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The discovery of new pharmacological agents is needed to control the progression of osteoarthritis (OA), characterized by joint cartilage damage. Human OA chondrocyte (OAC) cultures were either applied to S-allylcysteine (SAC), a sulfur-containing amino acid derivative, or colchicine, an ancient anti-inflammatory therapeutic, for 24 h. SAC or colchicine did not change viability at 1 nM-10 [micro]M but inhibited p-JNK/pan-JNK. While SAC seems to be more effective, both agents inhibited reactive oxygen species (ROS), 3-nitrotyrosine (3-NT), lipid hydroperoxides (LPO), advanced lipoxidation end-products (ALEs as 4-hydroxy-2-nonenal, HNE), advanced glycation end-products (AGEs), and increased glutathione peroxidase (GPx) and type-II-collagen (COL2). IL-1[beta], IL-6, and osteopontin (OPN) were more strongly inhibited by SAC than by colchicine. In contrast, TNF-[alpha] was inhibited only by SAC, and COX2 was only inhibited by colchicine. Casp-1/ICE, GM-CSF, receptor for advanced glycation end-products (RAGE), and toll-like receptors (TLR4) were inhibited by both agents, but bone morphogenetic protein 7 (BMP7) was partially inhibited by SAC and induced by colchicine. Nuclear factor erythroid 2-related factor 2 (Nrf2) was induced by SAC; in contrast, it was inhibited by colchicine. Although they exert opposite effects on TNF-[alpha], COX2, BMP7, and Nrf2, SAC and colchicine exhibit anti-osteoarthritic properties in OAC by modulating redox-sensitive inflammatory signaling. Key words: osteoarthritis, chondrocytes, S-allylcysteine, colchicine, toll-like receptor-4, redox signaling, inflammation, nuclear factor erythroid 2-related factor 2, oxidative stress. La découverte de nouveaux agents pharmacologiques est nécessaire pour contrôler la progression de l'ostéoarthrite (OA) caractérisée par des dommages progressifs du cartilage articulaire. Des cultures de chondrocytes humains atteints d'OA (COA) ont été traitées à la S-allylcystéine (SAC), un dérivé d'acide aminé contenant du soufre, ou à la colchicine, un ancien traitement anti-inflammatoire, pendant 24 heures. La SAC ou la colchicine ne modifiaient pas la viabilité des cellules à des concentrations allant de 1 nM à 10 [micro]m, mais inhibaient p-JNK/pan-JNK. Bien que la SAC semble plus efficace, les deux agents inhibaient les dérivés réactifs de l'oxygène (DRO), la 3-nitrotyrosine (3-NT), les hydroperoxydes de lipides (LPO), les produits finaux de la lipoxydation avancée (ALE, comme le 4-hydroxy-2-nonenal, HNE) et les produits finaux de la glycation avancée (AGE), et augmentaient la glutathion-peroxydase (GPx) et le collagène de type-II (COL2). L'IL-1[beta], l'IL-6 et l'ostéopontine (OPN) étaient plus fortement inhibées par la SAC que par la colchicine. Cependant, le TNF-[alpha] était inhibé uniquement par la SAC, et la COX2, uniquement par la colchicine. La Casp-1/ICE, le GM-CSF, le récepteur pour les produits finaux de glycation avancée (RAGE) et les récepteurs << toll-like >> (TLR4) étaient inhibés par les deux agents, mais la protéine morphogénétique osseuse 7 (BMP7) était partiellement inhibée par la SAC alors qu'elle était induite par la colchicine. Le facteur nucléaire Nrf2 était induit par la SAC; en revanche, il était inhibé par la colchicine. Bien qu'exerçant des effets opposés sur le TNF-[alpha], la COX2, la BMP7 et le Nrf2, la SAC et la colchicine présentent des propriétés anti-ostéoarthrose chez les COA en modulant la signalisation inflammatoire sensible à l'état redox. [Traduit par la Rédaction] Mots-clés : ostéoarthrite, chondrocytes, S-allylcystéine, colchicine, récepteur de type péage-4, signalisation redox, inflammation, nucléaire facteur 2 lié au facteur érythroïde 2, stress oxydant., Introduction Osteoarthritis (OA) is the most common age-related progressive and disabling joint disease characterized by inflammation and erosion of articular cartilage (Kolasinski et al. 2020). Although OA is a leading [...]

