RESUMEN

Fourier transform infrared spectroscopy (FTIRS) can provide rich information on the composition and content of samples, enabling the detection of subtle changes in tissue composition and structure. This study represents the first application of FTIRS to investigate cartilage under microgravity. Simulated microgravity cartilage model was firstly established by tail-suspension (TS) for 7, 14 and 21 days, which would be compared to control samples. A self-developed hollow optical fiber attenuated total reflection (HOF-ATR) probe coupled with a FTIR spectrometer was used for the spectral acquisition of cartilage samples in situ, and one-way analysis of variance (ANOVA) was employed to analyze the changes in the contents of cartilage matrix at different stages. The results indicate that cartilage degenerates in microgravity, the collagen content gradually decreases with the TS time, and the structure of collagen fibers changes. The trends of proteoglycan content and collagen integrity show an initial decrease followed by an increase, ultimately significantly decreasing. The findings provide the basis for the cartilage degeneration in microgravity with TS time, which must be of real significance for space science and health detection.

Asunto(s)

Cartílago Articular , Colágeno , Simulación de Ingravidez , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Cartílago Articular/patología , Cartílago Articular/química , Cartílago Articular/metabolismo , Colágeno/análisis , Colágeno/metabolismo , Colágeno/química , Animales , Proteoglicanos/análisis , Masculino

RESUMEN

Mesenchymal stem cells (MSCs) are expected to be useful therapeutics in osteoarthritis (OA), the most common joint disorder characterized by cartilage degradation. However, evidence is limited with regard to cartilage repair in clinical trials because of the uncontrolled differentiation and weak cartilage-targeting ability of MSCs after injection. To overcome these drawbacks, here we synthesized CuO@MSN nanoparticles (NPs) to deliver Sox9 plasmid DNA (favoring chondrogenesis) and recombinant protein Bmp7 (inhibiting hypertrophy). After taking up CuO@MSN/Sox9/Bmp7 (CSB NPs), the expressions of chondrogenic markers were enhanced while hypertrophic markers were decreased in response to these CSB-engineered MSCs. Moreover, a cartilage-targeted peptide (designated as peptide W) was conjugated onto the surface of MSCs via a click chemistry reaction, thereby prolonging the residence time of MSCs in both the knee joint cavity of mice and human-derived cartilage. In a surgery-induced OA mouse model, the NP and peptide dual-modified W-CSB-MSCs showed an enhancing therapeutic effect on cartilage repair in knee joints compared with other engineered MSCs after intra-articular injection. Most importantly, W-CSB-MSCs accelerated cartilage regeneration in damaged cartilage explants derived from OA patients. Thus, this new peptide and NPs dual engineering strategy shows potential for clinical applications to boost cartilage repair in OA using MSC therapy.

Asunto(s)

Diferenciación Celular , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Nanopartículas , Osteoartritis , Péptidos , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Animales , Osteoartritis/terapia , Osteoartritis/patología , Nanopartículas/química , Humanos , Diferenciación Celular/efectos de los fármacos , Péptidos/química , Trasplante de Células Madre Mesenquimatosas/métodos , Condrogénesis/efectos de los fármacos , Ratones , Factor de Transcripción SOX9/metabolismo , Factor de Transcripción SOX9/genética , Cartílago Articular/patología , Cartílago Articular/efectos de los fármacos , Proteína Morfogenética Ósea 7/química , Proteína Morfogenética Ósea 7/farmacología , Ingeniería de Tejidos/métodos , Regeneración/efectos de los fármacos

RESUMEN

Articular cartilage phenotypic homeostasis is crucial for life-long joint function, but the underlying cellular and molecular mechanisms governing chondrocyte stability remain poorly understood. Here, we show that the protein tyrosine phosphatase SHP2 is differentially expressed in articular cartilage (AC) and growth plate cartilage (GPC) and that it negatively regulates cell proliferation and cartilage phenotypic program. Postnatal SHP2 deletion in Prg4+ AC chondrocytes increased articular cellularity and thickness, whereas SHP2 deletion in Acan+ pan-chondrocytes caused excessive GPC chondrocyte proliferation and led to joint malformation post-puberty. These observations were verified in mice and in cultured chondrocytes following treatment with the SHP2 PROTAC inhibitor SHP2D26. Further mechanistic studies indicated that SHP2 negatively regulates SOX9 stability and transcriptional activity by influencing SOX9 phosphorylation and promoting its proteasome degradation. In contrast to published work, SHP2 ablation in chondrocytes did not impact IL-1-evoked inflammation responses, and SHP2's negative regulation of SOX9 could be curtailed by genetic or chemical SHP2 inhibition, suggesting that manipulating SHP2 signaling has translational potential for diseases of cartilage dyshomeostasis.

