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Osteoarthritis: From Molecular Pathways to Therapeutic Advances

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 (30 June 2021) | Viewed by 76704

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

Special Issue Editor

Prof. Dr. Nicola Veronese

grade E-Mail Website
Guest Editor
Department of Geriatric Medicine, University of Palermo, 90133 Palermo, Italy
Interests: epidemiology; geriatrics; magnesium; frailty; osteoarthritis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

As you know, osteoarthritis (OA) is an epidemiologically relevant age-related disorder commonly affecting synovial joints and finally culminating in the irreversible destruction of the articular cartilage. OA is the most common musculoskeletal condition, particularly in advanced age, but its exact etiology is still not clear.

In this sense, inflammation seems to be a relevant pathway involved in the etiology of OA, but OA is mostly a degenerative and not an inflammatory condition. Moreover, it seems that the apoptosis of the cells of the articular cartilage could be important, but research in this direction is still limited to a few in vitro experiments. Finally, the molecular pathways involved in the therapeutic approaches used in OA are still poorly known.

Given this background, this Special Issue calls for original research papers, mini and full reviews, and perspectives that address the progress and current knowledge of the pathophysiological mechanisms of OA, particularly those regarding molecular explanations of the etiology of the OA. The Special Issue will also include therapeutic pharmacological and cell-based strategies, including stem-cell therapy, for improving OA outcomes.

Prof. Dr. Nicola Veronese
Guest Editor

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Keywords

  • osteoarthritis
  • inflammation
  • pathophysiology of osteoarthritis (OA)
  • pharmacology
  • biomarkers for osteoarthritis

Published Papers (16 papers)