Osteoarthritis--the most common form of age-related degenerative whole-joint disease.sup.1--is primarily characterized by cartilage destruction, as well as by synovial inflammation, osteophyte formation and subchondral bone remodelling.sup.2,3. However, the molecular mechanisms that underlie the pathogenesis of osteoarthritis are largely unknown. Although osteoarthritis is currently considered to be associated with metabolic disorders, direct evidence for this is lacking, and the role of cholesterol metabolism in the pathogenesis of osteoarthritis has not been fully investigated.sup.4-6. Various types of cholesterol hydroxylases contribute to cholesterol metabolism in extrahepatic tissues by converting cellular cholesterol to circulating oxysterols, which regulate diverse biological processes.sup.7,8. Here we show that the CH25H-CYP7B1-ROR[alpha] axis of cholesterol metabolism in chondrocytes is a crucial catabolic regulator of the pathogenesis of osteoarthritis. Osteoarthritic chondrocytes had increased levels of cholesterol because of enhanced uptake, upregulation of cholesterol hydroxylases (CH25H and CYP7B1) and increased production of oxysterol metabolites. Adenoviral overexpression of CH25H or CYP7B1 in mouse joint tissues caused experimental osteoarthritis, whereas knockout or knockdown of these hydroxylases abrogated the pathogenesis of osteoarthritis. Moreover, retinoic acid-related orphan receptor alpha (ROR[alpha]) was found to mediate the induction of osteoarthritis by alterations in cholesterol metabolism. These results indicate that osteoarthritis is a disease associated with metabolic disorders and suggest that targeting the CH25H-CYP7B1-ROR[alpha] axis of cholesterol metabolism may provide a therapeutic avenue for treating osteoarthritis.In experimentally induced osteoarthritis, chondrocytes show increased uptake and metabolism of cholesterol, implicating the CH25H-CYP7B1-ROR[alpha] axis in the pathogenesis of osteoarthritis., Author(s): Wan-Su Choi [sup.1] , Gyuseok Lee [sup.1] [sup.2] , Won-Hyun Song [sup.2] , Jeong-Tae Koh [sup.2] , Jiye Yang [sup.1] , Ji-Sun Kwak [sup.1] , Hyo-Eun Kim [sup.1] , [...]

Osteoarthritis (OA) is a degenerative disease characterized by synovial inflammation. MiR-18a-3p was reported to be downregulated in knee anterior cruciate ligament of OA patients. In the present study, the specific functions and mechanism of miR-18a-3p in OA were explored. An in vitro model of OA was established using 10 ng/ml IL-1[beta] to treat ATDC5 cells, and medial meniscus instability surgery was performed on Wistar rats to establish in vivo rat model of OA. RT-qPCR revealed that miR-18a-3p was downregulated in IL-1[beta]-stimulated ATDC5 cells. MiR-18a-3p overexpression inhibited secretion of inflammatory cytokines and concentration of matrix metalloproteinases, as shown by ELISA and western blotting. The binding relation between miR-18a-3p and pyruvate dehydrogenase phosphatase catalytic subunit 1 (PDP1) was detected by luciferase reporter assays. MiR-18a-3p targeted PDP1 and negatively regulated PDP1 expression. Results of rescue assays revealed that PDP1 upregulation reserved the suppressive effect of miR-18a-3p overexpression on levels of inflammatory cytokines and matrix metalloproteinases in IL-1[beta]-stimulated ATDC5 cells. H&E staining was used to observe pathological changes of synovial tissues in the knee joint of Wistar rats. Safranin O-fast green/hematoxylin was used to stain cartilage samples of knee joints. MiR-18a-3p overexpression suppressed OA progression in vivo. Overall, miR-18a-3p improves cartilage matrix remodeling and suppresses inflammation in OA by targeting PDP1. Keywords: OA, miR-18a-3p, PDP1, Chondrocyte, Inflammation, Author(s): Xiaoguang Feng[sup.1], Jiajun Lu[sup.1], Yixiong Wu[sup.1] and Haiyun Xu[sup.1] Introduction Osteoarthritis (OA) is an articular joint disease with high morbidity in the elderly people [1]. From 2005 to 2015, [...]

