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.
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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/genéticaRESUMEN
Mechanosensitive ion channel Piezo1 is known to mediate a variety of inflammatory pathways and is also involved in the occurrence and development of many orthopedic diseases. Although its role in the inflammatory mechanism of knee osteoarthritis (KOA) has been reported, a systematic explanation is yet to be seen. This article aims to summarize the role of inflammatory responses in the pathogenesis of KOA and elucidate the mechanism by which the Piezo1-mediated inflammatory response contributes to the pathogenesis of KOA, providing a theoretical basis for the prevention and treatment of knee osteoarthritis. The results indicate that in the mechanism leading to knee osteoarthritis, Piezo1 can mediate the inflammatory response through chondrocytes and synovial cells, participating in the pathological progression of KOA. Piezo1 has the potential to become a new target for the prevention and treatment of this disease. Additionally, as pain is one of the most severe manifestations in KOA patients, the inflammatory response mediated by Piezo1, which causes the release of inflammatory mediators and pro-inflammatory factors leading to pain, can be further explored.
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Inflamación , Canales Iónicos , Osteoartritis de la Rodilla , Canales Iónicos/metabolismo , Humanos , Osteoartritis de la Rodilla/metabolismo , Osteoartritis de la Rodilla/patología , Inflamación/metabolismo , Animales , Condrocitos/metabolismo , Mecanotransducción CelularRESUMEN
OBJECTIVE: This study aims to quantitatively assess the relationship between the patella alignment and morphology and knee osteoarthritis (KOA), as well as the kinematics and kinetics of the knee, using gait analysis. METHODS: Eighty age-matched patients with KOA and control subjects were evaluated. Incident radiographic osteoarthritis (iROA) was identified using a Kellgren-Lawrence (KL) grade of ≥ 2. The modified Insall-Salvati ratio (Mod-ISR), patellar tilt angle (PTA), and patella index (PI) were utilized to evaluate the sagittal and transverse alignment of the patella and its morphology, respectively. Regression analyses were conducted to explore associations between patellar measurements and KOA, iROA, kinematics, and kinetics. RESULTS: Significant differences were observed between the control and KOA groups in terms of KL grade, patella alta, abduction angle, and reaction force to the ground (P < 0.05, respectively). Following adjustment for covariates, a significant positive association was found between patella alta and KOA (OR = 0.307, 95%CI: 0.103 to 0.918, P = 0.035). Additionally, a significant negative association was observed between PTA and abduction angle (B = -0.376, 95%CI: -0.751 to -0.002; P = 0.049). The PI exhibited a statistically significant association with log-transformed vertical ground reaction force (B = 0.002, 95%CI: 0.001 to 0.003, P = 0.002). Furthermore, adjustment for covariates did not reveal any significant correlations with other indicators (P > 0.05, respectively). CONCLUSION: This study provides further evidence that proper alignment and morphology of the patella might be associated with maintaining normal biomechanical function. In addition, intervention measures targeting relevant patellar parameters, such as Mod-ISR, PTA, and PI, may positively impact KOA treatment outcomes.
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Osteoartritis de la Rodilla , Rótula , Humanos , Osteoartritis de la Rodilla/diagnóstico por imagen , Osteoartritis de la Rodilla/fisiopatología , Osteoartritis de la Rodilla/patología , Rótula/diagnóstico por imagen , Rótula/patología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Fenómenos Biomecánicos , Marcha/fisiologíaRESUMEN
The (patho)physiological function of the sphingolipids ceramide-1-phosphate (C1P), sphingosine-1-phosphate (S1P), and sphingosylphosphorylcholine (SPC) in articular joints during osteoarthritis (OA) is largely unknown. Therefore, we investigated the influence of these lipids on protein expression by fibroblast-like synoviocytes (FLSs) from OA knees. Cultured human FLSs (n = 7) were treated with 1 of 3 lipid species-C1P, S1P, or SPC-IL-1ß, or with vehicle. The expression of individual proteins was determined by tandem mass tag peptide labeling followed by high-resolution electrospray ionization (ESI) mass spectrometry after liquid chromatographic separation (LC-MS/MS/MS). The mRNA levels of selected proteins were analyzed using RT-PCR. The 3sphingolipids were quantified in the SF of 18 OA patients using LC-MS/MS. A total of 4930 proteins were determined using multiplex MS, of which 136, 9, 1, and 0 were regulated both reproducibly and significantly by IL-1ß, C1P, S1P, and SPC, respectively. In the presence of IL-1ß, all 3 sphingolipids exerted ancillary effects. Only low SF levels of C1P and SPC were found. In conclusion, the 3 lipid species regulated proteins that have not been described in OA. Our results indicate that charged multivesicular body protein 1b, metal cation symporter ZIP14, glutamine-fructose-6-P transaminase, metallothionein-1F and -2A, ferritin, and prosaposin are particularly interesting proteins due to their potential to affect inflammatory, anabolic, catabolic, and apoptotic mechanisms.