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Research

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22 pages, 4716 KiB  
Article
Pleiotropic Roles of NOTCH1 Signaling in the Loss of Maturational Arrest of Human Osteoarthritic Chondrocytes
by Manuela Minguzzi, Veronica Panichi, Stefania D’Adamo, Silvia Cetrullo, Luca Cattini, Flavio Flamigni, Erminia Mariani and Rosa Maria Borzì
Int. J. Mol. Sci. 2021, 22(21), 12012; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222112012 - 05 Nov 2021
Cited by 7 | Viewed by 2136
Abstract
Notch signaling has been identified as a critical regulator of cartilage development and homeostasis. Its pivotal role was established by both several joint specific Notch signaling loss of function mouse models and transient or sustained overexpression. NOTCH1 is the most abundantly expressed NOTCH [...] Read more.
Notch signaling has been identified as a critical regulator of cartilage development and homeostasis. Its pivotal role was established by both several joint specific Notch signaling loss of function mouse models and transient or sustained overexpression. NOTCH1 is the most abundantly expressed NOTCH receptors in normal cartilage and its expression increases in osteoarthritis (OA), when chondrocytes exit from their healthy “maturation arrested state” and resume their natural route of proliferation, hypertrophy, and terminal differentiation. The latter are hallmarks of OA that are easily evaluated in vitro in 2-D or 3-D culture models. The aim of our study was to investigate the effect of NOTCH1 knockdown on proliferation (cell count and Picogreen mediated DNA quantification), cell cycle (flow cytometry), hypertrophy (gene and protein expression of key markers such as RUNX2 and MMP-13), and terminal differentiation (viability measured in 3-D cultures by luminescence assay) of human OA chondrocytes. NOTCH1 silencing of OA chondrocytes yielded a healthier phenotype in both 2-D (reduced proliferation) and 3-D with evidence of decreased hypertrophy (reduced expression of RUNX2 and MMP-13) and terminal differentiation (increased viability). This demonstrates that NOTCH1 is a convenient therapeutic target to attenuate OA progression. Full article
(This article belongs to the Special Issue Osteoarthritis: From Molecular Pathways to Therapeutic Advances)
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21 pages, 900 KiB  
Article
Chondrocytes from Osteoarthritis Patients Adopt Distinct Phenotypes in Response to Central TH1/TH2/TH17 Cytokines
by Antti Pemmari, Tiina Leppänen, Mari Hämäläinen, Teemu Moilanen and Eeva Moilanen
Int. J. Mol. Sci. 2021, 22(17), 9463; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179463 - 31 Aug 2021
Cited by 9 | Viewed by 2489
Abstract
Chronic low-grade inflammation plays a central role in the pathogenesis of osteoarthritis (OA), and several pro- and anti-inflammatory cytokines have been implicated to mediate and regulate this process. Out of these cytokines, particularly IFNγ, IL-1β, IL-4 and IL-17 are associated with different phenotypes [...] Read more.
Chronic low-grade inflammation plays a central role in the pathogenesis of osteoarthritis (OA), and several pro- and anti-inflammatory cytokines have been implicated to mediate and regulate this process. Out of these cytokines, particularly IFNγ, IL-1β, IL-4 and IL-17 are associated with different phenotypes of T helper (TH) cells and macrophages, both examples of cells known for great phenotypic and functional heterogeneity. Chondrocytes also display various phenotypic changes during the course of arthritis. We set out to study the hypothesis of whether chondrocytes might adopt polarized phenotypes analogous to TH cells and macrophages. We studied the effects of IFNγ, IL-1β, IL-4 and IL-17 on gene expression in OA chondrocytes with RNA-Seq. Chondrocytes were harvested from the cartilage of OA patients undergoing knee replacement surgery and then cultured with or without the cytokines for 24 h. Total RNA was isolated and sequenced, and GO (Gene Ontology) functional analysis was performed. We also separately investigated genes linked to OA in recent genome wide expression analysis (GWEA) studies. The expression of more than 2800 genes was significantly altered in chondrocytes treated with IL-1β [in the C(IL-1β) phenotype] with a fold change (FC) > 2.5 in either direction. These included a large number of genes associated with inflammation, cartilage degradation and attenuation of metabolic signaling. The profile of genes differentially affected by IFNγ (the C(IFNγ) phenotype) was relatively distinct from