Danshen (Salvia miltiorrhiza) is a traditional Chinese medicine herb that can alleviate the symptoms of osteoarthritis (OA) (Soder et al. 2006) in animals. However, the underlying mechanisms remain poorly understood and require further investigation. In this study, rabbits with experimentally induced OA were given an intra-articular injection of danshen (0.7 mL/day) for 5 weeks. In addition to attenuating the cartilage degeneration of OA in the rabbits, danshen decreased the expression and activity of matrix metalloproteinase 9 (MMP-9) and MMP-13, and increased the expression of their natural inhibitors: tissue inhibitor of matrix metalloproteinase 1 (TIMP-1) and TIMP-2. Apoptosis in osteoarthritic cartilage tissues was attenuated by danshen, accompanied with increased expression of B cell lymphoma 2 (Bcl-2) and decreased levels of Bcl-2-associated X protein (Bax). Further, danshen inhibited the nuclear accumulation of nuclear factor kappa-B (NF-[kappa]B) p65 in osteoarthritic cartilage. The therapeutic effects of danshen in vivo were comparable to that of sodium hyaluronate, which is a drug used clinically for the treatment OA. In vitro, sodium nitroprusside (SNP) was used to stimulate apoptosis in primary rabbit chondrocytes. We found that the SNP-induced apoptosis was mitigated by danshen. BAY11-7028, an inhibitor of the NF-[kappa]B pathway, augmented danshen's anti-apoptotic effects in cells exposed to SNP. When these results are considered together, they indicate that danshen alleviates the cartilage injury in rabbit OA through inhibition of the NF-[kappa]B signaling pathway. Key words: osteoarthritis, danshen, cartilage degradation, apoptosis, NF-[kappa]B signaling pathway. Resume : Le danshen est une herbe medicinale traditionnelle chinoise qui peut soulager les symptomes de l'osteoarthrite (OA) chez l'animal (Soder et al. 2006). Cependant, les mecanismes sous-jacents demeurent peu compris et necessitent d'etre etudies davantage. Dans cette etude, des lapins ayant developpe une OA experimental ont recu une injection intra-articulaire de danshen (0.7 mL/jour) pendant 5 semaines. En plus d'attenuer la degenerescence du cartilage chez les lapins O.A., le danshen diminuait l'expression et l'activite de la metalloprotease matricielle 9 (MMP-9) et de MMP-13, alors qu'il augmentait celles de leurs inhibiteurs naturels, l'inhibiteur tissulaire des MMP1 (TIMP-1) et TIMP-2. L'apoptose des tissus du cartilage osteo-arthritique etait attenuee par le danshen, ce qui etait accompagne de l'augmentation de l'expression de Bcl-2 (B cell lymphoma 2) et d'une diminution de l'expression de Bax (Bcl-2-associated X protein). De plus, le danshen inhibait l'accumulation nucleaire de la sous-unite p65 du facteur nucleaire kappa-B (NF-[kappa]B) dans les cartilages osteo-arthritiques. Les effets therapeutiques du danshen in vivo etaient comparables a ceux de l'hyaluronate de sodium, un medicament utilise en clinique pour l'OA In vitro, le nitroprussiate de sodium (SNP) a ete utilise pour stimuler l'apoptose de chondrocytes primaires de lapin. Les auteurs ont trouve que l'apoptose induite par le SNP etait attenuee par le danshen. Le BAY11-7028, un inhibiteur de la voie du NF-[kappa]B, accroissait les effets anti-apoptotiques du danshen chez les cellules exposees au SNP. Globalement, le danshen attenue le dommage au cartilage cause par l'OA chez les lapins, au moins par l'inhibition de la voie de signalisation du NF-[kappa]B. [Traduit par la Redaction] Mots-cles: osteoarthrite, danshen, degradation du cartilage, apoptose, voie de signalisation du NF-[kappa]B., Introduction Osteoarthritis (OA) (Soder et al. 2006) is a common joint disease accompanied with pain and disability, and about 15% of the world's population suffers from OA (Huskisson 2008). OA [...]

