International Journal of Molecular Sciences

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12 pages, 2891 KiB

Open AccessArticle

Hypoxia-Inducible Factor-2 Alpha Regulates the Migration of Fibroblast-like Synoviocytes via Oxidative Stress-Induced CD70 Expression in Patients with Rheumatoid Arthritis

by Su-Jin Yoo, Ha-Reum Lee, Jinhyun Kim, In Seol Yoo, Chan Keol Park and Seong Wook Kang

Int. J. Mol. Sci. 2022, 23(4), 2342; https://doi.org/10.3390/ijms23042342 - 20 Feb 2022

Cited by 6 | Viewed by 2478

Abstract

This study aimed to examine the role of CD70, which is highly expressed on fibroblast-like synoviocytes (FLS), in rheumatoid arthritis (RA) patients. FLS isolated from RA (n = 14) and osteoarthritis (OA, n = 4) patients were stimulated with recombinant interleukin-17 (IL-17; [...] Read more.

This study aimed to examine the role of CD70, which is highly expressed on fibroblast-like synoviocytes (FLS), in rheumatoid arthritis (RA) patients. FLS isolated from RA (n = 14) and osteoarthritis (OA, n = 4) patients were stimulated with recombinant interleukin-17 (IL-17; 5 ng/mL) and tumor necrosis factor alpha (TNF-α; 5 ng/mL) for 24 h. Expression of CD70, CD27/soluble CD27 (sCD27), and hypoxia-inducible factor-2 alpha (HIF-2α) was analyzed by RT-qPCR, flow cytometry, and ELISA assays, respectively. Reactive oxygen species (ROS) expression and cell migration were also examined. The HIF-2α inhibitor PT-2385 and CD70 inhibitor BU69 were used to specifically suppress these pathways. Stimulation with IL-17 and TNF-α significantly induced CD70 expression in RA FLS. Although the synovial fluids from patients with RA contained high levels of sCD27, surface expression of CD27, a ligand of CD70, was rarely detected in RA FLS. Cytokine-induced CD70 expression was significantly decreased following antioxidant treatment. Following HIF-2α inhibition, RA FLS had decreased expression of CD70 and ROS levels. Migration of RA FLS was also inhibited by inhibition of CD70 or HIF-2α. The surface expression of CD70 is regulated by HIF-2α and ROS levels and is a key contributor to cytokine-enhanced migration in RA FLS. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Rheumatoid Arthritis)

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25 pages, 63416 KiB

Open AccessArticle

by Hrvoje Omrčen, Sanja Zoričić Cvek, Lara Batičić, Sandra Šućurović and Tanja Grubić Kezele

Int. J. Mol. Sci. 2021, 22(22), 12163; https://doi.org/10.3390/ijms222212163 - 10 Nov 2021

Cited by 2 | Viewed by 2324

Abstract

BMPs regulate synovial quiescence and adult neurogenesis in the hippocampus in non-stress conditions. However, changes in BMP expression that are induced by inflammation during rheumatoid arthritis (RA) have not yet been reported. Here, we show that signalling with synovial BMPs (BMP-4 and -7) [...] Read more.