Asunto(s)

Cartílago Articular , Condrocitos , Osteoartritis , Proteína Tirosina Fosfatasa no Receptora Tipo 11 , Factor de Transcripción SOX9 , Factor de Transcripción SOX9/metabolismo , Factor de Transcripción SOX9/genética , Animales , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Condrocitos/metabolismo , Condrocitos/patología , Ratones , Cartílago Articular/metabolismo , Cartílago Articular/patología , Osteoartritis/metabolismo , Osteoartritis/patología , Proliferación Celular , Células Cultivadas , Ratones Endogámicos C57BL , Ratones Noqueados , Masculino

RESUMEN

Osteoarthritis (OA) is an age-related disease characterized by inflammation, pain, articular cartilage damage, synovitis, and irreversible disability. Gynostemma pentaphyllum (Thunb.) Makino (GP), a herbal medicine traditionally used in East Asia for its anti-inflammatory properties, was investigated for its potential to modulate OA pathology and symptoms. This study evaluated GP's efficacy in inhibiting pain, functional decline, and cartilage destruction in monosodium iodoacetate-induced OA and acetic acid-induced writhing models. Additionally, the effects of GP on OA-related inflammatory targets were assessed via mRNA and protein expression in rat knee cartilage and lipopolysaccharide-induced RAW 264.7 cells. The GP group demonstrated significant pain relief, functional improvement, and cartilage protection. Notably, GP inhibited key inflammatory mediators, including interleukin (IL)-1ß, IL-6, matrix metalloproteinases (MMP)-3 and MMP-13, cyclooxygenase-2, and prostaglandin E receptor 2, surpassing the effects of active controls. These findings suggest that GP is a promising candidate for disease-modifying OA drugs and warrants further comprehensive studies.

Asunto(s)

Analgésicos , Antiinflamatorios , Gynostemma , Osteoartritis , Extractos Vegetales , Animales , Gynostemma/química , Ratones , Osteoartritis/tratamiento farmacológico , Osteoartritis/patología , Osteoartritis/inducido químicamente , Osteoartritis/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Células RAW 264.7 , Ratas , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Analgésicos/farmacología , Analgésicos/uso terapéutico , Masculino , Cartílago Articular/efectos de los fármacos , Cartílago Articular/patología , Cartílago Articular/metabolismo , Modelos Animales de Enfermedad , Ratas Sprague-Dawley , Dolor/tratamiento farmacológico

RESUMEN

BACKGROUND: Osteoarthritis (OA) is a prevalent degenerative disease. We explored the role and regulatory mechanisms of lncRNA-FAS-AS1 in OA progression. METHODS: We exposed human immortalized chondrocytes to IL-1ß for 24 h to induce an OA cell model. The target molecule levels were assessed using western blot and quantitative real-time PCR (RT-qPCR). Cell viability and apoptosis were measured using CCK-8 and flow cytometry. The m6A modification of FAS-AS1 was determined using MeRIP. We examined the binding relationships between FAS-AS1, Fragile X mental retardation 1 (FMR1), and A disintegrin and metalloproteinase 8 (ADAM8) using RIP and RNA pull-down. The OA animal model was established by separating the medial collateral ligament and medial meniscus. Safranin-O staining and Mankin's scale were employed to evaluate pathological changes within the cartilage. RESULTS: FAS-AS1, METTL14, and ADAM8 were upregulated, and the JAK/STAT3 signaling pathway was activated in OA mice and IL-1ß-induced chondrocytes. FAS-AS1 knockdown inhibited extracellular matrix degradation in IL-1ß-induced chondrocytes; however, ADAM8 overexpression reversed this effect. FAS-AS1 maintained the stability of ADAM8 mRNA by recruiting FMR1. METTL14 knockdown repressed FAS-AS1 expression in an m6A-dependent manner. FAS-AS1 overexpression reversed the inhibitory effects of METTL14 knockdown on JAK/STAT3 signaling and cartilage damage in the OA model both in vitro and in vivo. CONCLUSION: METTL14-mediated FAS-AS1 promotes OA progression through the FMR1/ADAM8/JAK/STAT3 axis.

Asunto(s)

Proteínas ADAM , Condrocitos , Progresión de la Enfermedad , Proteínas de la Membrana , ARN Largo no Codificante , Factor de Transcripción STAT3 , Transducción de Señal , Regulación hacia Arriba , Animales , Humanos , Masculino , Ratones , Proteínas ADAM/metabolismo , Proteínas ADAM/genética , Adenosina/análogos & derivados , Apoptosis , Artritis Experimental/metabolismo , Artritis Experimental/genética , Artritis Experimental/patología , Cartílago Articular/metabolismo , Cartílago Articular/patología , Línea Celular , Condrocitos/metabolismo , Condrocitos/patología , Modelos Animales de Enfermedad , Interleucina-1beta/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Metiltransferasas/metabolismo , Metiltransferasas/genética , Ratones Endogámicos C57BL , Osteoartritis/metabolismo , Osteoartritis/genética , Osteoartritis/patología , Osteoartritis de la Rodilla/metabolismo , Osteoartritis de la Rodilla/genética , Osteoartritis de la Rodilla/patología , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/genética