The effect of acute osteoarthritis (OA) on peripheral nerve fibers (NFs) in synovial tissue, and their association with histological changes were investigated in collagenase-induced OA mice. Collagenase (10 U in 5 µL saline) was injected into the right knee, and the same volume of saline was injected into the left knee as the control. Mice were sacrificed 1, 2, 3, and 4 weeks after the collagenase injection. Histopathological changes in the knee joints were evaluated. The numbers of protein gene product (PGP) 9.5-, calcitonin-gene-related peptide (CGRP)-, and substance P (SP)-positive NFs in the synovial tissue were determined, and their densities in the tissue were calculated. The densities of PGP 9.5- and CGRP-positive NFs in the synovium were drastically decreased 1 week after the collagenase injection. However, by week 4, the density of PGP 9.5- and CGRP-positive NFs had recovered to 84% and 79% of their normal levels, respectively. Despite the poor correlation between the synovitis score and the density of CGRP- or SP-positive NFs in the synovium, the ossification rate of chondrophytes in chondro/osteophyte lesions correlated strongly with the density of CGRP-positive NFs (R = 0.855). These results suggest that the ossification of chondrophytes occurred in parallel with the increase in CGRP-positive fiber density in the synovium during the acute phase of collagenase-induced OA. Key words: calcitonin gene-related peptide, ossification, osteoarthritis, osteophyte, peripheral nerve fibers, substance P, synovium. Nous avons etudie les effets de l'arthrose aigue sur les fibres nerveuses peripheriques dans le tissu synovial et leur association a des modifications histologiques dans un modele d'arthrose aigue induite par la collagenase chez la souris. La collagenase (10 U dans 5 µL de solution saline) a ete injectee dans le genou droit, et le meme volume de solution saline a ete injecte dans le genou gauche comme temoin. Les souris ont ete sacrifiees aux semaines 1, 2, 3 ou 4 apres l'injection de collagenase. Les modifications histopathologiques ont ete evaluees dans les genoux. Les nombres de fibres nerveuses presentant des produits de proteines exprimees par les genes (PGP) 9.5, des peptides lies au gene de la calcitonine (CGRP) et de la substance P (SP) dans le tissu synovial ont ete determines et leurs densites tissulaires, calculees. Une semaine apres l'injection de collagenase, les densites de fibres nerveuses presentant des PGP 9.5 et des CGRP dans la synovie etaient diminuees de facon marquee. Cependant, a la semaine 4, la densite des fibres nerveuses presentant des PGP 9.5 et des CGRP s'etait retablie a 84 et 79 % de leurs valeurs normales, respectivement. En depit de la mauvaise correlation entre le score de synovite et la densite des fibres nerveuses presentant des CGRP ou de la SP dans la synovie, le taux d'ossification des chondrophytes au sein des lesions chondrales-osteophytiques etaient fortement correles avec la densite des fibres nerveuses presentant des CGRP (R = 0,855). Ces resultats laissent entendre que l'ossification des chrondrophytes s'est etendue en parallele avec l'augmentation de la densite des fibres nerveuses presentant des CGRP dans la synovie pendant la phase aigue de l'arthrose aigue induite par la collagenase. [Traduit par la Redaction] Mots-cles : peptide lie au gene de la calcitonine, ossification, arthrose, osteophyte, fibres nerveuses peripheriques, substance P, synovie., Introduction Osteoarthritis (OA) is the most common musculoskeletal disease (Pelletier et al. 2006). Various pathological changes can be seen in OA, such as cartilage erosion, ulceration, sclerosis of the subchondral [...]

