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Pathways Contributing to Cartilage and Bone Destruction in Arthritis

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A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (1 July 2019) | Viewed by 76736

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Special Issue Editor

Prof. Dr. Charles J. Malemud

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Guest Editor

Department of Medicine, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH 44106-5076, USA
Interests: inflammation; apoptosis; arthritis; chondrocytes; matrix metalloproteinases; signal transduction; pro-inflammatory; anti-inflammatory & anabolic cytokines
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It is my distinct honor and privilege to have been asked to guest edit a Special issue of Cells devoted to “Pathways Contributing to Cartilage and Bone Destruction in Arthritis.” For those of us working in this field of research, we can appreciate the complexity of the mechanisms involved in the degradation of cartilage and bone in rheumatoid arthritis, psoriatic arthritis, gouty arthritis, and osteoarthritis. In fact, over the past 20 years or so we have come to appreciate the fact that there now exist many overlapping components of these musculoskeletal diseases that accompany destructive arthritis and limit tissue repair, which ultimately results in synovial joint failure. Fortunately, academic researchers have partnered with the biopharmaceutical industry to take a leadership role in the development of novel arthritis therapies. However, I trust that we can all appreciate that mainly through basic, fundamental pre-clinical studies in the laboratory will novel targets for the future treatments of various types of arthritis emerge. Thus, I invite you to contribute your expertise to this Special Issue of Cells. If you are interested in participating in this writing project, please convey the title of your paper to me by 31 January 2019 using the E-mail address located above. The deadline for submission of manuscripts will be 1 July 2019. All submitted papers will be subject to rigorous external peer-review.

Sincerely,

Prof. Dr. Charles J. Malemud
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

arthritis
bone
cartilage
cytokines
inflammation
proteolytic enzymes
signal transduction

Published Papers (10 papers)

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Research

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15 pages, 3103 KiB

Open AccessArticle

Physical Activity Prevents Cartilage Degradation: A Metabolomics Study Pinpoints the Involvement of Vitamin B6

by Michela Deiana, Giovanni Malerba, Luca Dalle Carbonare, Samuele Cheri, Cristina Patuzzo, Grygoriy Tsenov, Lucas Moron Dalla Tor, Antonio Mori, Gianantonio Saviola, Donato Zipeto, Federico Schena, Monica Mottes and Maria Teresa Valenti

Cells 2019, 8(11), 1374; https://doi.org/10.3390/cells8111374 - 01 Nov 2019

Cited by 10 | Viewed by 6187

Abstract

Osteoarthritis (OA) is predominantly characterized by the progressive degradation of articular cartilage, the connective tissue produced by chondrocytes, due to an imbalance between anabolic and catabolic processes. In addition, physical activity (PA) is recognized as an important tool for counteracting OA. To evaluate PA effects on the chondrocyte lineage, we analyzed the expression of SOX9, COL2A1, and COMP in circulating progenitor cells following a half marathon (HM) performance. Therefore, we studied in-depth the involvement of metabolites affecting chondrocyte lineage, and we compared the metabolomic profile associated with PA by analyzing runners’ sera before and after HM performance. Interestingly, this study highlighted that metabolites involved in vitamin B6 salvage, such as pyridoxal 5′-phosphate and pyridoxamine 5′-phosphate, were highly modulated. To evaluate the effects of vitamin B6 in cartilage cells, we treated differentiated mesenchymal stem cells and the SW1353 chondrosarcoma cell line with vitamin B6 in the presence of IL1β, the inflammatory cytokine involved in OA. Our study describes, for the first time, the modulation of the vitamin B6 salvage pathway following PA and suggests a protective role of PA in OA through modulation of this pathway. Full article

(This article belongs to the Special Issue Pathways Contributing to Cartilage and Bone Destruction in Arthritis)

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17 pages, 4562 KiB

Open AccessArticle

Physioxia Has a Beneficial Effect on Cartilage Matrix Production in Interleukin-1 Beta-Inhibited Mesenchymal Stem Cell Chondrogenesis

by Girish Pattappa, Ruth Schewior, Isabelle Hofmeister, Jennifer Seja, Johannes Zellner, Brian Johnstone, Denitsa Docheva and Peter Angele

