA and OA, but also selectively inhibit synovial angiogenesis, while preventing healthy tissue damage. This narrative review of the literature in PubMed focuses on the evidence illustrating the therapeutic benefits of modulating angiogenic activity in experimental RA and OA. This evidence points to new treatment targets in these diseases. Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis)
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14 pages, 2606 KiB  
Review
Structural Biology of the TNFα Antagonists Used in the Treatment of Rheumatoid Arthritis
by Heejin Lim, Sang Hyung Lee, Hyun Tae Lee, Jee Un Lee, Ji Young Son, Woori Shin and Yong-Seok Heo
Int. J. Mol. Sci. 2018, 19(3), 768; https://doi.org/10.3390/ijms19030768 - 07 Mar 2018
Cited by 71 | Viewed by 8761
Abstract
The binding of the tumor necrosis factor α (TNFα) to its cognate receptor initiates many immune and inflammatory processes. The drugs, etanercept (Enbrel®), infliximab (Remicade®), adalimumab (Humira®), certolizumab-pegol (Cimzia®), and golimumab (Simponi®), are [...] Read more.
The binding of the tumor necrosis factor α (TNFα) to its cognate receptor initiates many immune and inflammatory processes. The drugs, etanercept (Enbrel®), infliximab (Remicade®), adalimumab (Humira®), certolizumab-pegol (Cimzia®), and golimumab (Simponi®), are anti-TNFα agents. These drugs block TNFα from interacting with its receptors and have enabled the development of breakthrough therapies for the treatment of several autoimmune inflammatory diseases, including rheumatoid arthritis, Crohn’s disease, and psoriatic arthritis. In this review, we describe the latest works on the structural characterization of TNFα–TNFα antagonist interactions related to their therapeutic efficacy at the atomic level. A comprehensive comparison of the interactions of the TNFα blockers would provide a better understanding of the molecular mechanisms by which they neutralize TNFα. In addition, an enhanced understanding of the higher order complex structures and quinary structures of the TNFα antagonists can support the development of better biologics with the improved pharmacokinetic properties. Accumulation of these structural studies can provide a basis for the improvement of therapeutic agents against TNFα for the treatment of rheumatoid arthritis and other autoimmune inflammatory diseases in which TNFα plays an important role in pathogenesis. Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis)
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20 pages, 1846 KiB  
Review
Targeting IgG in Arthritis: Disease Pathways and Therapeutic Avenues
by Kutty Selva Nandakumar
Int. J. Mol. Sci. 2018, 19(3), 677; https://doi.org/10.3390/ijms19030677 - 28 Feb 2018
Cited by 13 | Viewed by 4615
Abstract
Rheumatoid arthritis (RA) is a polygenic and multifactorial syndrome. Many complex immunological and genetic interactions are involved in the final outcome of the clinical disease. Autoantibodies (rheumatoid factors, anti-citrullinated peptide/protein antibodies) are present in RA patients’ sera for a long time before the [...] Read more.
Rheumatoid arthritis (RA) is a polygenic and multifactorial syndrome. Many complex immunological and genetic interactions are involved in the final outcome of the clinical disease. Autoantibodies (rheumatoid factors, anti-citrullinated peptide/protein antibodies) are present in RA patients’ sera for a long time before the onset of clinical disease. Prior to arthritis onset, in the autoantibody response, epitope spreading, avidity maturation, and changes towards a pro-inflammatory Fc glycosylation phenotype occurs. Genetic association of epitope specific autoantibody responses and the induction of inflammation dependent and independent changes in the cartilage by pathogenic autoantibodies emphasize the crucial contribution of antibody-initiated inflammation in RA development. Targeting IgG by glyco-engineering, bacterial enzymes to specifically cleave IgG/alter N-linked Fc-glycans at Asn 297 or blocking the downstream effector pathways offers new avenues to develop novel therapeutics for arthritis treatment. Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis)
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15 pages, 245 KiB  
Review
Therapeutics in Osteoarthritis Based on an Understanding of Its Molecular Pathogenesis
by Ju-Ryoung Kim, Jong Jin Yoo and Hyun Ah Kim
Int. J. Mol. Sci. 2018, 19(3), 674; https://doi.org/10.3390/ijms19030674 - 27 Feb 2018
Cited by 77 | Viewed by 19587
Abstract
Osteoarthritis (OA) is the most prevalent joint disease in older people and is characterized by the progressive destruction of articular cartilage, synovial inflammation, changes in subchondral bone and peri-articular muscle, and pain. Because our understanding of the aetiopathogenesis of OA remains incomplete, we [...] Read more.