BMPs regulate synovial quiescence and adult neurogenesis in the hippocampus in non-stress conditions. However, changes in BMP expression that are induced by inflammation during rheumatoid arthritis (RA) have not yet been reported. Here, we show that signalling with synovial BMPs (BMP-4 and -7) mediates the effect of systemic inflammation on adult neurogenesis in the hippocampus during pristane-induced arthritis (PIA) in Dark Agouti (DA) rats, an animal model of RA. Moreover, we show gender differences in BMP expressions and their antagonists (Noggin and Gremlin) during PIA and their correlations with the clinical course and IL-17A and TNF-α levels in serum. Our results indicate gender differences in the clinical course, where male rats showed earlier onset and earlier recovery but a worse clinical course in the first two phases of the disease (onset and peak), which correlates with the initial increase of serum IL-17A level. The clinical course of the female rats worsened in remission. Their prolonged symptoms could be a reflection of an increased TNF-α level in serum during remission. Synovial inflammation was greater in females in PIA-remission with greater synovial BMP and antagonist expressions. More significant correlations between serum cytokines (IL-17A and TNF-α), and synovial BMPs and their antagonists were found in females than in males. On the other hand, males showed an increase in hippocampal BMP-4 expression during the acute phase, but both genders showed a decrease in antagonist expressions during PIA in general. Both genders showed a decrease in the number of Ki-67⁺ and SOX-2⁺ and DCX⁺ cells and in the ratio of DCX⁺ to Ki67⁺ cells in the dentate gyrus during PIA. However, in PIA remission, females showed a faster increase in the number of Ki67⁺, SOX-2⁺, and DCX⁺ cells and a faster increase in the DCX/Ki67 ratio than males. Both genders showed an increase of hippocampal BMP-7 expression during remission, although males constantly showed greater BMP-7 expression at all time points. Our data show that gender differences exist in the BMP expressions in the periphery–hippocampus axis and in the IL-17A and TNF-α levels in serum, which could imply differences in the mechanisms for the onset and progression of the disease, the clinical course severity, and adult neurogenesis with subsequent neurological complications between genders. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Rheumatoid Arthritis)

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12 pages, 2531 KiB

Open AccessArticle

Salubrinal Alleviates Collagen-Induced Arthritis through Promoting P65 Degradation in Osteoclastogenesis

by Ziyu Wang, Zijian Li, Guojue Wang, Ying Sun, Yuanyang Yuan and Hong Nie

Int. J. Mol. Sci. 2021, 22(7), 3501; https://doi.org/10.3390/ijms22073501 - 28 Mar 2021

Cited by 6 | Viewed by 2349

Abstract

Rheumatoid arthritis (RA) is a complex systemic autoimmune disorder that primarily involves joints, further affects the life quality of patients, and has increased mortality. The pathogenesis of RA involves multiple pathways, resulting in some patients showing resistance to the existing drugs. Salubrinal is [...] Read more.

Rheumatoid arthritis (RA) is a complex systemic autoimmune disorder that primarily involves joints, further affects the life quality of patients, and has increased mortality. The pathogenesis of RA involves multiple pathways, resulting in some patients showing resistance to the existing drugs. Salubrinal is a small molecule compound that has recently been shown to exert multiple beneficial effects on bone tissue. However, the effect of Salubrinal in RA has not been clearly confirmed. Hence, we induced collagen-induced arthritis (CIA) in DBA/1J mice and found that Salubrinal treatment decreased the clinical score of CIA mice, inhibiting joint damage and bone destruction. Furthermore, Salubrinal treatment downregulated osteoclast number in knee joint of CIA in mice, and suppressed bone marrow-derived osteoclast formation and function, downregulated osteoclast-related gene expression. Moreover, Salubrinal treatment inhibited RANKL-induced NF-κB signaling pathway, and promoted P65 degradation through the ubiquitin-proteasome system, further restrained RANKL-induced osteoclastogenesis. This study explains the mechanism by which Salubrinal ameliorates arthritis of CIA in mice, indicating that Salubrinal may be a potential drug for RA, and expands the potential uses of Salubrinal in the treatment of bone destruction-related diseases. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Rheumatoid Arthritis)

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17 pages, 9365 KiB

Open AccessArticle

Microbiota-Derived Metabolites, Indole-3-aldehyde and Indole-3-acetic Acid, Differentially Modulate Innate Cytokines and Stromal Remodeling Processes Associated with Autoimmune Arthritis

by David Langan, Darren J. Perkins, Stefanie N. Vogel and Kamal D. Moudgil

Int. J. Mol. Sci. 2021, 22(4), 2017; https://doi.org/10.3390/ijms22042017 - 18 Feb 2021