that of the C(IL-1β) phenotype and included several genes associated with antigen processing and presentation. The IL-17-induced C(IL-17) phenotype was characterized by the induction of a more limited set of proinflammatory factors compared to C(IL-1β) cells. The C(IL-4) phenotype induced by IL-4 displayed a differential expression of a rather small set of genes compared with control, primarily those associated with TGFβ signaling and the regulation of inflammation. In conclusion, our results show that OA chondrocytes can adopt diverse phenotypes partly analogously to TH cells and macrophages. This phenotypic plasticity may play a role in the pathogenesis of arthritis and open new therapeutic avenues for the development of disease-modifying treatments for (osteo)arthritis. Full article
(This article belongs to the Special Issue Osteoarthritis: From Molecular Pathways to Therapeutic Advances)
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20 pages, 2575 KiB  
Article
A Combination of Celecoxib and Glucosamine Sulfate Has Anti-Inflammatory and Chondroprotective Effects: Results from an In Vitro Study on Human Osteoarthritic Chondrocytes
by Sara Cheleschi, Sara Tenti, Stefano Giannotti, Nicola Veronese, Jean-Yves Reginster and Antonella Fioravanti
Int. J. Mol. Sci. 2021, 22(16), 8980; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168980 - 20 Aug 2021
Cited by 15 | Viewed by 3847
Abstract
This study investigated the possible anti-inflammatory and chondroprotective effects of a combination of celecoxib and prescription-grade glucosamine sulfate (GS) in human osteoarthritic (OA) chondrocytes and their possible mechanism of action. Chondrocytes were treated with celecoxib (1.85 µM) and GS (9 µM), alone or [...] Read more.
This study investigated the possible anti-inflammatory and chondroprotective effects of a combination of celecoxib and prescription-grade glucosamine sulfate (GS) in human osteoarthritic (OA) chondrocytes and their possible mechanism of action. Chondrocytes were treated with celecoxib (1.85 µM) and GS (9 µM), alone or in combination with IL-1β (10 ng/mL) and a specific nuclear factor (NF)-κB inhibitor (BAY-11-7082, 1 µM). Gene expression and release of some pro-inflammatory mediators, metalloproteinases (MMPs), and type II collagen (Col2a1) were evaluated by qRT-PCR and ELISA; apoptosis and mitochondrial superoxide anion production were assessed by cytometry; B-cell lymphoma (BCL)2, antioxidant enzymes, and p50 and p65 NF-κB subunits were analyzed by qRT-PCR. Celecoxib and GS alone or co-incubated with IL-1β significantly reduced expression and release of cyclooxygenase (COX)-2, prostaglandin (PG)E2, IL-1β, IL-6, tumor necrosis factor (TNF)-α, and MMPs, while it increased Col2a1, compared to baseline or IL-1β. Both drugs reduced apoptosis and superoxide production; reduced the expression of superoxide dismutase, catalase, and nuclear factor erythroid; increased BCL2; and limited p50 and p65. Celecoxib and GS combination demonstrated an increased inhibitory effect on IL-1β than that observed by each single treatment. Drugs effects were potentiated by pre-incubation with BAY-11-7082. Our results demonstrated the synergistic effect of celecoxib and GS on OA chondrocyte metabolism, apoptosis, and oxidative stress through the modulation of the NF-κB pathway, supporting their combined use for the treatment of OA. Full article
(This article belongs to the Special Issue Osteoarthritis: From Molecular Pathways to Therapeutic Advances)
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22 pages, 26561 KiB  
Article
Osteoarthritis-Related Inflammation Blocks TGF-β’s Protective Effect on Chondrocyte Hypertrophy via (de)Phosphorylation of the SMAD2/3 Linker Region
by Nathalie Thielen, Margot Neefjes, Renske Wiegertjes, Guus van den Akker, Elly Vitters, Henk van Beuningen, Esmeralda Blaney Davidson, Marije Koenders, Peter van Lent, Fons van de Loo, Arjan van Caam and Peter van der Kraan
Int. J. Mol. Sci. 2021, 22(15), 8124; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158124 - 29 Jul 2021
Cited by 13 | Viewed by 2589
Abstract
Osteoarthritis (OA) is a degenerative joint disease characterized by irreversible cartilage damage, inflammation and altered chondrocyte phenotype. Transforming growth factor-β (TGF-β) signaling via SMAD2/3 is crucial for blocking hypertrophy. The post-translational modifications of these SMAD proteins in the linker domain regulate their function [...] Read more.