Cells 2019, 8(8), 936; https://doi.org/10.3390/cells8080936 - 20 Aug 2019

Cited by 29 | Viewed by 4098

Abstract

Osteoarthritis (OA) is a degenerative condition that involves the production of inflammatory cytokines (e.g., interleukin-1β (IL-1β), tumour necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6)) that stimulate degradative enzymes, matrix metalloproteinases (MMPs) and aggrecanases (ADAMTS) resulting in articular cartilage breakdown. The presence of interleukin-1β (IL-1β) is one reason for poor clinical outcomes in current cell-based tissue engineering strategies for treating focal early osteoarthritic defects. Mesenchymal stem cells (MSCs) are a potential cell source for articular cartilage regeneration, although IL-1β has been shown to inhibit in vitro chondrogenesis. In vivo, articular chondrocytes reside under a low oxygen environment between 2–5% oxygen (physioxia) and have been shown to enhance in vitro MSC chondrogenic matrix content with reduced hypertrophic marker expression under these conditions. The present investigation sought to understand the effect of physioxia on IL-1β inhibited MSC chondrogenesis. MSCs expanded under physioxic (2% oxygen) and hyperoxic (20%) conditions, then chondrogenically differentiated as pellets in the presence of TGF-β1 and either 0.1 or 0.5 ng/mL IL-1β. Results showed that there were donor variations in response to physioxic culture based on intrinsic GAG content under hyperoxia. In physioxia responsive donors, MSC chondrogenesis significantly increased GAG and collagen II content, whilst hypertrophic markers were reduced compared with hyperoxia. In the presence of IL-1β, these donors showed a significant increase in cartilage matrix gene expression and GAG content relative to hyperoxic conditions. In contrast, a set of MSC donors were unresponsive to physioxia and showed no significant increase in matrix production independent of IL-1β presence. Thus, physioxia has a beneficial effect on MSC cartilage matrix production in responsive donors with or without IL-1β application. The mechanisms controlling the MSC chondrogenic response in both physioxia responsive and unresponsive donors are to be elucidated in future investigations. Full article

(This article belongs to the Special Issue Pathways Contributing to Cartilage and Bone Destruction in Arthritis)

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21 pages, 1856 KiB

Open AccessArticle

MicroRNA-34a and MicroRNA-181a Mediate Visfatin-Induced Apoptosis and Oxidative Stress via NF-κB Pathway in Human Osteoarthritic Chondrocytes

by Sara Cheleschi, Sara Tenti, Nicola Mondanelli, Claudio Corallo, Marcella Barbarino, Stefano Giannotti, Ines Gallo, Antonio Giordano and Antonella Fioravanti

Cells 2019, 8(8), 874; https://doi.org/10.3390/cells8080874 - 11 Aug 2019

Cited by 55 | Viewed by 4841

Abstract

Current evidence suggests a complex interaction between adipokines and microRNA (miRNA) in osteoarthritis (OA) pathogenesis. The present study explored the role of miR-34a and miR-181a in regulating apoptosis and oxidative stress induced by visfatin in human OA chondrocytes. Chondrocytes were transfected with miR-34a and miR-181a inhibitors and stimulated with visfatin for 24 h, in the presence of nuclear factor (NF)-κB inhibitor (BAY-11-7082, 2 h pre-incubation). Apoptosis and reactive oxygen species (ROS) production were detected by cytometry, miRNA, antioxidant enzymes, nuclear factor erythroid (NRF)2 and B-cell lymphoma (BCL)2 expressions by quantitative real time polymerase chain reaction (real time PCR) and western blot. P50 NF-κB subunit was measured by immunofluorescence. Visfatin significantly induced apoptosis and superoxide anion production, increased miR-34a, miR-181a, superoxide dismutase (SOD)-2, catalase (CAT), NRF2 and decreased BCL2 gene and protein expression in OA chondrocytes. All the visfatin-caused effects were suppressed by using miR-34a and miR-181a inhibitors. Pre-incubation with BAY-11-7082 counteracted visfatin-induced expression of miRNA, BCL2, SOD-2, CAT and NRF2. Inhibition of miR-34a and miR-181a significantly reduced the activation of p50 NF-κB. Visfatin confirms its ability to induce apoptosis and oxidative stress in human OA chondrocytes; these effects appeared mediated by miR-34a and miR-181a via NF-κB pathway. We highlight the relevance of visfatin as potential therapeutic target for OA treatment. Full article