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Ceramidas , Fibroblastos , Lisofosfolípidos , Proteómica , Esfingosina , Sinoviocitos , Humanos , Sinoviocitos/metabolismo , Sinoviocitos/patología , Lisofosfolípidos/metabolismo , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Proteómica/métodos , Fibroblastos/metabolismo , Ceramidas/metabolismo , Esfingolípidos/metabolismo , Femenino , Células Cultivadas , Masculino , Anciano , Interleucina-1beta/metabolismo , Espectrometría de Masas en Tándem , Persona de Mediana Edad , Osteoartritis/metabolismo , Osteoartritis/patología , Osteoartritis/genética , Osteoartritis de la Rodilla/metabolismo , Osteoartritis de la Rodilla/patología , Osteoartritis de la Rodilla/genética , Fosforilcolina/análogos & derivadosRESUMEN
This study aimed to investigate whether the beneficial effects of PCA on chondrocyte senescence are mediated through the regulation of mitophagy. Chondrocyte senescence plays a significant role in the development and progression of knee osteoarthritis (OA). The compound protocatechuic aldehyde (PCA), which is abundant in the roots of Salvia miltiorrhiza, has been reported to have antioxidant properties and the ability to protect against cellular senescence. To achieve this goal, a destabilization of the medial meniscus (DMM)-induced mouse OA model and a lipopolysaccharide (LPS)-induced chondrocyte senescence model were used, in combination with PINK1 gene knockdown or overexpression. After treatment with PCA, cellular senescence was assessed using Senescence-Associated ß-Galactosidase (SA-ß-Gal) staining, DNA damage was evaluated using Hosphorylation of the Ser-139 (γH2AX) staining, reactive oxygen species (ROS) levels were measured using Dichlorodihydrofluorescein diacetate (DCFH-DA) staining, mitochondrial membrane potential was determined using a 5,5',6,6'-TETRACHLORO-1,1',3,3'-*. TETRAETHYBENZIMIDA (JC-1) kit, and mitochondrial autophagy was examined using Mitophagy staining. Western blot analysis was also performed to detect changes in senescence-related proteins, PINK1/Parkin pathway proteins, and mitophagy-related proteins. Our results demonstrated that PCA effectively reduced chondrocyte senescence, increased the mitochondrial membrane potential, facilitated mitochondrial autophagy, and upregulated the PINK1/Parkin pathway. Furthermore, silencing PINK1 weakened the protective effects of PCA, whereas PINK1 overexpression enhanced the effects of PCA on LPS-induced chondrocytes. PCA attenuates chondrocyte senescence by regulating PINK1/Parkin-mediated mitochondrial autophagy, ultimately reducing cartilage degeneration.