Osteoarthritis (OA) is a degenerative joint disease characterized by irreversible cartilage damage, inflammation and altered chondrocyte phenotype. Transforming growth factor-β (TGF-β) signaling via SMAD2/3 is crucial for blocking hypertrophy. The post-translational modifications of these SMAD proteins in the linker domain regulate their function and these can be triggered by inflammation through the activation of kinases or phosphatases. Therefore, we investigated if OA-related inflammation affects TGF-β signaling via SMAD2/3 linker-modifications in chondrocytes. We found that both Interleukin (IL)-1β and OA-synovium conditioned medium negated SMAD2/3 transcriptional activity in chondrocytes. This inhibition of TGF-β signaling was enhanced if SMAD3 could not be phosphorylated on Ser213 in the linker region and the inhibition by IL-1β was less if the SMAD3 linker could not be phosphorylated at Ser204. Our study shows evidence that inflammation inhibits SMAD2/3 signaling in chondrocytes via SMAD linker (de)-phosphorylation. The involvement of linker region modifications may represent a new therapeutic target for OA. Full article
(This article belongs to the Special Issue Osteoarthritis: From Molecular Pathways to Therapeutic Advances)
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17 pages, 39885 KiB  
Article
Males and Females Have Distinct Molecular Events in the Articular Cartilage during Knee Osteoarthritis
by Chenshuang Li and Zhong Zheng
Int. J. Mol. Sci. 2021, 22(15), 7876; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22157876 - 23 Jul 2021
Cited by 7 | Viewed by 1956
Abstract
Osteoarthritis (OA) is a major public health challenge that imposes a remarkable burden on the affected individuals and the healthcare system. Based on the clinical observation, males and females have different prevalence rates and severity levels of OA. Thus, sex-based differences may play [...] Read more.
Osteoarthritis (OA) is a major public health challenge that imposes a remarkable burden on the affected individuals and the healthcare system. Based on the clinical observation, males and females have different prevalence rates and severity levels of OA. Thus, sex-based differences may play essential roles in OA’s prognosis and treatment outcomes. To date, the comprehensive understanding of the relationship between sex and OA is still largely lacking. In the current study, we analyzed a published transcriptome dataset of knee articular cartilage (GSE114007) from 18 healthy (five females, 13 males) and 20 OA (11 females, nine males) donors to provide a slight insight into this important but complex issue. First, comparing female healthy cartilage samples with those of males revealed 36 differential expression genes (DEGs), indicating the fundamental sex-related differences at the molecular level. Meanwhile, 923 DEGs were distinguished between OA and healthy female cartilage, which can be enriched to 15 Reactome pathways. On the other hand, when comparing OA and healthy male cartilage, there are only 419 DEGs were identified, and only six pathways were enriched against the Reactome database. The different signaling response to OA in the male and female cartilage was further enforced by recognizing 50 genes with significantly different OA-responsive expression fold changes in males and females. Particularly, 14 Reactome pathways, such as “Extracellular matrix organization”, “Collagen biosynthesis and modifying enzymes”, “Dissolution of fibrin clot”, and “Platelet Aggregation (Plug formation)”, can be noted from these 50 sex-dependent OA-responsive genes. Overall, the current study explores the Sex as a Biological Variable (SABV) at the transcriptomic level in the knee articular cartilage in both healthy status and OA event, which could help predict the differential OA prognosis and treatment outcome of males and female patients. Full article
(This article belongs to the Special Issue Osteoarthritis: From Molecular Pathways to Therapeutic Advances)
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16 pages, 3459 KiB  
Article
The Hexosamine Biosynthetic Pathway as a Therapeutic Target after Cartilage Trauma: Modification of Chondrocyte Survival and Metabolism by Glucosamine Derivatives and PUGNAc in an Ex Vivo Model
by Jana Riegger, Julia Baumert, Frank Zaucke and Rolf E. Brenner
Int. J. Mol. Sci. 2021, 22(14), 7247; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147247 - 06 Jul 2021
Cited by 8 | Viewed by 4165
Abstract
The hexosamine biosynthetic pathway (HBP) is essential for the production of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), the building block of glycosaminoglycans, thus playing a crucial role in cartilage anabolism. Although O-GlcNAcylation represents a protective regulatory mechanism in cellular processes, it has been associated with [...] Read more.