Osteoarthritis (OA) is the most prevalent joint disease in older people and is characterized by the progressive destruction of articular cartilage, synovial inflammation, changes in subchondral bone and peri-articular muscle, and pain. Because our understanding of the aetiopathogenesis of OA remains incomplete, we haven’t discovered a cure for OA yet. This review appraises novel therapeutics based on recent progress in our understanding of the molecular pathogenesis of OA, including pro-inflammatory and pro-catabolic mediators and the relevant signalling mechanisms. The changes in subchondral bone and peri-articular muscle accompanying cartilage damage are also reviewed. Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis)
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17 pages, 3594 KiB  
Review
The Effect of Triptolide in Rheumatoid Arthritis: From Basic Research towards Clinical Translation
by Danping Fan, Qingqing Guo, Jiawen Shen, Kang Zheng, Cheng Lu, Ge Zhang, Aiping Lu and Xiaojuan He
Int. J. Mol. Sci. 2018, 19(2), 376; https://doi.org/10.3390/ijms19020376 - 26 Jan 2018
Cited by 78 | Viewed by 7994
Abstract
Triptolide (TP), a major extract of the herb Tripterygium wilfordii Hook F (TWHF), has been shown to exert potent pharmacological effects, especially an immunosuppressive effect in the treatment of rheumatoid arthritis (RA). However, its multiorgan toxicity prevents it from being widely used in [...] Read more.
Triptolide (TP), a major extract of the herb Tripterygium wilfordii Hook F (TWHF), has been shown to exert potent pharmacological effects, especially an immunosuppressive effect in the treatment of rheumatoid arthritis (RA). However, its multiorgan toxicity prevents it from being widely used in clinical practice. Recently, several attempts are being performed to reduce TP toxicity. In this review, recent progress in the use of TP for RA, including its pharmacological effects and toxicity, is summarized. Meanwhile, strategies relying on chemical structural modifications, innovative delivery systems, and drug combinations to alleviate the disadvantages of TP are also reviewed. Furthermore, we also discuss the challenges and perspectives in their clinical translation. Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis)
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18 pages, 958 KiB  
Review
Human MHC-II with Shared Epitope Motifs Are Optimal Epstein-Barr Virus Glycoprotein 42 Ligands—Relation to Rheumatoid Arthritis
by Nicole Trier, Jose Izarzugaza, Anna Chailyan, Paolo Marcatili and Gunnar Houen
Int. J. Mol. Sci. 2018, 19(1), 317; https://doi.org/10.3390/ijms19010317 - 21 Jan 2018
Cited by 24 | Viewed by 9908
Abstract
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disorder of unknown etiology, which is characterized by inflammation in the synovium and joint damage. Although the pathogenesis of RA remains to be determined, a combination of environmental (e.g., viral infections) and genetic factors influence [...] Read more.
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disorder of unknown etiology, which is characterized by inflammation in the synovium and joint damage. Although the pathogenesis of RA remains to be determined, a combination of environmental (e.g., viral infections) and genetic factors influence disease onset. Especially genetic factors play a vital role in the onset of disease, as the heritability of RA is 50–60%, with the human leukocyte antigen (HLA) alleles accounting for at least 30% of the overall genetic risk. Some HLA-DR alleles encode a conserved sequence of amino acids, referred to as the shared epitope (SE) structure. By analyzing the structure of a HLA-DR molecule in complex with Epstein-Barr virus (EBV), the SE motif is suggested to play a vital role in the interaction of MHC II with the viral glycoprotein (gp) 42, an essential entry factor for EBV. EBV has been repeatedly linked to RA by several lines of evidence and, based on several findings, we suggest that EBV is able to induce the onset of RA in predisposed SE-positive individuals, by promoting entry of B-cells through direct contact between SE and gp42 in the entry complex. Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis)
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Review
Role of Stem Cells in Pathophysiology and Therapy of Spondyloarthropathies—New Therapeutic Possibilities?
by Magdalena Krajewska-Włodarczyk, Agnieszka Owczarczyk-Saczonek, Waldemar Placek, Adam Osowski, Piotr Engelgardt and Joanna Wojtkiewicz
Int. J. Mol. Sci. 2018, 19(1), 80; https://doi.org/10.3390/ijms19010080 - 28 Dec 2017
Cited by 18 | Viewed by 5817
Abstract
Considerable progress has been made recently in understanding the complex pathogenesis and treatment of spondyloarthropathies (SpA). Currently, along with traditional disease modifying anti-rheumatic drugs (DMARDs), TNF-α, IL-12/23 and IL-17 are available for treatment of such diseases as ankylosing spondylitis (AS) and psoriatic arthritis [...] Read more.
Considerable progress has been made recently in understanding the complex pathogenesis and treatment of spondyloarthropathies (SpA). Currently, along with traditional disease modifying anti-rheumatic drugs (DMARDs), TNF-α, IL-12/23 and IL-17 are available for treatment of such diseases as ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Although they adequately control inflammatory symptoms, they do not affect the abnormal bone formation processes associated with SpA. However, the traditional therapeutic approach does not cover the regenerative treatment of damaged tissues. In this regards, stem cells may offer a promising, safe and effective therapeutic option. The aim of this paper is to present the role of mesenchymal stromal cells (MSC) in pathogenesis of SpA and to highlight the opportunities for using stem cells in regenerative processes and in the treatment of inflammatory changes in articular structures. Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis)
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