Cited by 23 | Viewed by 3935

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the synovial joints. Inflammation, new blood vessel formation (angiogenesis) and bone resorption (osteoclastogenesis) are three key processes involved in the joint damage and deformities of arthritis. Various gut microbiota-derived metabolites are [...] Read more.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the synovial joints. Inflammation, new blood vessel formation (angiogenesis) and bone resorption (osteoclastogenesis) are three key processes involved in the joint damage and deformities of arthritis. Various gut microbiota-derived metabolites are implicated in RA pathogenesis. However, there is barely any information about the impact of two such metabolites, indole-3-aldehyde (IAld) and indole-3-acetic acid (I3AA), on arthritis-related processes. We conducted a comparative analysis of IAld and I3AA using established cell-based models to understand how they might influence RA pathogenesis. Although structurally similar, the bioactivities of these two metabolites were profoundly different. IAld but not I3AA, inhibited the expression of pro-inflammatory cytokines (IL-1β and IL-6) in RAW 264.7 (RAW) cells stimulated with heat-killed M. tuberculosis sonicate (Mtb) and lipopolysaccharide (LPS). IAld also exhibited pro-angiogenic activity and pro-osteoclastogenic activity. In contrast, I3AA exhibited anti-angiogenic activity on endothelial cell tube formation but had no effect on osteoclastogenesis. Both IAld and I3AA have been proposed as aryl hydrocarbon receptor (AhR) agonists. Use of CH-223191, an inhibitor of the AhR, suppressed the anti-angiogenic activity of I3AA but failed to mitigate the effects of IAld. Further investigation of the anti-inflammatory activities of IAld and I3AA in LPS-treated RAW cells indicated that inhibition of MyD88-dependent activation of NF-κB and MAPK pathways was not likely involved. Our results suggest that the relative bioavailability of these indole derivatives may differentially impact RA progression and possibly other diseases that share similar cellular processes. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Rheumatoid Arthritis)

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15 pages, 2139 KiB

Open AccessArticle

Antibodies Isolated from Rheumatoid Arthritis Patients against Lysine-Containing Proteus mirabilis O3 (S1959) Lipopolysaccharide May React with Collagen Type I

by Katarzyna Durlik-Popińska, Paulina Żarnowiec, Łukasz Lechowicz, Józef Gawęda and Wiesław Kaca

Int. J. Mol. Sci. 2020, 21(24), 9635; https://doi.org/10.3390/ijms21249635 - 17 Dec 2020

Cited by 6 | Viewed by 2238

Abstract

Most rheumatic diseases, including rheumatoid arthritis (RA), are characterized by immune disorders that affect antibody activity. In the present study, using Dot blot and ELISA assay, we showed that patients with rheumatic disease produced significantly more antibodies against lipopolysaccharide (LPS) P. mirabilis O3 [...] Read more.

Most rheumatic diseases, including rheumatoid arthritis (RA), are characterized by immune disorders that affect antibody activity. In the present study, using Dot blot and ELISA assay, we showed that patients with rheumatic disease produced significantly more antibodies against lipopolysaccharide (LPS) P. mirabilis O3 compared to healthy donors (p < 0.05), and affinity purified antibodies against LPS O3 may cross-react with collagen type I. It was demonstrated that purified of antibodies isolated from RA patients sera, reacted stronger with the collagen than healthy donors (p = 0.015), and cross-reaction was correlated with level of anti-citrullinated peptide antibodies (r = 0.7, p = 0.003). Moreover, using six different lipopolysaccharides were demonstrated the significant correlations in sera reactivity among lysine-containing lipopolysaccharides observed in patients’ sera (p < 0.05). Using Attenuated Total Reflection Fourier Transform Infrared Spectroscopy (ATR-FTIR) it was shown that unique wavenumbers of sera spectra correlate with reactivity with lipopolysaccharides allowing distinguish patients from healthy blood donors. Antibodies adsorption by synthetic antigens shows that in patients’ group anti-LPS O3 antibodies can be adsorbed by both amides of galacturonic acid and lysine or threonine, which suggests less specificity of antibodies binding with non-carbohydrate LPS component. The observed correlations suggest that non-carbohydrate components of LPS may be an important epitope for less specific anti-LPS antibodies, which might lead to cross-reactions and affect disease development. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Rheumatoid Arthritis)