RESUMEN

Osteoarthritis is a degenerative joint disease with joint pain as the main symptom, caused by fibrosis and loss of articular cartilage. Due to the complexity and heterogeneity of osteoarthritis, there is a lack of effective individualized disease-modifying osteoarthritis drugs in clinical practice. Chondrocyte senescence is reported to participate in occurrence and progression of osteoarthritis. Here we show that small molecule 10-hydroxy-2-decenoic acid suppresses cartilage degeneration and relieves pain in the chondrocytes, cartilage explants from osteoarthritis patients, surgery-induced medial meniscus destabilization or naturally aged male mice. We further confirm that 10-hydroxy-2-decenoic acid exerts a protective effect by targeting the glycosylation site in the Asp_Arg_Hydrox domain of aspartyl ß-hydroxylase. Mechanistically, 10-hydroxy-2-decenoic acid alleviate cellular senescence through the ERK/p53/p21 and GSK3ß/p16 pathways in the chondrocytes. Our study uncovers that 10-hydroxy-2-decenoic acid modulate cartilage metabolism by targeting aspartyl ß-hydroxylase to inhibit chondrocyte senescence in osteoarthritis. 10-hydroxy-2-decenoic acid may be a promising therapeutic drug against osteoarthritis.

Asunto(s)

Cartílago Articular , Senescencia Celular , Condrocitos , Ácidos Grasos Monoinsaturados , Osteoartritis , Animales , Condrocitos/efectos de los fármacos , Condrocitos/metabolismo , Condrocitos/patología , Masculino , Osteoartritis/metabolismo , Osteoartritis/patología , Osteoartritis/tratamiento farmacológico , Osteoartritis/prevención & control , Ratones , Senescencia Celular/efectos de los fármacos , Humanos , Ácidos Grasos Monoinsaturados/farmacología , Cartílago Articular/efectos de los fármacos , Cartílago Articular/metabolismo , Cartílago Articular/patología , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Femenino

RESUMEN

Osteoarthritis (OA) is the most common form of arthritic disease, and phenotypic modification of chondrocytes is an important mechanism that contributes to the loss of cartilage homeostasis. This study identified that Fascin actin-bundling protein 1 (FSCN1) plays a pivotal role in regulating chondrocytes phenotype and maintaining cartilage homeostasis. Proteome-wide screening revealed markedly upregulated FSCN1 protein expression in human OA cartilage. FSCN1 accumulation was confirmed in the superficial layer of OA cartilage from humans and mice, primarily in dedifferentiated-like chondrocytes, associated with enhanced actin stress fiber formation and upregulated type I and III collagens. FSCN1-inducible knockout mice exhibited delayed cartilage degeneration following experimental OA surgery. Mechanistically, FSCN1 promoted actin polymerization and disrupted the inhibition of Decorin on TGF-ß1, leading to excessive TGF-ß1 production and ALK1/Smad1/5 signaling activation, thus, accelerated chondrocyte dedifferentiation. Intra-articular injection of FSCN1-overexpressing adeno-associated virus exacerbated OA progression in mice, which was mitigated by an ALK1 inhibitor. Moreover, FSCN1 inhibitor NP-G2-044 effectively reduced extracellular matrix degradation in OA mice, cultured human OA chondrocytes, and cartilage explants by suppressing ALK1/Smad1/5 signaling. These findings suggest that targeting FSCN1 represents a promising therapeutic approach for OA.

Asunto(s)

Proteínas Portadoras , Condrocitos , Proteínas de Microfilamentos , Osteoartritis , Animales , Humanos , Masculino , Ratones , Proteínas Portadoras/metabolismo , Proteínas Portadoras/genética , Cartílago Articular/metabolismo , Cartílago Articular/patología , Condrocitos/metabolismo , Condrocitos/patología , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Microfilamentos/genética , Proteínas de Microfilamentos/metabolismo , Osteoartritis/patología , Osteoartritis/metabolismo , Osteoartritis/genética , Fenotipo , Receptores Odorantes , Transducción de Señal

RESUMEN

Osteoarthritis (OA) is a chronic joint disease characterized by the degeneration, destruction, and excessive ossification of articular cartilage. The prevalence of OA is rising annually, concomitant with the aging global population and increasing rates of obesity. This condition imposes a substantial and escalating burden on individual health, healthcare systems, and broader social and economic frameworks. The etiology of OA is multifaceted and not fully understood. Current research suggests that the death of chondrocytes, encompassing mechanisms such as cellular apoptosis, pyroptosis, autophagy, ferroptosis and cuproptosis, contributes to both the initiation and progression of the disease. These cell death pathways not only diminish the population of chondrocytes but also exacerbate joint damage through the induction of inflammation and other deleterious processes. This paper delineates the morphological characteristics associated with various modes of cell death and summarizes current research results on the molecular mechanisms of different cell death patterns in OA. The objective is to review the advancements in understanding chondrocyte cell death in OA, thereby offering novel insights for potential clinical interventions.