(This article belongs to the Special Issue Pathways Contributing to Cartilage and Bone Destruction in Arthritis)

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15 pages, 55194 KiB

Open AccessArticle

Investigation of Cytokine Changes in Osteoarthritic Knee Joint Tissues in Response to Hyperacute Serum Treatment

by Dorottya Kardos, Bence Marschall, Melinda Simon, István Hornyák, Adél Hinsenkamp, Olga Kuten, Zsuzsanna Gyevnár, Gábor Erdélyi, Tamás Bárdos, Tamás Mirkó Paukovits, Krisztián Magos, György Béres, Kálmán Szenthe, Ferenc Bánáti, Susan Szathmary, Stefan Nehrer and Zsombor Lacza

Cells 2019, 8(8), 824; https://doi.org/10.3390/cells8080824 - 03 Aug 2019

Cited by 21 | Viewed by 4637

Abstract

One option to fight joint degradation and inflammation in osteoarthritis is the injection of activated blood products into the synovial space. It has been demonstrated that hyperacute serum is the most proliferative among plasma products, so we investigated how the cytokine milieu of osteoarthritic knee joint reacts to hyperacute serum treatment in vitro. Cartilage, subchondral bone, and synovial membrane explanted from osteoarthritic knees were stimulated by interleukin-1 beta (IL-1β) and the concentration of 39 biomarkers was measured in the co-culture supernatant after hyperacute serum treatment. The IL-1β stimulation triggered a strong inflammatory response and enhanced the concentrations of matrix metalloproteinase 3 and 13 (MMP-3 and MMP-13), while hyperacute serum treatment reduced inflammation by decreasing the concentrations of IL-1β, tumor necrosis factor alpha (TNF-α), interleukin-6 receptor alpha (IL-6Rα), and by increasing the level of interleukin-1 antagonist (IL-1RA) Cell viability increased by day 5 in the presence of hyperacute serum. The level of MMPs-1, 2, and 9 were higher on day 3, but did not increase further until day 5. The concentrations of collagen 1 alpha 1 (COL1A1) and osteonectin were increased and receptor activator of nuclear factor kappa-B ligand (RANKL) was reduced in response to hyperacute serum. We concluded that hyperacute serum treatment induces cell proliferation of osteoarthritic joint tissues and affects the cytokine milieu towards a less inflamed state. Full article

(This article belongs to the Special Issue Pathways Contributing to Cartilage and Bone Destruction in Arthritis)

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13 pages, 2021 KiB

Open AccessArticle

The Adenosine A_2B Receptor Drives Osteoclast-Mediated Bone Resorption in Hypoxic Microenvironments

by Helen J. Knowles

Cells 2019, 8(6), 624; https://doi.org/10.3390/cells8060624 - 21 Jun 2019

Cited by 12 | Viewed by 4113

Abstract

Osteoclast-mediated bone destruction is amplified in the hypoxic synovial microenvironment of rheumatoid arthritis (RA). This increased bone resorption is driven by the hypoxia-inducible transcription factor HIF. We identified hypoxic induction of the HIF-regulated adenosine A_2B receptor in primary human osteoclasts (mRNA, 3.8-fold increase, p < 0.01) and sought to identify the role(s) of purinergic signaling via this receptor in the bone resorption process. Primary human osteoclasts were differentiated from CD14+ monocytes and exposed to hypoxia (2% O₂) and A_2B receptor inhibitors (MRS1754, PSB603). The hypoxic increase in bone resorption was prevented by the inhibition of the A_2B receptor, at least partly by the attenuation of glycolytic and mitochondrial metabolism via inhibition of HIF. A_2B receptor inhibition also reduced osteoclastogenesis in hypoxia by inhibiting early cell fusion (day 3–4, p < 0.05). The A_2B receptor is only functional in hypoxic or inflammatory environments when the extracellular concentrations of adenosine (1.6-fold increase, p < 0.05) are sufficient to activate the receptor. Inhibition of the A_2B receptor under normoxic conditions therefore did not affect any parameter tested. Reciprocal positive regulation of HIF and the A_2B receptor in a hypoxic microenvironment thus enhances glycolytic and mitochondrial metabolism in osteoclasts to drive increased bone resorption. A_2B receptor inhibition could potentially prevent the pathological osteolysis associated with hypoxic diseases such as rheumatoid arthritis. Full article