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10 pages, 5509 KiB

Open AccessArticle

Erythroid Differentiation Regulator 1 Ameliorates Collagen-Induced Arthritis via Activation of Regulatory T Cells

by Myun Soo Kim, Sora Lee, Sunyoung Park, Kyung Eun Kim, Hyun Jeong Park and Daeho Cho

Int. J. Mol. Sci. 2020, 21(24), 9555; https://doi.org/10.3390/ijms21249555 - 15 Dec 2020

Cited by 3 | Viewed by 1873

Abstract

Erythroid differentiation regulator 1 (Erdr1) has been identified as an anti-inflammatory factor in several disease models, including collagen-induced arthritis (CIA), but its exact mechanisms are still not fully understood. Here, the involvement of regulatory T (Treg) cells in Erdr1-improved CIA was investigated. In [...] Read more.

Erythroid differentiation regulator 1 (Erdr1) has been identified as an anti-inflammatory factor in several disease models, including collagen-induced arthritis (CIA), but its exact mechanisms are still not fully understood. Here, the involvement of regulatory T (Treg) cells in Erdr1-improved CIA was investigated. In the CIA model, Erdr1 was confirmed to reduce collagen-specific IgM in plasma and plasma cells in draining lymph nodes. Importantly, the downregulated Treg cell ratio in draining lymph nodes from CIA mice was recovered by Erdr1 treatment. In addition, administration of Erdr1 improved the CIA score and joint tissue damage, while it revealed no effect in Treg cell-depleted CIA mice, indicating that Treg cells mediate the therapeutic effects of Erdr1 in the CIA model. Results from in vitro experiments also demonstrated that Erdr1 significantly induced Treg cell differentiation and the expression of Treg activation markers, including CD25, CD69, and CTLA4 in CD4⁺Foxp3⁺ cells. Furthermore, Erdr1-activated Treg cells dramatically suppressed the proliferation of responder T cells, suggesting that they are functionally active. Taken together, these results show that Erdr1 induces activation of Treg cells and ameliorates rheumatoid arthritis via Treg cells. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Rheumatoid Arthritis)

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17 pages, 4708 KiB

Open AccessArticle

Dendritic Nanotheranostic for the Delivery of Infliximab: A Potential Carrier in Rheumatoid Arthritis Therapy

by Tamara Rodríguez-Prieto, Borja Hernández-Breijo, Miguel A. Ortega, Rafael Gómez, Javier Sánchez-Nieves and Luis G. Guijarro

Int. J. Mol. Sci. 2020, 21(23), 9101; https://doi.org/10.3390/ijms21239101 - 30 Nov 2020

Cited by 6 | Viewed by 2119

Abstract

Antibodies are macromolecules that specifically recognize their target, making them good candidates to be employed in various therapies. The possibility of attaching a drug to an immunoglobulin makes it possible to release it specifically into the affected tissue as long as it overexpresses [...] Read more.

Antibodies are macromolecules that specifically recognize their target, making them good candidates to be employed in various therapies. The possibility of attaching a drug to an immunoglobulin makes it possible to release it specifically into the affected tissue as long as it overexpresses the target. However, chemical coupling could affect the functionality (specificity and affinity) of the antibody. It has been observed that the use of intermediaries, such as dendrimers, could resolve this issue. Because carbosilane dendrimers have aroused great interest in the field of biomedicine, this report describes the synthesis of an anionic carbosilane dendrimer with a fluorochrome on its surface that then forms a conjugate with an antibody. It has been used as immunoglobulin and infliximab, whose target is TNF-α, which is a cytokine that is overexpressed in the inflamed area or even in the blood of patients with autoimmune diseases, such as rheumatoid arthritis. In addition, the integrity and functionality of the antibody has been studied to see if they have been affected after the chemical coupling process. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Rheumatoid Arthritis)

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Review

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15 pages, 1202 KiB

Open AccessReview

Rheumatoid Arthritis: Pathogenic Roles of Diverse Immune Cells

by Sunhee Jang, Eui-Jong Kwon and Jennifer Jooha Lee

Int. J. Mol. Sci. 2022, 23(2), 905; https://doi.org/10.3390/ijms23020905 - 14 Jan 2022

Cited by 134 | Viewed by 14103

Abstract

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease associated with synovial tissue proliferation, pannus formation, cartilage destruction, and systemic complications. Currently, advanced understandings of the pathologic mechanisms of autoreactive CD4+ T cells, B cells, macrophages, inflammatory cytokines, chemokines, and autoantibodies that cause [...] Read more.