Osteoarthritis (OA) is a chronic degenerative joint disorder. Previous studies have shown abnormally increased apoptosis of chondrocytes in patients and animal models of OA. TNF-a and nitric oxide have been reported to induce chondrocyte ageing; however, the mechanism of chondrocyte apoptosis induced by IL-1β has remained unclear. The aim of this study is to identify the role of the c-Jun N-terminal kinase (JNK) - c-Jun pathway in regulating induction of Bim, and its implication in chondrocyte apoptosis. This study showed that Bim is upregulated in chondrocytes obtained from the articular cartilage of OA patients and in cultured mouse chondrocytes treated with IL-1β. Upregulation of Bim was found to be critical for chondrocyte apoptosis induced by IL-1β, as revealed by the genetic knockdown of Bim, wherein apoptosis was greatly reduced in the chondrocytes. Moreover, activation of the JNK-c-Jun pathway was observed under IL-1β treatment, as indicated by the increased expression levels of c-Jun protein. Suppression of the JNK-c-Jun pathway, using chemical inhibitors and RNA interference, inhibited the Bim upregulation induced by IL-1β. These findings suggest that the JNK-c-Jun pathway is involved in the upregulation of Bim during OA and that the JNK-c-Jun-Bim pathway is vital for chondrocyte apoptosis. Key words: JNK-c-Jun, Bim, osteoarthritis, apoptosis. L'osteoarthrite (OA) est une maladie degenerative chronique des articulations. Des etudes anterieures ont montre la presence d'une apoptose des chondrocytes anormalement elevee chez les patients et dans des modeles animaux d'OA. On rapporte que le TNF-a et l'oxyde nitrique induisent le vieillissement des chondrocytes ; toutefois, le mecanisme responsable de l'induction de l'apoptose des chondrocytes par l'IL-1β demeure flou. Le but de cette etude consiste a identifier le role de la voie JNK-c-Jun dans la regulation de l'induction de Bim, et son implication dans l'apoptose des chondrocytes. L'etude presente a montre que Bim est regule a la hausse chez les chondrocytes obtenus de cartilages articulaires de patients atteints d'OA et les chondrocytes de souris en culture traites a l'IL-1β. La regulation a la hausse de Bim s'est averee importante dans l'apoptose des chondrocytes induite par l'IL-1β, comme l'a revele l'ablation genetique de Bim qui reduisait grandement l'apoptose des chondrocytes. De plus, l'activation de la voie JNK-c-Jun etait observee lors d'un traitement a l'IL-1β, tel qu'indique par les niveaux accrus d'expression de c-Jun. La suppression de la voie JNK-c-Jun a l'aide d'inhibiteurs chimiques et de l'interference a l'ARN a conduit a l'inhibition de la regulation a la hausse de Bim induite par l'IL-1β. Ces donnees suggerent que la voie JNK-c-Jun est impliquee dans la regulation a la hausse de Bim en situation d'OA et que la voie JNK-c-Jun-Bim est cruciale a l'apoptose des chondrocytes. [Traduit par la Redaction] Mots-cles: JNK-c-Jun, Bim, osteoarthrite, apoptose., Introduction Osteoarthritis (OA) is the most widespread joint disorder, involving the degradation of articular cartilage and subchondral bone. It is characterized by pain, tenderness, limitation of movement, crepitus, and intra-articular [...]