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Benzaldehídos , Catecoles , Senescencia Celular , Condrocitos , Mitofagia , Proteínas Quinasas , Ubiquitina-Proteína Ligasas , Condrocitos/efectos de los fármacos , Condrocitos/metabolismo , Condrocitos/patología , Animales , Senescencia Celular/efectos de los fármacos , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Mitofagia/efectos de los fármacos , Proteínas Quinasas/metabolismo , Ratones , Catecoles/farmacología , Benzaldehídos/farmacología , Especies Reactivas de Oxígeno/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/patología , Masculino , Ratones Endogámicos C57BL , Autofagia/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Osteoartritis de la Rodilla/patología , Osteoartritis de la Rodilla/metabolismo , Osteoartritis de la Rodilla/tratamiento farmacológicoRESUMEN
This study aimed to assess the clinical efficacy of umbilical cord mesenchymal stem cells (hUC-MSCs) from different passages (P3, P8, and P13) in the treatment of knee osteoarthritis (OA) and explore the underlying mechanisms. The hUC-MSCs from each passage were characterized and evaluated for their stemness, migration, proliferation, and marker expression. Rats with OA were treated with hUC-MSCs from each passage, and the therapeutic effects were assessed based on knee swelling, discomfort, and pathological examination of the knee joint. Co-culture experiments were conducted to examine the ability of hUC-MSCs to stimulate type II collagen synthesis and inhibit MMP13 expression in chondrocytes. Telomere length and telomerase activity of hUC-MSCs from each passage were measured to investigate the reasons for the observed differences in clinical efficacy. The results revealed that P3 and P8 hUC-MSCs exhibited superior osteogenic and chondrogenic differentiation potential compared to P13, while P13 demonstrated stronger adipogenic differentiation. The wound healing rate was significantly higher in the P3 and P8 groups compared to P13. All hUC-MSC groups expressed high levels of CD90 and CD105, indicating their mesenchymal stem cell characteristics, while CD31 and CD45 were not expressed. CD105 expression was significantly reduced in the P13 group. In the treatment of rat osteoarthritis, there were no significant differences in knee swelling, discomfort, Mankin scores, and pathological findings between P3 and P8 hUC-MSC treatments. However, there was a significant difference between the 8th and 13th passages. Co-culture experiments showed that hUC-MSCs from P3 and P8 enhanced type II collagen synthesis and reduced MMP13 expression in chondrocytes. Although no significant difference was observed between the P3 and P8 groups, a significant difference was found between the P13 and P8 groups. Telomere length analysis revealed that P13 samples had significantly shorter telomeres compared to both P3 and P8. The telomerase activity was positive in P3 and P8 hUC-MSCs, indicating no significant difference between these passages, while it was negative in P13 hUC-MSCs. In conclusion, P3 and P8 hUC-MSCs exhibited superior therapeutic potential for knee osteoarthritis compared to P13, possibly due to their enhanced differentiation capacity and telomerase activity.
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Diferenciación Celular , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Cordón Umbilical , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/citología , Animales , Humanos , Cordón Umbilical/citología , Ratas , Osteoartritis de la Rodilla/terapia , Osteoartritis de la Rodilla/patología , Osteoartritis de la Rodilla/metabolismo , Masculino , Condrocitos/metabolismo , Condrocitos/citología , Ratas Sprague-Dawley , Osteoartritis/terapia , Osteoartritis/patología , Osteoartritis/metabolismo , Telomerasa/metabolismo , Técnicas de Cocultivo , Proliferación Celular , Osteogénesis , CondrogénesisRESUMEN
INTRODUCTION: Osteoarthritis (OA) is a chronic inflammatory disease where pro-inflammatory cytokines, damage-associated molecular patterns and macrophages play a crucial role. However, the interaction of these mediators, the exact cause, and the treatment of knee osteoarthritis (KOA) are still unclear. Moreover, the interaction of interleukin (IL)-33, platelet-derived growth factor-BB (PDGF-BB), and matrix metalloproteinase-9 (MMP-9) with other factors in the pathogenesis of KOA has not been elaborately explored. METHOD: Therefore, in this study, we analyzed the expression of IL-33, PDGF-BB, and MMP-9 in the knee cartilage tissue of model mice, murine KOA was induced by using the destabilization of the medial meniscus (DMM) model. RESULTS: Compared with the sham operation control group, the expression levels of PDGF-BB, IL-33, and MMP-9 were increased significantly, and the pathological sections showed obvious cartilage damage. Additionally, we assessed the levels of IL-33 and MMP-9 expression in the knee joint of KOA model mice following intervention with PDGF-BB antibody, and we found that the expression level of MMP-9 was reduced following intervention with IL-33 antibody. When the effects of the three antibodies were compared in a mouse disease model, it was discovered that the IL-33 antibody could dramatically lower the relative expression level of MMP-9, resulting in the least amount of cartilage damage and improved protection. In conclusion, inhibiting IL-33 can significantly lower inflammatory factor levels in the knee joint, including IL-33 and MMP-9, and it can improve cartilage breakdown in osteoarthritis of the knee. CONCLUSION: Overall, the results indicate that IL-33 has a therapeutic function in the treatment of knee osteoarthritis and may be a novel target for treatment of the underlying causes of KOA. Additionally, PDGF-BB might be an upstream pathway of IL-33, and KOA's MMP-9 is an downstream pathway of IL-33.