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease associated with synovial tissue proliferation, pannus formation, cartilage destruction, and systemic complications. Currently, advanced understandings of the pathologic mechanisms of autoreactive CD4+ T cells, B cells, macrophages, inflammatory cytokines, chemokines, and autoantibodies that cause RA have been achieved, despite the fact that much remains to be elucidated. This review provides an updated pathogenesis of RA which will unveil novel therapeutic targets. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Rheumatoid Arthritis)

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17 pages, 729 KiB

Open AccessReview

The Genetic, Environmental, and Immunopathological Complexity of Autoantibody-Negative Rheumatoid Arthritis

by Ludovico De Stefano, Bernardo D’Onofrio, Antonio Manzo, Carlomaurizio Montecucco and Serena Bugatti

Int. J. Mol. Sci. 2021, 22(22), 12386; https://doi.org/10.3390/ijms222212386 - 17 Nov 2021

Cited by 15 | Viewed by 2887

Abstract

Differences in clinical presentation, response to treatment, and long-term outcomes between autoantibody-positive and -negative rheumatoid arthritis (RA) highlight the need for a better comprehension of the immunopathogenic events underlying the two disease subtypes. Whilst the drivers and perpetuators of autoimmunity in autoantibody-positive RA [...] Read more.

Differences in clinical presentation, response to treatment, and long-term outcomes between autoantibody-positive and -negative rheumatoid arthritis (RA) highlight the need for a better comprehension of the immunopathogenic events underlying the two disease subtypes. Whilst the drivers and perpetuators of autoimmunity in autoantibody-positive RA have started to be disclosed, autoantibody-negative RA remains puzzling, also due its wide phenotypic heterogeneity and its possible misdiagnosis. Genetic susceptibility appears to mostly rely on class I HLA genes and a number of yet unidentified non-HLA loci. On the background of such variable genetic predisposition, multiple exogeneous, endogenous, and stochastic factors, some of which are not shared with autoantibody-positive RA, contribute to the onset of the inflammatory cascade. In a proportion of the patients, the immunopathology of synovitis, at least in the initial stages, appears largely myeloid driven, with abundant production of proinflammatory cytokines and only minor involvement of cells of the adaptive immune system. Better understanding of the complexity of autoantibody-negative RA is still needed in order to open new avenues for targeted intervention and improve clinical outcomes. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Rheumatoid Arthritis)

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18 pages, 3450 KiB

Open AccessReview

Epigenetic Regulation (Including Micro-RNAs, DNA Methylation and Histone Modifications) of Rheumatoid Arthritis: A Systematic Review

by Melissa Payet, Farouk Dargai, Philippe Gasque and Xavier Guillot

Int. J. Mol. Sci. 2021, 22(22), 12170; https://doi.org/10.3390/ijms222212170 - 10 Nov 2021

Cited by 12 | Viewed by 2509

Abstract

The inflammatory reaction in rheumatoid arthritis (RA) is controlled by major epigenetic modifications that modulate the phenotype of synovial and immune cells. The aim of this work was to perform a systematic review focusing on miR expression, DNA methylation and histone modifications in [...] Read more.