(This article belongs to the Special Issue Pathways Contributing to Cartilage and Bone Destruction in Arthritis)

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Review

Jump to: Research

20 pages, 2546 KiB

Open AccessReview

Intraarticular Ligament Degeneration Is Interrelated with Cartilage and Bone Destruction in Osteoarthritis

by Gundula Schulze-Tanzil

Cells 2019, 8(9), 990; https://doi.org/10.3390/cells8090990 - 27 Aug 2019

Cited by 59 | Viewed by 9785

Abstract

Osteoarthritis (OA) induces inflammation and degeneration of all joint components including cartilage, joint capsule, bone and bone marrow, and ligaments. Particularly intraarticular ligaments, which connect the articulating bones such as the anterior cruciate ligament (ACL) and meniscotibial ligaments, fixing the fibrocartilaginous menisci to the tibial bone, are prone to the inflamed joint milieu in OA. However, the pathogenesis of ligament degeneration on the cellular level, most likely triggered by OA associated inflammation, remains poorly understood. Hence, this review sheds light into the intimate interrelation between ligament degeneration, synovitis, joint cartilage degradation, and dysbalanced subchondral bone remodeling. Various features of ligament degeneration accompanying joint cartilage degradation have been reported including chondroid metaplasia, cyst formation, heterotopic ossification, and mucoid and fatty degenerations. The entheses of ligaments, fixing ligaments to the subchondral bone, possibly influence the localization of subchondral bone lesions. The transforming growth factor (TGF)β/bone morphogenetic (BMP) pathway could present a link between degeneration of the osteochondral unit and ligaments with misrouted stem cell differentiation as one likely reason for ligament degeneration, but less studied pathways such as complement activation could also contribute to inflammation. Facilitation of OA progression by changed biomechanics of degenerated ligaments should be addressed in more detail in the future. Full article

(This article belongs to the Special Issue Pathways Contributing to Cartilage and Bone Destruction in Arthritis)

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18 pages, 655 KiB

Open AccessReview

Targeting the CD40-CD154 Signaling Pathway for Treatment of Autoimmune Arthritis

by Jenn-Haung Lai, Shue-Fen Luo and Ling-Jun Ho

Cells 2019, 8(8), 927; https://doi.org/10.3390/cells8080927 - 18 Aug 2019

Cited by 25 | Viewed by 10540

Abstract

Full activation of T lymphocytes requires signals from both T cell receptors and costimulatory molecules. In addition to CD28, several T cell molecules could deliver costimulatory signals, including CD154, which primarily interacts with CD40 on B-cells. CD40 is a critical molecule regulating several B-cell functions, such as antibody production, germinal center formation and cellular proliferation. Upregulated expression of CD40 and CD154 occurs in immune effector cells and non-immune cells in different autoimmune diseases. In addition, therapeutic benefits have been observed by blocking the CD40-CD154 interaction in animals with collagen-induced arthritis. Given the therapeutic success of the biologics abatacept, which blocks CD28 costimulation, and rituximab, which deletes B cells in the treatment of autoimmune arthritis, the inhibition of the CD40-CD154 axis has two advantages, namely, attenuating CD154-mediated T cell costimulation and suppressing CD40-mediated B-cell stimulation. Furthermore, blockade of the CD40-CD154 interaction drives the conversion of CD4+ T cells to regulatory T cells that mediate immunosuppression. Currently, several biological products targeting the CD40-CD154 axis have been developed and are undergoing early phase clinical trials with encouraging success in several autoimmune disorders, including autoimmune arthritis. This review addresses the roles of the CD40-CD154 axis in the pathogenesis of autoimmune arthritis and its potential as a therapeutic target. Full article

(This article belongs to the Special Issue Pathways Contributing to Cartilage and Bone Destruction in Arthritis)