Asunto(s)

Muerte Celular , Condrocitos , Progresión de la Enfermedad , Osteoartritis , Condrocitos/patología , Humanos , Osteoartritis/patología , Osteoartritis/terapia , Muerte Celular/fisiología , Apoptosis/fisiología , Cartílago Articular/patología , Autofagia/fisiología , Animales , Piroptosis/fisiología , Ferroptosis/fisiología

RESUMEN

The study aims to elucidate the therapeutic mechanism of Baicalin (BAI) in alleviating cartilage injury in osteoarthritic (OA) rat models, concentrating on its regulation of the miR-766-3p/AIFM1 axis. An OA rat model was developed with unilateral anterior cruciate ligament transection (ACLT). Interventions comprised of BAI treatment and intra-articular administration of miR-766-3p inhibitor. For evaluation, histopathological staining was conducted to investigate the pathological severity of knee cartilage injury. The levels of oxidative stress (OS) indicators including MDA, SOD, and GSH-Px, were quantified using colorimetric assays. Inflammatory factors (IFs; TNF-?, IL-1?, and IL-6) in knee joint lavage fluids were assessed using ELISA, while RT-PCR was employed to quantify miR-766-3p expression. TUNEL apoptosis staining was utilized to detect chondrocyte apoptosis, and western blotting examined autophagy-related markers (LC3, Beclin, p62), extracellular matrix (ECM) synthesis-associated indices (COL2A, ACAN, MMP13), and apoptosis-inducing factor mitochondrion-associated 1 (AIFM1). Histological examination revealed a marked amelioration of cartilage injury in the BAI-treated OA rat models compared to controls. BAI treatment significantly reduced inflammation and OS of knee joint fluid, activated autophagy, and decreased chondrocyte apoptosis and ECM degradation. Interestingly, the inhibitory effects of BAI on these pathological markers were significantly decreased by the miR-766-3p inhibitor. Further assessment revealed that BAI efficiently promoted miR-766-3p expression while inhibiting AIFM1 protein expression. BAI potentially mitigates articular cartilage injury in OA rats, likely through modulation of miR-766-3p/AIFM1 axis. Keywords: Baicalin, microRNA, AIFM1, Osteoarthritisv, Rat.

Asunto(s)

Flavonoides , MicroARNs , Ratas Sprague-Dawley , Animales , Flavonoides/farmacología , Flavonoides/uso terapéutico , MicroARNs/metabolismo , MicroARNs/genética , MicroARNs/biosíntesis , Ratas , Masculino , Osteoartritis/tratamiento farmacológico , Osteoartritis/metabolismo , Osteoartritis/patología , Cartílago Articular/efectos de los fármacos , Cartílago Articular/metabolismo , Cartílago Articular/patología , Factor Inductor de la Apoptosis/metabolismo , Estrés Oxidativo/efectos de los fármacos , Apoptosis/efectos de los fármacos

RESUMEN

OBJECTIVE: The aim of this study was to investigate whether ASA VI controls osteoarthritis (OA) by regulating mitochondrial function. METHODS: Primary chondrocytes were isolated and cultured from rat knee joints. The chondrocytes were treated with ASA VI and interleukin-1ß (IL-1ß) to simulate the inflammatory environment of OA. Cell viability, apoptosis, inflammatory cytokine levels, and extracellular matrix (ECM) component levels were assessed. Mitochondrial function, including ATP levels, mitochondrial membrane potential, reactive oxygen species (ROS) levels, and mitochondrial DNA content, was evaluated. The expression of Sirtuin 3 (Sirt3), a key regulator of mitochondrial homeostasis, was examined. Additionally, a rat OA model was established by destabilizing the medial meniscus, and the effects of ASA VI on cartilage degeneration were assessed. RESULTS: ASA VI treatment improved cell viability, reduced apoptosis, and decreased IL-6 and TNF-α levels in IL-1ß-induced chondrocytes. ASA VI also upregulated Collagen II and Aggrecan expression, while downregulating ADAMTS5 and MMP-13 expression. Furthermore, ASA VI mitigated IL-1ß-induced mitochondrial dysfunction by increasing ATP levels, restoring mitochondrial membrane potential, reducing ROS production, and preserving mitochondrial DNA content. These effects were accompanied by the activation of Sirt3. In the rat OA model, ASA VI treatment increased Sirt3 expression and alleviated cartilage degeneration. CONCLUSION: ASA VI exerts chondroprotective and anti-inflammatory effects on IL-1ß-induced chondrocytes by improving mitochondrial function through Sirt3 activation. ASA VI also attenuates cartilage degeneration in a rat OA model. These findings suggest that ASA VI may be a potential therapeutic agent for the treatment of osteoarthritis by targeting mitochondrial dysfunction.

Asunto(s)

Condrocitos , Homeostasis , Mitocondrias , Osteoartritis , Saponinas , Sirtuina 3 , Animales , Masculino , Ratones , Ratas , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Apoptosis/efectos de los fármacos , Cartílago Articular/patología , Cartílago Articular/metabolismo , Cartílago Articular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Condrocitos/efectos de los fármacos , Condrocitos/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Interleucina-1beta/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Osteoartritis/tratamiento farmacológico , Osteoartritis/metabolismo , Osteoartritis/patología , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Sirtuina 3/metabolismo , Sirtuina 3/genética , Saponinas/farmacología

RESUMEN

BACKGROUND: Juvenile osteochondritis dissecans of the knee joint is the most common osteochondral lesion during growth, usually occurring between the 10th and 14th year of age. PATHOGENESIS: Repetitive microtraumata lead to a subchondral osseus lesion, which is commonly located at the medial aspect of the femoral condyle. Sport activities are considered to be the main cause, although genetic and hereditary factors as well as vitamin D3 deficiency also play a role. Current classification systems distinguish between stable and unstable osteochondral lesions, which is decisive for further treatment. TREATMENT: Stable lesions may heal through conservative treatment by avoiding weight bearing and sport. Unstable lesions, on the other hand, can lead to a complete defect of the joint surface with the formation of a free joint body. In such cases, various surgical techniques aim at reconstructing the surface of the joint, in order to reduce the risk of secondary arthritis.