The inflammatory reaction in rheumatoid arthritis (RA) is controlled by major epigenetic modifications that modulate the phenotype of synovial and immune cells. The aim of this work was to perform a systematic review focusing on miR expression, DNA methylation and histone modifications in RA. We demonstrated that, in human samples, the expressions of miR-155, miR-146a and miR-150 were significantly decreased while the expression of miR-410-3p was significantly increased in the RA group. Moreover, miR-146a significantly decreased pro-autoimmune IL-17 cytokine expression in RA. In a murine model, miR-34a inhibition can ameliorate the arthritis score. However, this evidence remain critically insufficient to support current therapeutic applications in RA patients. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Rheumatoid Arthritis)

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28 pages, 1601 KiB

Open AccessReview

Impact of Posttranslational Modification in Pathogenesis of Rheumatoid Arthritis: Focusing on Citrullination, Carbamylation, and Acetylation

by Eui-Jong Kwon and Ji Hyeon Ju

Int. J. Mol. Sci. 2021, 22(19), 10576; https://doi.org/10.3390/ijms221910576 - 30 Sep 2021

Cited by 23 | Viewed by 4918

Abstract

Rheumatoid arthritis (RA) is caused by prolonged periodic interactions between genetic, environmental, and immunologic factors. Posttranslational modifications (PTMs) such as citrullination, carbamylation, and acetylation are correlated with the pathogenesis of RA. PTM and cell death mechanisms such as apoptosis, autophagy, NETosis, leukotoxic hypercitrullination [...] Read more.

Rheumatoid arthritis (RA) is caused by prolonged periodic interactions between genetic, environmental, and immunologic factors. Posttranslational modifications (PTMs) such as citrullination, carbamylation, and acetylation are correlated with the pathogenesis of RA. PTM and cell death mechanisms such as apoptosis, autophagy, NETosis, leukotoxic hypercitrullination (LTH), and necrosis are related to each other and induce autoantigenicity. Certain microbial infections, such as those caused by Porphyromonasgingivalis, Aggregatibacter actinomycetemcomitans, and Prevotella copri, can induce autoantigens in RA. Anti-modified protein antibodies (AMPA) containing anti-citrullinated protein/peptide antibodies (ACPAs), anti-carbamylated protein (anti-CarP) antibodies, and anti-acetylated protein antibodies (AAPAs) play a role in pathogenesis as well as in prediction, diagnosis, and prognosis. Interestingly, smoking is correlated with both PTMs and AMPAs in the development of RA. However, there is lack of evidence that smoking induces the generation of AMPAs. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Rheumatoid Arthritis)

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17 pages, 1573 KiB

Open AccessReview

Cognitive Decline in Rheumatoid Arthritis: Insight into the Molecular Pathogenetic Mechanisms

by Maria Sofia Basile, Rosella Ciurleo, Alessia Bramanti, Maria Cristina Petralia, Paolo Fagone, Ferdinando Nicoletti and Eugenio Cavalli

Int. J. Mol. Sci. 2021, 22(3), 1185; https://doi.org/10.3390/ijms22031185 - 26 Jan 2021

Cited by 23 | Viewed by 6487

Abstract

Cognitive decline refers to a deterioration of intellectual and learning abilities and related memory problems, and is often associated with behavioral alterations, which prevents sufferers from carrying out the most common daily activities, such as maintaining normal productive interpersonal relationships, communicating, and leading [...] Read more.

Cognitive decline refers to a deterioration of intellectual and learning abilities and related memory problems, and is often associated with behavioral alterations, which prevents sufferers from carrying out the most common daily activities, such as maintaining normal productive interpersonal relationships, communicating, and leading an autonomous life. Numerous studies have highlighted the association between cognitive decline and autoimmune disorders, including rheumatoid arthritis (RA). RA is a chronic, inflammatory, autoimmune disease that involves systems and organs other than the bones and joints, with varying severity among patients. Here, we review the studies investigating the link between cognitive decline and RA, focusing on the main molecular pathogenetic mechanisms involved. The emerging body of data suggests that clinical, psychological, and biological factors may contribute to the pathogenesis of cognitive decline in RA, including cardiovascular complications, chronic pain, depression, inflammatory factors, changes in hormone levels, drug side effects, and genetics. Further studies are warranted in order to fully clarify the basis underlying the association between cognitive decline and RA and to find new possible diagnostic strategies and therapeutic targets for RA patients. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Rheumatoid Arthritis)