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31 pages, 2060 KiB

Open AccessReview

Cartilage and Bone Destruction in Arthritis: Pathogenesis and Treatment Strategy: A Literature Review

by Daisuke Tateiwa, Hideki Yoshikawa and Takashi Kaito

Cells 2019, 8(8), 818; https://doi.org/10.3390/cells8080818 - 02 Aug 2019

Cited by 101 | Viewed by 11006

Abstract

Arthritis is inflammation of the joints accompanied by osteochondral destruction. It can take many forms, including osteoarthritis, rheumatoid arthritis, and psoriatic arthritis. These diseases share one commonality—osteochondral destruction based on inflammation. The background includes a close interaction between osseous tissues and immune cells through various inflammatory cytokines. However, the tissues and cytokines that play major roles are different in each disease, and as a result, the mechanism of osteochondral destruction also differs. In recent years, there have been many findings regarding not only extracellular signaling pathways but also intracellular signaling pathways. In particular, we anticipate that the intracellular signals of osteoclasts, which play a central role in bone destruction, will become novel therapeutic targets. In this review, we have summarized the pathology of arthritis and the latest findings on the mechanism of osteochondral destruction, as well as present and future therapeutic strategies for these targets. Full article

(This article belongs to the Special Issue Pathways Contributing to Cartilage and Bone Destruction in Arthritis)

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21 pages, 1153 KiB

Open AccessReview

NF-κB Signaling Pathways in Osteoarthritic Cartilage Destruction

by Moon-Chang Choi, Jiwon Jo, Jonggwan Park, Hee Kyoung Kang and Yoonkyung Park

Cells 2019, 8(7), 734; https://doi.org/10.3390/cells8070734 - 17 Jul 2019

Cited by 309 | Viewed by 14486

Abstract

Osteoarthritis (OA) is a type of joint disease associated with wear and tear, inflammation, and aging. Mechanical stress along with synovial inflammation promotes the degradation of the extracellular matrix in the cartilage, leading to the breakdown of joint cartilage. The nuclear factor-kappaB (NF-κB) transcription factor has long been recognized as a disease-contributing factor and, thus, has become a therapeutic target for OA. Because NF-κB is a versatile and multi-functional transcription factor involved in various biological processes, a comprehensive understanding of the functions or regulation of NF-κB in the OA pathology will aid in the development of targeted therapeutic strategies to protect the cartilage from OA damage and reduce the risk of potential side-effects. In this review, we discuss the roles of NF-κB in OA chondrocytes and related signaling pathways, including recent findings, to better understand pathological cartilage remodeling and provide potential therapeutic targets that can interfere with NF-κB signaling for OA treatment. Full article

(This article belongs to the Special Issue Pathways Contributing to Cartilage and Bone Destruction in Arthritis)

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15 pages, 842 KiB

Open AccessReview

The Importance of the Knee Joint Meniscal Fibrocartilages as Stabilizing Weight Bearing Structures Providing Global Protection to Human Knee-Joint Tissues

by James Melrose

Cells 2019, 8(4), 324; https://doi.org/10.3390/cells8040324 - 06 Apr 2019

Cited by 14 | Viewed by 6237

Abstract

The aim of this study was to review aspects of the pathobiology of the meniscus in health and disease and show how degeneration of the meniscus can contribute to deleterious changes in other knee joint components. The menisci, distinctive semilunar weight bearing fibrocartilages, provide knee joint stability, co-ordinating functional contributions from articular cartilage, ligaments/tendons, synovium, subchondral bone and infra-patellar fat pad during knee joint articulation. The meniscus contains metabolically active cell populations responsive to growth factors, chemokines and inflammatory cytokines such as interleukin-1 and tumour necrosis factor-alpha, resulting in the synthesis of matrix metalloproteases and A Disintegrin and Metalloprotease with ThromboSpondin type 1 repeats (ADAMTS)-4 and 5 which can degrade structural glycoproteins and proteoglycans leading to function-limiting changes in meniscal and other knee joint tissues. Such degradative changes are hall-marks of osteoarthritis (OA). No drugs are currently approved that change the natural course of OA and translate to long-term, clinically relevant benefits. For any pharmaceutical therapeutic intervention in OA to be effective, disease modifying drugs will have to be developed which actively modulate the many different cell types present in the knee to provide a global therapeutic. Many individual and combinatorial approaches are being developed to treat or replace degenerate menisci using 3D printing, bioscaffolds and hydrogel delivery systems for therapeutic drugs, growth factors and replacement progenitor cell populations recognising the central role the menisci play in knee joint health. Full article

(This article belongs to the Special Issue Pathways Contributing to Cartilage and Bone Destruction in Arthritis)

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