Asunto(s)

Articulación de la Rodilla , Osteocondritis Disecante , Osteocondritis Disecante/genética , Osteocondritis Disecante/patología , Humanos , Articulación de la Rodilla/patología , Adolescente , Masculino , Femenino , Traumatismos de la Rodilla/patología , Traumatismos de la Rodilla/complicaciones , Niño , Cartílago Articular/patología

RESUMEN

Osteoarthritis (OA) is a prevalent cause of joint algesia, loss of function, and disability in adults, with cartilage injury being its core pathological manifestation. Since cartilage damage is non-renewable, the treatment outcome in the middle and late stages of OA is unsatisfactory, which can be minimized by changing lifestyle and other treatment modalities if diagnosed and managed in the early stages, indicating the importance of early diagnosis and monitoring of cartilage injury. Ultrasound technology has been used for timely diagnosis and even cartilage injury treatment, which is convenient and safe for the patient owing to no radiation exposure. Studies have demonstrated the effectiveness of ultrasound and its various quantitative ultrasound parameters, like ultrasound roughness index (URI), reflection coefficient (R), apparent integrated backscatter (AIB), thickness, and ultrasound elastography, in the early and accurate assessment of OA cartilage pathological changes, including surface and internal tissue, hardness, and thickness. Although many challenges are faced in the clinical application of this technology in diagnosis, ultrasound and ultrasound-assisted techniques offer a lot of promise for detecting early cartilage damage in OA. In this review, we have discussed the evaluation of ultrasonic cartilage quantitative parameters for early pathological cartilage changes.

Asunto(s)

Cartílago Articular , Osteoartritis , Ultrasonografía , Humanos , Osteoartritis/diagnóstico por imagen , Ultrasonografía/métodos , Cartílago Articular/diagnóstico por imagen , Cartílago Articular/patología

RESUMEN

Osteoarthritis (OA) is a common joint disease associated with the aging of the population, and it reduces the quality of life of patients. It is characterized by the destruction of articular cartilage and the secretion of inflammatory cytokines. Owing to the unclear pathogenesis of OA, current treatment methods have significant limitations. Oxidative stress has been revealed to play an important role in the development of OA. Our experiments indicated that the levels of GSH decreased and the level of MDA increased in chondrocytes, which induced ferroptosis in chondrocytes in OA. We also revealed that ferroptosis was the main mechanism of cartilage destruction caused by the addition of the ferroptosis activator erastin and the ferroptosis inhibitor ferrostatin-1. NOX1 is the main modulator of oxidative stress by increasing the generation of reactive oxidative species (ROS). We suppressed the expression of NOX1 in chondrocytes through cell transfection. The expression of collagen II and MMP13, and the secretion of IL-1ß and TNF-α were reversed. An increase in the mitochondrial membrane potential and a decrease in the level of intracellular ROS indicate an improvement in oxidative damage. Additionally, we determined the effect of the Nrf2/HO-1 pathway on NOX1-mediated chondrocyte injury. We found that NOX1 inhibited the expression of Nrf2/HO-1, but the activation of Nrf2 improved the oxidative damage to chondrocytes in vivo and vitro. This study revealed that NOX1-mediated oxidative stress induces chondrocyte ferroptosis by inhibiting the Nrf2/HO-1 pathway. Our findings contribute to revealing the pathogenesis of OA, providing targets for drug design and optimizing the clinical treatment of OA.

Asunto(s)

Condrocitos , Ferroptosis , Hemo-Oxigenasa 1 , NADPH Oxidasa 1 , Factor 2 Relacionado con NF-E2 , Osteoartritis , Estrés Oxidativo , Especies Reactivas de Oxígeno , Transducción de Señal , Condrocitos/metabolismo , Ferroptosis/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Animales , NADPH Oxidasa 1/metabolismo , NADPH Oxidasa 1/genética , Hemo-Oxigenasa 1/metabolismo , Ratones , Osteoartritis/metabolismo , Osteoartritis/patología , Especies Reactivas de Oxígeno/metabolismo , Ciclohexilaminas/farmacología , Masculino , Cartílago Articular/metabolismo , Cartílago Articular/patología , Humanos , Proteínas de la Membrana , Fenilendiaminas

RESUMEN

Temporomandibular joint osteoarthritis (TMJOA) is considered to be a low-grade inflammatory disease involving multiple joint tissues. The crosstalk between synovium and cartilage plays an important role in TMJOA. Synovial cells are a group of heterogeneous cells and synovial microenvironment is mainly composed of synovial fibroblasts (SF) and synovial macrophages. In TMJOA, SF and synovial macrophages release a large number of inflammatory cytokines and extracellular vesicles and promote cartilage destruction. Cartilage wear particles stimulate SF proliferation and macrophages activation and exacerbate synovitis. In TMJOA, chondrocytes and synovial cells exhibit increased glycolytic activity and lactate secretion, leading to impaired chondrocyte matrix synthesis. Additionally, the synovium contains mesenchymal stem cells, which are the seed cells for cartilage repair in TMJOA. Co-culture of chondrocytes and synovial mesenchymal stem cells enhances the chondrogenic differentiation of stem cells. This review discusses the pathological changes of synovium in TMJOA, the means of crosstalk between synovium and cartilage, and their influence on each other. Based on the crosstalk between synovium and cartilage in TMJOA, we illustrate the treatment strategies for improving synovial microenvironment, including reducing cell adhesion, utilizing extracellular vesicles to deliver biomolecules, regulating cellular metabolism and targeting inflammatory cytokines.