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31 pages, 1790 KiB

Open AccessReview

Effects of Biological Therapies on Molecular Features of Rheumatoid Arthritis

by Chary Lopez-Pedrera, Nuria Barbarroja, Alejandra M. Patiño-Trives, Maria Luque-Tévar, Eduardo Collantes-Estevez, Alejandro Escudero-Contreras and Carlos Pérez-Sánchez

Int. J. Mol. Sci. 2020, 21(23), 9067; https://doi.org/10.3390/ijms21239067 - 28 Nov 2020

Cited by 22 | Viewed by 7041

Abstract

Rheumatoid arthritis (RA) is an autoimmune and chronic inflammatory disease primarily affecting the joints, and closely related to specific autoantibodies that mostly target modified self-epitopes. Relevant findings in the field of RA pathogenesis have been described. In particular, new insights come from studies [...] Read more.

Rheumatoid arthritis (RA) is an autoimmune and chronic inflammatory disease primarily affecting the joints, and closely related to specific autoantibodies that mostly target modified self-epitopes. Relevant findings in the field of RA pathogenesis have been described. In particular, new insights come from studies on synovial fibroblasts and cells belonging to the innate and adaptive immune system, which documented the aberrant production of inflammatory mediators, oxidative stress and NETosis, along with relevant alterations of the genome and on the regulatory epigenetic mechanisms. In recent years, the advances in the understanding of RA pathogenesis by identifying key cells and cytokines allowed the development of new targeted disease-modifying antirheumatic drugs (DMARDs). These drugs considerably improved treatment outcomes for the majority of patients. Moreover, numerous studies demonstrated that the pharmacological therapy with biologic DMARDs (bDMARDs) promotes, in parallel to their clinical efficacy, significant improvement in all these altered molecular mechanisms. Thus, continuous updating of the knowledge of molecular processes associated with the pathogenesis of RA, and on the specific effects of bDMARDs in the correction of their dysregulation, are essential in the early and correct approach to the treatment of this complex autoimmune disorder. The present review details basic mechanisms related to the physiopathology of RA, along with the core mechanisms of response to bDMARDs. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Rheumatoid Arthritis)

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38 pages, 600 KiB

Open AccessReview

Aromatase Inhibitors—Induced Musculoskeletal Disorders: Current Knowledge on Clinical and Molecular Aspects

by Sara Tenti, Pierpaolo Correale, Sara Cheleschi, Antonella Fioravanti and Luigi Pirtoli

Int. J. Mol. Sci. 2020, 21(16), 5625; https://doi.org/10.3390/ijms21165625 - 6 Aug 2020

Cited by 47 | Viewed by 9334

Abstract

Aromatase inhibitors (AIs) have radically changed the prognosis of hormone receptor positive breast cancer (BC) in post-menopausal women, and are a mainstay of the adjuvant therapy for BC after surgery in place of, or following, Tamoxifen. However, AIs aren’t side effect-free; frequent adverse [...] Read more.

Aromatase inhibitors (AIs) have radically changed the prognosis of hormone receptor positive breast cancer (BC) in post-menopausal women, and are a mainstay of the adjuvant therapy for BC after surgery in place of, or following, Tamoxifen. However, AIs aren’t side effect-free; frequent adverse events involve the musculoskeletal system, in the form of bone loss, AI-associated arthralgia (AIA) syndrome and autoimmune rheumatic diseases. In this narrative review, we reported the main clinical features of these three detrimental conditions, their influence on therapy adherence, the possible underlying molecular mechanisms and the available pharmacological and non-pharmacological treatments. The best-known form is the AIs-induced osteoporosis, whose molecular pathway and therapeutic possibilities were extensively investigated in the last decade. AIA syndrome is a high prevalent joint pain disorder which often determines a premature discontinuation of the therapy. Several points still need to be clarified, as a universally accepted diagnostic definition, the pathogenetic mechanisms and satisfactory management strategies. The association of AIs therapy with autoimmune diseases is of the utmost interest. The related literature has been recently expanded, but many issues remain to be explored, the first being the molecular mechanisms. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Rheumatoid Arthritis)

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