The hexosamine biosynthetic pathway (HBP) is essential for the production of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), the building block of glycosaminoglycans, thus playing a crucial role in cartilage anabolism. Although O-GlcNAcylation represents a protective regulatory mechanism in cellular processes, it has been associated with degenerative diseases, including osteoarthritis (OA). The present study focuses on HBP-related processes as potential therapeutic targets after cartilage trauma. Human cartilage explants were traumatized and treated with GlcNAc or glucosamine sulfate (GS); PUGNAc, an inhibitor of O-GlcNAcase; or azaserine (AZA), an inhibitor of GFAT-1. After 7 days, cell viability and gene expression analysis of anabolic and catabolic markers, as well as HBP-related enzymes, were performed. Moreover, expression of catabolic enzymes and type II collagen (COL2) biosynthesis were determined. Proteoglycan content was assessed after 14 days. Cartilage trauma led to a dysbalanced expression of different HBP-related enzymes, comparable to the situation in highly degenerated tissue. While GlcNAc and PUGNAc resulted in significant cell protection after trauma, only PUGNAc increased COL2 biosynthesis. Moreover, PUGNAc and both glucosamine derivatives had anti-catabolic effects. In contrast, AZA increased catabolic processes. Overall, “fueling” the HBP by means of glucosamine derivatives or inhibition of deglycosylation turned out as cells and chondroprotectives after cartilage trauma. Full article
(This article belongs to the Special Issue Osteoarthritis: From Molecular Pathways to Therapeutic Advances)
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15 pages, 2513 KiB  
Article
A Novel Method Facilitating the Simple and Low-Cost Preparation of Human Osteochondral Slice Explants for Large-Scale Native Tissue Analysis
by Jacob Spinnen, Lennard K. Shopperly, Carsten Rendenbach, Anja A. Kühl, Ufuk Sentürk, Daniel Kendoff, Shabnam Hemmati-Sadeghi, Michael Sittinger and Tilo Dehne
Int. J. Mol. Sci. 2021, 22(12), 6394; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126394 - 15 Jun 2021
Cited by 2 | Viewed by 2248
Abstract
For in vitro modeling of human joints, osteochondral explants represent an acceptable compromise between conventional cell culture and animal models. However, the scarcity of native human joint tissue poses a challenge for experiments requiring high numbers of samples and makes the method rather [...] Read more.
For in vitro modeling of human joints, osteochondral explants represent an acceptable compromise between conventional cell culture and animal models. However, the scarcity of native human joint tissue poses a challenge for experiments requiring high numbers of samples and makes the method rather unsuitable for toxicity analyses and dosing studies. To scale their application, we developed a novel method that allows the preparation of up to 100 explant cultures from a single human sample with a simple setup. Explants were cultured for 21 days, stimulated with TNF-α or TGF-β3, and analyzed for cell viability, gene expression and histological changes. Tissue cell viability remained stable at >90% for three weeks. Proteoglycan levels and gene expression of COL2A1, ACAN and COMP were maintained for 14 days before decreasing. TNF-α and TGF-β3 caused dose-dependent changes in cartilage marker gene expression as early as 7 days. Histologically, cultures under TNF-α stimulation showed a 32% reduction in proteoglycans, detachment of collagen fibers and cell swelling after 7 days. In conclusion, thin osteochondral slice cultures behaved analogously to conventional punch explants despite cell stress exerted during fabrication. In pharmacological testing, both the shorter diffusion distance and the lack of need for serum in the culture suggest a positive effect on sensitivity. The ease of fabrication and the scalability of the sample number make this manufacturing method a promising platform for large-scale preclinical testing in joint research. Full article
(This article belongs to the Special Issue Osteoarthritis: From Molecular Pathways to Therapeutic Advances)
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20 pages, 3386 KiB  
Article
Exploring the Crosstalk between Hydrostatic Pressure and Adipokines: An In Vitro Study on Human Osteoarthritic Chondrocytes
by Sara Cheleschi, Sara Tenti, Marcella Barbarino, Stefano Giannotti, Francesca Bellisai, Elena Frati and Antonella Fioravanti