Asunto(s)

Microambiente Celular , Condrocitos , Osteoartritis , Membrana Sinovial , Articulación Temporomandibular , Humanos , Osteoartritis/metabolismo , Osteoartritis/patología , Osteoartritis/terapia , Condrocitos/metabolismo , Condrocitos/patología , Membrana Sinovial/metabolismo , Membrana Sinovial/patología , Animales , Articulación Temporomandibular/metabolismo , Articulación Temporomandibular/patología , Trastornos de la Articulación Temporomandibular/metabolismo , Trastornos de la Articulación Temporomandibular/patología , Trastornos de la Articulación Temporomandibular/terapia , Células Madre Mesenquimatosas/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patología , Citocinas/metabolismo , Macrófagos/metabolismo , Cartílago Articular/metabolismo , Cartílago Articular/patología

RESUMEN

Connexin 43 (Cx43) is crucial for the development and homeostasis of the musculoskeletal system, where it plays multifaceted roles, including intercellular communication, transcriptional regulation and influencing osteogenesis and chondrogenesis. Here, we investigated Cx43 modulation mediated by inflammatory stimuli involved in osteoarthritis, i.e., 10 ng/mL Tumor Necrosis Factor alpha (TNFα) and/or 1 ng/mL Interleukin-1 beta (IL-1ß), in primary chondrocytes (CH) and osteoblasts (OB). Additionally, we explored the impact of synovial fluids from osteoarthritis patients in CH and cartilage explants, providing a more physio-pathological context. The effect of TNFα on Cx43 expression in cartilage explants was also assessed. TNFα downregulated Cx43 levels both in CH and OB (-73% and -32%, respectively), while IL-1ß showed inconclusive effects. The reduction in Cx43 levels was associated with a significant downregulation of the coding gene GJA1 expression in OB only (-65%). The engagement of proteasome in TNFα-induced effects, already known in CH, was also observed in OB. TNFα treatment significantly decreased Cx43 expression also in cartilage explants. Of note, Cx43 expression was halved by synovial fluid in both CH and cartilage explants. This study unveils the regulation of Cx43 in diverse musculoskeletal cell types under various stimuli and in different contexts, providing insights into its modulation in inflammatory joint disorders.

Asunto(s)

Condrocitos , Conexina 43 , Interleucina-1beta , Osteoartritis , Osteoblastos , Factor de Necrosis Tumoral alfa , Humanos , Conexina 43/metabolismo , Conexina 43/genética , Condrocitos/metabolismo , Osteoblastos/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Interleucina-1beta/metabolismo , Interleucina-1beta/farmacología , Osteoartritis/metabolismo , Osteoartritis/patología , Osteoartritis/genética , Líquido Sinovial/metabolismo , Cartílago Articular/metabolismo , Cartílago Articular/patología , Células Cultivadas , Anciano , Persona de Mediana Edad , Inflamación/metabolismo , Inflamación/genética , Inflamación/patología , Cartílago/metabolismo , Cartílago/patología , Artropatías/metabolismo , Artropatías/patología , Artropatías/genética

RESUMEN

Vitamin A derivatives have inhibitory effects on cartilage tissue, such as decreasing chondrocyte proliferation and collagen synthesis, and increasing the loss of glycosaminoglycans and proteoglycans. Therefore, isotretinoin (a vitamin A derivative) may play a role in the pathogenesis of cartilage-related diseases like osteoarthritis by affecting the balance of cartilage tissue. The aim of this study was to evaluate the distal femoral cartilage thickness in acne patients under the systemic isotretinoin therapy and to determine whether it constitutes a risk factor for the development of osteoarthritis. The study included 52 patients (42 female, 10 male, mean age 23.31 ± 3.89 years) who were prescribed systemic isotretinoin for acne and completed at least 3 months of treatment, along with 45 healthy controls ((35 female, 10 male, mean age 23.85 ± 4.77 years). Bilateral distal femoral cartilage thickness was measured by ultrasonography before isotretinoin treatment and after the completion of the third month of treatment. After treatment, a statistically significant increase was found in the thickness of the right medial, right lateral, left medial, left lateral, and left intercondylar cartilage (p = 0.014, 0.012, 0.019, 0.027, 0.002, respectively). There was also an increase in the right intercondylar cartilage thickness, but this was not statistically significant (p = 0.1). Systemic isotretinoin seems to make cartilage thicker. The increase in femoral cartilage thickness observed after short-term isotretinoin treatment might be an indicator of very early-stage osteoarthritis. Extended follow-up studies with larger participant pools are necessary to substantiate this result.