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Modelos Animales de Enfermedad , Interleucina-33 , Metaloproteinasa 9 de la Matriz , Osteoartritis de la Rodilla , Animales , Interleucina-33/metabolismo , Osteoartritis de la Rodilla/metabolismo , Osteoartritis de la Rodilla/patología , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Becaplermina/metabolismo , Cartílago Articular/patología , Cartílago Articular/metabolismo , Masculino , Ratones Endogámicos C57BL , Proteínas Proto-Oncogénicas c-sis/metabolismoRESUMEN
Knee osteoarthritis (KOA) is a chronic joint disease that significantly affects the health of the elderly. As an herbal remedy, Gubi decoction (GBD) has been traditionally used for the treatment of osteoarthritis-related syndromes. However, the anti-KOA efficacy and mechanism of GBD remain unclear. This study aimed to experimentally investigate the anti-KOA efficacy and the underlying mechanism of GBD. The medial meniscus (DMM) mice model and IL-1ß-stimulated chondrocytes were, respectively, constructed as in vivo and in vitro models of KOA to evaluate the osteoprotective effect and molecular mechanism of GBD. The UPLC-MS/MS analysis showed that GBD mainly contained pinoresinol diglucoside, rehmannioside D, hesperidin, liquiritin, baohuoside I, glycyrrhizic acid, kaempferol and tangeretin. Animal experiment showed that GBD could alleviate articular cartilage destruction and recover histopathological alterations in DMM mice. In addition, GBD inhibited chondrocyte apoptosis and restored DMM-induced dysregulated autophagy evidenced by the upregulation of ATG7 and LC3 II/LC3 I but decreased P62 level. Mechanistically, METTL3-mediated m6A modification decreased the expression of ATG7 in DMM mice, as it could be significantly attenuated by GBD. METTL3 overexpression significantly counteracted the protective effect of GBD on chondrocyte autophagy. Further research showed that GBD promoted proteasome-mediated ubiquitination degradation of METLL3. Our findings suggest that GBD could act as a protective agent against KOA. The protective effect of GBD may result from its promotion on chondrocyte autophagy by suppressing METTL3-dependent ATG7 m6A methylation.
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Proteína 7 Relacionada con la Autofagia , Autofagia , Condrocitos , Metiltransferasas , Osteoartritis de la Rodilla , Animales , Condrocitos/metabolismo , Condrocitos/efectos de los fármacos , Autofagia/efectos de los fármacos , Osteoartritis de la Rodilla/metabolismo , Osteoartritis de la Rodilla/patología , Osteoartritis de la Rodilla/tratamiento farmacológico , Ratones , Proteína 7 Relacionada con la Autofagia/metabolismo , Proteína 7 Relacionada con la Autofagia/genética , Metiltransferasas/metabolismo , Metilación/efectos de los fármacos , Masculino , Medicamentos Herbarios Chinos/farmacología , Modelos Animales de Enfermedad , Apoptosis/efectos de los fármacos , Ratones Endogámicos C57BL , Adenosina/análogos & derivados , Adenosina/farmacología , Adenosina/metabolismo , Humanos , Cartílago Articular/metabolismo , Cartílago Articular/efectos de los fármacos , Cartílago Articular/patologíaRESUMEN
Background: Knee osteoarthritis is a common, degenerative joint disease that causes chronic pain that affects daily life. Our study aims to evaluate geriatric patients aged 65 and over with knee pain in terms of osteoarthritis with radiography and magnetic resonance imaging and to investigate its relationship with meniscal pathologies. Methods: Radiography and magnetic resonance imaging of patients aged 65-88 years with knee pain were evaluated in terms of knee osteoarthritis and staging was performed. Meniscal pathologies were evaluated in magnetic resonance imaging, and the prevalence of different meniscal lesion types was calculated. In addition, the relationship between knee osteoarthritis and meniscal pathologies was analyzed. Results: Radiographic evidence of knee osteoarthritis was found in 182 (84.2%) of the 216 cases in our study group. A strong correlation was found between the degrees of knee osteoarthritis on magnetic resonance imaging and radiography. At least one meniscus pathology was observed in all 182 radiography cases with knee osteoarthritis findings. At least one meniscus pathology was observed in 29 (85.3%) of those without osteoarthritis signs. It was determined that meniscus degeneration, tear, and extrusion were observed more frequently in patients with knee osteoarthritis than in patients without osteoarthritis. Meniscal extrusion and complex and horizontaltype tears were the most common lesions. Conclusions: Osteoarthritis was found to be common in geriatric patients with knee pain. A correlation was found between radiography and magnetic resonance imaging regarding knee osteoarthritis. It was observed that meniscal pathologies were detected more frequently in patients with knee osteoarthritis.