Int. J. Mol. Sci. 2021, 22(5), 2745; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052745 - 09 Mar 2021
Cited by 8 | Viewed by 2323
Abstract
Obesity is a risk factor for osteoarthritis (OA) development and progression due to an altered biomechanical stress on cartilage and an increased release of inflammatory adipokines from adipose tissue. Evidence suggests an interplay between loading and adipokines in chondrocytes metabolism modulation. We investigated [...] Read more.
Obesity is a risk factor for osteoarthritis (OA) development and progression due to an altered biomechanical stress on cartilage and an increased release of inflammatory adipokines from adipose tissue. Evidence suggests an interplay between loading and adipokines in chondrocytes metabolism modulation. We investigated the role of loading, as hydrostatic pressure (HP), in regulating visfatin-induced effects in human OA chondrocytes. Chondrocytes were stimulated with visfatin (24 h) and exposed to high continuous HP (24 MPa, 3 h) in the presence of visfatin inhibitor (FK866, 4 h pre-incubation). Apoptosis and oxidative stress were detected by cytometry, B-cell lymphoma (BCL)2, metalloproteinases (MMPs), type II collagen (Col2a1), antioxidant enzymes, miRNA, cyclin D1 expressions by real-time PCR, and β-catenin protein by western blot. HP exposure or visfatin stimulus significantly induced apoptosis, superoxide anion production, and MMP-3, -13, antioxidant enzymes, and miRNA gene expression, while reducing Col2a1 and BCL2 mRNA. Both stimuli significantly reduced β-catenin protein and increased cyclin D1 gene expression. HP exposure exacerbated visfatin-induced effects, which were counteracted by FK866 pre-treatment. Our data underline the complex interplay between loading and visfatin in controlling chondrocytes’ metabolism, contributing to explaining the role of obesity in OA etiopathogenesis, and confirming the importance of controlling body weight for disease treatment. Full article
(This article belongs to the Special Issue Osteoarthritis: From Molecular Pathways to Therapeutic Advances)
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13 pages, 2140 KiB  
Article
Inhibition of Inducible Nitric Oxide Synthase Prevents IL-1β-Induced Mitochondrial Dysfunction in Human Chondrocytes
by Annett Eitner, Sylvia Müller, Christian König, Arne Wilharm, Rebecca Raab, Gunther O. Hofmann, Thomas Kamradt and Hans-Georg Schaible
Int. J. Mol. Sci. 2021, 22(5), 2477; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052477 - 01 Mar 2021
Cited by 18 | Viewed by 2411
Abstract
Interleukin (IL)-1β is an important pro-inflammatory cytokine in the progression of osteoarthritis (OA), which impairs mitochondrial function and induces the production of nitric oxide (NO) in chondrocytes. The aim was to investigate if blockade of NO production prevents IL-1β-induced mitochondrial dysfunction in chondrocytes [...] Read more.
Interleukin (IL)-1β is an important pro-inflammatory cytokine in the progression of osteoarthritis (OA), which impairs mitochondrial function and induces the production of nitric oxide (NO) in chondrocytes. The aim was to investigate if blockade of NO production prevents IL-1β-induced mitochondrial dysfunction in chondrocytes and whether cAMP and AMP-activated protein kinase (AMPK) affects NO production and mitochondrial function. Isolated human OA chondrocytes were stimulated with IL-1β in combination with/without forskolin, L-NIL, AMPK activator or inhibitor. The release of NO, IL-6, PGE2, MMP3, and the expression of iNOS were measured by ELISA or Western blot. Parameters of mitochondrial respiration were measured using a seahorse analyzer. IL-1β significantly induced NO release and mitochondrial dysfunction. Inhibition of iNOS by L-NIL prevented IL-1β-induced NO release and mitochondrial dysfunction but not IL-1β-induced release of IL-6, PGE2, and MMP3. Enhancement of cAMP by forskolin reduced IL-1β-induced NO release and prevented IL-1β-induced mitochondrial impairment. Activation of AMPK increased IL-1β-induced NO production and the negative impact of IL-1β on mitochondrial respiration, whereas inhibition of AMPK had the opposite effects. NO is critically involved in the IL-1β-induced impairment of mitochondrial respiration in human OA chondrocytes. Increased intracellular cAMP or inhibition of AMPK prevented both IL-1β-induced NO release and mitochondrial dysfunction. Full article
(This article belongs to the Special Issue Osteoarthritis: From Molecular Pathways to Therapeutic Advances)
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Review