Asunto(s)

Acné Vulgar , Cartílago Articular , Fémur , Isotretinoína , Humanos , Isotretinoína/efectos adversos , Isotretinoína/uso terapéutico , Isotretinoína/administración & dosificación , Femenino , Masculino , Acné Vulgar/tratamiento farmacológico , Acné Vulgar/patología , Acné Vulgar/diagnóstico , Adulto , Adulto Joven , Cartílago Articular/patología , Cartílago Articular/efectos de los fármacos , Cartílago Articular/diagnóstico por imagen , Fémur/diagnóstico por imagen , Fémur/efectos de los fármacos , Fémur/patología , Ultrasonografía , Fármacos Dermatológicos/efectos adversos , Fármacos Dermatológicos/uso terapéutico , Fármacos Dermatológicos/administración & dosificación , Osteoartritis/tratamiento farmacológico , Osteoartritis/patología , Osteoartritis/diagnóstico por imagen , Factores de Riesgo , Estudios de Casos y Controles

RESUMEN

Osteoarthritis (OA) pain is often associated with the expression of tumor necrosis factor alpha (TNF-α), suggesting that TNF-α is one of the main contributing factors that cause inflammation, pain, and OA pathology. Thus, inhibition of TNF-α could potentially improve OA symptoms and slow disease progression. Anti-TNF-α treatments with antibodies, however, require multiple treatments and cannot entirely block TNF-α. TNF-α-induced protein 8-like 2 (TIPE2) was found to regulate the immune system's homeostasis and inflammation through different mechanisms from anti-TNF-α therapies. With a single treatment of adeno-associated virus (AAV)-TIPE2 gene delivery in the accelerated aging Zmpste24-/- (Z24-/-) mouse model, we found differences in Safranin O staining intensity within the articular cartilage (AC) region of the knee between TIPE2-treated mice and control mice. The glycosaminoglycan content (orange-red) was degraded in the Z24-/- cartilage while shown to be restored in the TIPE2-treated Z24-/- cartilage. We also observed that chondrocytes in Z24-/- mice exhibited a variety of senescent-associated phenotypes. Treatment with TIPE2 decreased TNF-α-positive cells, ß-galactosidase (ß-gal) activity, and p16 expression seen in Z24-/- mice. Our study demonstrated that AAV-TIPE2 gene delivery effectively blocked TNF-α-induced inflammation and senescence, resulting in the prevention or delay of knee OA in our accelerated aging Z24-/- mouse model.

Asunto(s)

Senescencia Celular , Dependovirus , Modelos Animales de Enfermedad , Terapia Genética , Inflamación , Péptidos y Proteínas de Señalización Intracelular , Osteoartritis , Progeria , Animales , Ratones , Osteoartritis/terapia , Osteoartritis/genética , Osteoartritis/metabolismo , Osteoartritis/etiología , Osteoartritis/patología , Senescencia Celular/genética , Inflamación/genética , Inflamación/metabolismo , Inflamación/terapia , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Terapia Genética/métodos , Progeria/genética , Progeria/terapia , Progeria/metabolismo , Dependovirus/genética , Envejecimiento , Cartílago Articular/metabolismo , Cartílago Articular/patología , Técnicas de Transferencia de Gen , Vectores Genéticos/administración & dosificación , Vectores Genéticos/genética , Condrocitos/metabolismo , Ratones Noqueados , Factor de Necrosis Tumoral alfa/metabolismo , Humanos

RESUMEN

BACKGROUND: Osteoarthritis (OA) is a chronic and degenerative joint disease that remains a great challenge in treatment due to the lack of effective therapies. 4-octyl itaconate (4-OI) is a novel and potent modulator of inflammation for the treatment of inflammatory disease. However, the clinical usage of 4-OI is limited due to its poor solubility and low bioavailability. As a promising drug delivery strategy, injectable hydrogels offers an effective approach to address these limitations of 4-OI. OBJECTIVE: The aim of the study was to verify that the composite 4-OI/SA hydrogels could achieve a controlled release of 4-OI and reduce damage to articular cartilage in the group of osteoarthritic rats treated with the system. METHODS: In this study, an injectable composite hydrogel containing sodium alginate (SA) and 4-octyl itaconate (4-OI) has been developed for continuous intra-articular administration in the treatment of OA. RESULTS: After intra-articular injection in arthritic rats, the as-prepared 4-OI/SA hydrogel containing of 62.5 µM 4-OI effectively significantly reduced the expression of TNF-α, IL-1ß, IL-6 and MMP3 in the ankle fluid. Most importantly, the as-prepared 4-OI/SA hydrogel system restored the morphological parameters of the ankle joints close to normal. CONCLUSION: 4-OI/SA hydrogel shows a good anti-inflammatory activity and reverse cartilage disruption, which provide a new strategy for the clinical treatment of OA.