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22 pages, 397 KiB  
Review
Nutraceutical Approach to Chronic Osteoarthritis: From Molecular Research to Clinical Evidence
by Alessandro Colletti and Arrigo F. G. Cicero
Int. J. Mol. Sci. 2021, 22(23), 12920; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222312920 - 29 Nov 2021
Cited by 32 | Viewed by 8325
Abstract
Osteoarthritis (OA) is a degenerative inflammatory condition of the joint cartilage that currently affects approximately 58 million adults in the world. It is characterized by pain, stiffness, and a reduced range of motion with regard to the arthritic joints. These symptoms can cause [...] Read more.
Osteoarthritis (OA) is a degenerative inflammatory condition of the joint cartilage that currently affects approximately 58 million adults in the world. It is characterized by pain, stiffness, and a reduced range of motion with regard to the arthritic joints. These symptoms can cause in the long term a greater risk of overweight/obesity, diabetes mellitus, and falls and fractures. Although the current guidelines for the treatment of OA suggest, as the gold standard for this condition, pharmacological treatment characterized by non-steroidal anti-inflammatory drugs (NSAID), opioids, and cyclooxygenase (COX)-2-specific drugs, a great interest has been applied to nutraceutical supplements, which include a heterogeneous class of molecules with great potential to reduce inflammation, oxidative stress, pain, and joint stiffness and improve cartilage formation. The purpose of this review is to describe the potential application of nutraceuticals in OA, highlighting its molecular mechanisms of actions and data of efficacy and safety (when available). Full article
(This article belongs to the Special Issue Osteoarthritis: From Molecular Pathways to Therapeutic Advances)
23 pages, 3005 KiB  
Review
Cytokines and Chemokines Involved in Osteoarthritis Pathogenesis
by Vilim Molnar, Vid Matišić, Ivan Kodvanj, Roko Bjelica, Željko Jeleč, Damir Hudetz, Eduard Rod, Fabijan Čukelj, Trpimir Vrdoljak, Dinko Vidović, Mario Starešinić, Srećko Sabalić, Borut Dobričić, Tadija Petrović, Darko Antičević, Igor Borić, Rok Košir, Uršula Prosenc Zmrzljak and Dragan Primorac
Int. J. Mol. Sci. 2021, 22(17), 9208; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179208 - 26 Aug 2021
Cited by 183 | Viewed by 16543
Abstract
Osteoarthritis is a common cause of disability worldwide. Although commonly referred to as a disease of the joint cartilage, osteoarthritis affects all joint tissues equally. The pathogenesis of this degenerative process is not completely understood; however, a low-grade inflammation leading to an imbalance [...] Read more.
Osteoarthritis is a common cause of disability worldwide. Although commonly referred to as a disease of the joint cartilage, osteoarthritis affects all joint tissues equally. The pathogenesis of this degenerative process is not completely understood; however, a low-grade inflammation leading to an imbalance between anabolic and katabolic processes is a well-established factor. The complex network of cytokines regulating these processes and cell communication has a central role in the development and progression of osteoarthritis. Concentrations of both proinflammatory and anti-inflammatory cytokines were found to be altered depending on the osteoarthritis stage and activity. In this review, we analyzed individual cytokines involved in the immune processes with an emphasis on their function in osteoarthritis. Full article
(This article belongs to the Special Issue Osteoarthritis: From Molecular Pathways to Therapeutic Advances)
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20 pages, 995 KiB  
Review
Role of Physical Exercise and Nutraceuticals in Modulating Molecular Pathways of Osteoarthritis
by Alessandro de Sire, Nicola Marotta, Cinzia Marinaro, Claudio Curci, Marco Invernizzi and Antonio Ammendolia
Int. J. Mol. Sci. 2021, 22(11), 5722; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115722 - 27 May 2021
Cited by 29 | Viewed by 4913
Abstract
Osteoarthritis (OA) is a painful and disabling disease that affects millions of patients. Its etiology is largely unknown, but it is most likely multifactorial. OA pathogenesis involves the catabolism of the cartilage extracellular matrix and is supported by inflammatory and oxidative signaling pathways [...] Read more.
Osteoarthritis (OA) is a painful and disabling disease that affects millions of patients. Its etiology is largely unknown, but it is most likely multifactorial. OA pathogenesis involves the catabolism of the cartilage extracellular matrix and is supported by inflammatory and oxidative signaling pathways and marked epigenetic changes. To delay OA progression, a wide range of exercise programs and naturally derived compounds have been suggested. This literature review aims to analyze the main signaling pathways and the evidence about the synergistic effects of these two interventions to counter OA. The converging nutrigenomic and physiogenomic intervention could slow down and reduce the complex pathological features of OA. This review provides a comprehensive picture of a possible signaling approach for targeting OA molecular pathways, initiation, and progression. Full article
(This article belongs to the Special Issue Osteoarthritis: From Molecular Pathways to Therapeutic Advances)
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17 pages, 1152 KiB  
Review
Vibrational Spectroscopy in Assessment of Early Osteoarthritis—A Narrative Review
by Chen Yu, Bing Zhao, Yan Li, Hengchang Zang and Lian Li
Int. J. Mol. Sci. 2021, 22(10), 5235; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22105235 - 15 May 2021
Cited by 11 | Viewed by 3337
Abstract
Osteoarthritis (OA) is a degenerative disease, and there is currently no effective medicine to cure it. Early prevention and treatment can effectively reduce the pain of OA patients and save costs. Therefore, it is necessary to diagnose OA at an early stage. There [...] Read more.