Asunto(s)

Alginatos , Antiinflamatorios , Preparaciones de Acción Retardada , Hidrogeles , Osteoartritis , Ratas Sprague-Dawley , Succinatos , Animales , Hidrogeles/química , Alginatos/química , Succinatos/química , Succinatos/farmacología , Antiinflamatorios/administración & dosificación , Antiinflamatorios/química , Antiinflamatorios/farmacología , Antiinflamatorios/farmacocinética , Preparaciones de Acción Retardada/química , Osteoartritis/tratamiento farmacológico , Osteoartritis/patología , Ratas , Masculino , Inyecciones Intraarticulares , Cartílago Articular/efectos de los fármacos , Cartílago Articular/patología , Cartílago Articular/metabolismo

RESUMEN

Osteoarthritis (OA) is a chronic and progressive degenerative disease that affects joint structures, such as the hips, knees, and hands, involving the articular cartilage, subchondral bone, ligaments, capsule, and synovium. OA is characterized by a progressive degeneration of the joint structures, resulting in pain and decreased quality of life. Local and systemic risk factors pave the way for OA development. Different phenotypes may be identified, but three main molecular mechanisms define the endotypes: the bone-driven endotype, the synovitis-driven endotype, and the cartilage-driven endotype. The hallmark of OA pathophysiology involves more than just mechanical degradation; it includes the release of pro-inflammatory mediators, such as interleukins and TNF-α, which elucidates the significant roles of metabolic syndrome, diabetes, and cellular senescence in its development. OA is distinguished by a clinical presentation that varies significantly between people and is marked by pain, stiffness, and functional impairments. The clinical course can be split into Pre-OA, Early OA, Evident OA, and End-Stage. Depending on the stage of the disease, OA diagnosis frequently necessitates a complex strategy that combines clinical evaluation to detect joint tenderness, range of motion, and joint swelling or abnormalities, medical history assessment, imaging modalities, and laboratory investigations. There is no known treatment for OA, and different therapies are usually evaluated based on the stage of the disease to minimize pain and stiffness while maintaining joint function. Treatments are divided into the reduction of modifiable risk factors, pharmacologic therapies, rehabilitation, complementary therapies, interventional pain procedures, and surgery. OA clinical heterogeneity underlines the importance of prevention, early diagnosis, and identifying the phenotype and endotype to tailor the treatment.

Asunto(s)

Osteoartritis , Humanos , Osteoartritis/terapia , Osteoartritis/diagnóstico , Osteoartritis/fisiopatología , Factores de Riesgo , Articulaciones/patología , Articulaciones/fisiopatología , Cartílago Articular/patología , Cartílago Articular/metabolismo

RESUMEN

BACKGROUND: Cam morphology develops during skeletal growth, but its influence on cartilage and the labrum in high-impact athletes later in life is unknown. PURPOSE: To (1) explore the association between the presence and duration of cam morphology during adolescence and the cartilage and labral status 7 to 12 years later and (2) report the prevalence of cartilage loss and labral damage in a population of young male athletes (<32 years old) who played professional soccer during skeletal growth. STUDY DESIGN: Cohort study (Prognosis); Level of evidence, 2. METHODS: A total of 89 healthy male academy soccer players from the Dutch soccer club Feyenoord (aged 12-19 years) were included at baseline. At baseline and 2.5- and 5-year follow-ups, standardized supine anteroposterior pelvis and frog-leg lateral radiographs of each hip were obtained. At 12-year follow-up, magnetic resonance imaging of both hips was performed. Cam morphology was defined by a validated alpha angle ≥60° on radiographs at baseline or 2.5- or 5-year follow-up when the growth plates were closed. Hips with the presence of cam morphology at baseline or at 2.5-year follow-up were classified as having a "longer duration" of cam morphology. Hips with cam morphology only present since 5-year follow-up were classified as having a "shorter duration" of cam morphology. At 12-year follow-up, cartilage loss and labral abnormalities were assessed semiquantitatively. Associations were estimated using logistic regression, adjusted for age and body mass index. RESULTS: Overall, 35 patients (70 hips) with a mean age of 28.0 ± 2.0 years and mean body mass index of 24.1 ± 1.8 participated at 12-year follow-up. Cam morphology was present in 56 of 70 hips (80%). The prevalence of cartilage loss was 52% in hips with cam morphology and 21% in hips without cam morphology (adjusted odds ratio, 4.52 [95% CI, 1.16-17.61]; P = .03). A labral abnormality was present in 77% of hips with cam morphology and in 64% of hips without cam morphology (adjusted odds ratio, 1.99 [95% CI, 0.59-6.73]; P = .27). The duration of cam morphology did not influence these associations. CONCLUSION: The development of cam morphology during skeletal growth was associated with future magnetic resonance imaging findings consistent with cartilage loss in young adults but not with labral abnormalities.

Asunto(s)

Cartílago Articular , Fútbol , Humanos , Masculino , Adolescente , Estudios Prospectivos , Adulto Joven , Estudios de Seguimiento , Fútbol/lesiones , Cartílago Articular/diagnóstico por imagen , Cartílago Articular/crecimiento & desarrollo , Cartílago Articular/patología , Niño , Imagen por Resonancia Magnética , Adulto , Desarrollo Óseo , Radiografía , Atletas , Pinzamiento Femoroacetabular/diagnóstico por imagen , Articulación de la Cadera/diagnóstico por imagen , Articulación de la Cadera/crecimiento & desarrollo