Osteoarthritis (OA) is a degenerative disease, and there is currently no effective medicine to cure it. Early prevention and treatment can effectively reduce the pain of OA patients and save costs. Therefore, it is necessary to diagnose OA at an early stage. There are various diagnostic methods for OA, but the methods applied to early diagnosis are limited. Ordinary optical diagnosis is confined to the surface, while laboratory tests, such as rheumatoid factor inspection and physical arthritis checks, are too trivial or time-consuming. Evidently, there is an urgent need to develop a rapid nondestructive detection method for the early diagnosis of OA. Vibrational spectroscopy is a rapid and nondestructive technique that has attracted much attention. In this review, near-infrared (NIR), infrared, (IR) and Raman spectroscopy were introduced to show their potential in early OA diagnosis. The basic principles were discussed first, and then the research progress to date was discussed, as well as its limitations and the direction of development. Finally, all methods were compared, and vibrational spectroscopy was demonstrated that it could be used as a promising tool for early OA diagnosis. This review provides theoretical support for the application and development of vibrational spectroscopy technology in OA diagnosis, providing a new strategy for the nondestructive and rapid diagnosis of arthritis and promoting the development and clinical application of a component-based molecular spectrum detection technology. Full article
(This article belongs to the Special Issue Osteoarthritis: From Molecular Pathways to Therapeutic Advances)
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15 pages, 1616 KiB  
Review
Control of the Autophagy Pathway in Osteoarthritis: Key Regulators, Therapeutic Targets and Therapeutic Strategies
by Maria Teresa Valenti, Luca Dalle Carbonare, Donato Zipeto and Monica Mottes
Int. J. Mol. Sci. 2021, 22(5), 2700; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052700 - 07 Mar 2021
Cited by 21 | Viewed by 3424
Abstract
Autophagy is involved in different degenerative diseases and it may control epigenetic modifications, metabolic processes, stem cells differentiation as well as apoptosis. Autophagy plays a key role in maintaining the homeostasis of cartilage, the tissue produced by chondrocytes; its impairment has been associated [...] Read more.
Autophagy is involved in different degenerative diseases and it may control epigenetic modifications, metabolic processes, stem cells differentiation as well as apoptosis. Autophagy plays a key role in maintaining the homeostasis of cartilage, the tissue produced by chondrocytes; its impairment has been associated to cartilage dysfunctions such as osteoarthritis (OA). Due to their location in a reduced oxygen context, both differentiating and mature chondrocytes are at risk of premature apoptosis, which can be prevented by autophagy. AutophagomiRNAs, which regulate the autophagic process, have been found differentially expressed in OA. AutophagomiRNAs, as well as other regulatory molecules, may also be useful as therapeutic targets. In this review, we describe and discuss the role of autophagy in OA, focusing mainly on the control of autophagomiRNAs in OA pathogenesis and their potential therapeutic applications. Full article
(This article belongs to the Special Issue Osteoarthritis: From Molecular Pathways to Therapeutic Advances)
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21 pages, 3443 KiB  
Review
Overview of MMP-13 as a Promising Target for the Treatment of Osteoarthritis
by Qichan Hu and Melanie Ecker
Int. J. Mol. Sci. 2021, 22(4), 1742; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041742 - 09 Feb 2021
Cited by 161 | Viewed by 11271
Abstract
Osteoarthritis (OA) is a common degenerative disease characterized by the destruction of articular cartilage and chronic inflammation of surrounding tissues. Matrix metalloproteinase-13 (MMP-13) is the primary MMP involved in cartilage degradation through its particular ability to cleave type II collagen. Hence, it is [...] Read more.
Osteoarthritis (OA) is a common degenerative disease characterized by the destruction of articular cartilage and chronic inflammation of surrounding tissues. Matrix metalloproteinase-13 (MMP-13) is the primary MMP involved in cartilage degradation through its particular ability to cleave type II collagen. Hence, it is an attractive target for the treatment of OA. However, the detailed molecular mechanisms of OA initiation and progression remain elusive, and, currently, there are no interventions available to restore degraded cartilage. This review fully illustrates the involvement of MMP-13 in the initiation and progression of OA through the regulation of MMP-13 activity at the molecular and epigenetic levels, as well as the strategies that have been employed against MMP-13. The aim of this review is to identify MMP-13 as an attractive target for inhibitor development in the treatment of OA. Full article
(This article belongs to the Special Issue Osteoarthritis: From Molecular Pathways to Therapeutic Advances)
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8 pages, 1014 KiB  
Brief Report
Proteomic Analysis of the Meniscus Cartilage in Osteoarthritis
by Jisook Park, Hyun-Seung Lee, Eun-Bi Go, Ju Yeon Lee, Jin Young Kim, Soo-Youn Lee and Dae-Hee Lee
Int. J. Mol. Sci. 2021, 22(15), 8181; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158181 - 30 Jul 2021
Cited by 4 | Viewed by 2286
Abstract
The distribution of differential extracellular matrix (ECM) in the lateral and medial menisci can contribute to knee instability, and changes in the meniscus tissue can lead to joint disease. Thus, deep proteomic identification of the lateral and medial meniscus cartilage is expected to [...] Read more.
The distribution of differential extracellular matrix (ECM) in the lateral and medial menisci can contribute to knee instability, and changes in the meniscus tissue can lead to joint disease. Thus, deep proteomic identification of the lateral and medial meniscus cartilage is expected to provide important information for treatment and diagnosis of various knee joint diseases. We investigated the proteomic profiles of 12 lateral/medial meniscus pairs obtained from excess tissue of osteoarthritis patients who underwent knee arthroscopy surgery using mass spectrometry-based techniques and measured 75 ECM protein levels in the lesions using a multiple reaction monitoring (MRM) assay we developed. A total of 906 meniscus proteins with a 1% false discovery rate (FDR) was identified through a tandem mass tag (TMT) analysis showing that the lateral and medial menisci had similar protein expression profiles. A total of 131 ECM-related proteins was included in meniscus tissues such as collagen, fibronectin, and laminin. Our data showed that 14 ECM protein levels were differentially expressed in lateral and medial lesions (p < 0.05). We present the proteomic characterization of meniscal tissue with mass spectrometry-based comparative proteomic analysis and developed an MRM-based assay of ECM proteins correlated with tissue regeneration. The mass spectrometry dataset has been deposited to the MassIVE repository with the dataset identifier MSV000087753. Full article
(This article belongs to the Special Issue Osteoarthritis: From Molecular Pathways to Therapeutic Advances)
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