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Imagen por Resonancia Magnética , Meniscos Tibiales , Osteoartritis de la Rodilla , Radiografía , Humanos , Osteoartritis de la Rodilla/diagnóstico por imagen , Osteoartritis de la Rodilla/patología , Anciano , Femenino , Masculino , Anciano de 80 o más Años , Meniscos Tibiales/diagnóstico por imagen , Meniscos Tibiales/patología , Articulación de la Rodilla/diagnóstico por imagen , Articulación de la Rodilla/patología , Prevalencia , Lesiones de Menisco Tibial/diagnóstico por imagen , Lesiones de Menisco Tibial/complicaciones , Menisco/diagnóstico por imagen , Menisco/patologíaRESUMEN
BACKGROUND: Synovial fibrosis is a common complication of knee osteoarthritis (KOA), a pathological process characterized by myofibroblast activation and excessive extracellular matrix (ECM) deposition. Fibroblast-like synoviocytes (FLSs) are implicated in KOA pathogenesis, contributing to synovial fibrosis through diverse mechanisms. Nuclear protein 1 (NUPR1) is a recently identified transcription factor with crucial roles in various fibrotic diseases. However, its molecular determinants in KOA synovial fibrosis remain unknown. This study aims to investigate the role of NUPR1 in KOA synovial fibrosis through in vivo and in vitro experiments. METHODS: We examined NUPR1 expression in the murine synovium and determined the impact of NUPR1 on synovial fibrosis by knockdown models in the destabilization of the medial meniscus (DMM)-induced KOA mouse model. TGF-ß was employed to induce fibrotic response and myofibroblast activation in mouse FLSs, and the role and molecular mechanisms in synovial fibrosis were evaluated under conditions of NUPR1 downexpression. Additionally, the pharmacological effect of NUPR1 inhibitor in synovial fibrosis was assessed using a surgically induced mouse KOA model. RESULTS: We found that NUPR1 expression increased in the murine synovium after DMM surgical operation. The adeno-associated virus (AAV)-NUPR1 shRNA promoted NUPR1 deficiency, attenuating synovial fibrosis, inhibiting synovial hyperplasia, and significantly reducing the expression of pro-fibrotic molecules. Moreover, the lentivirus-mediated NUPR1 deficiency alleviated synoviocyte proliferation and inhibited fibroblast to myofibroblast transition. It also decreased the expression of fibrosis markers α-SMA, COL1A1, CTGF, Vimentin and promoted the activation of the SMAD family member 3 (SMAD3) pathway. Importantly, trifluoperazine (TFP), a NUPR1 inhibitor, attenuated synovial fibrosis in DMM mice. CONCLUSIONS: These findings indicate that NUPR1 is an antifibrotic modulator in KOA, and its effect on anti-synovial fibrosis is partially mediated by SMAD3 signaling. This study reveals a promising target for developing novel antifibrotic treatment.
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Fibroblastos , Fibrosis , Transducción de Señal , Proteína smad3 , Sinoviocitos , Animales , Proteína smad3/metabolismo , Sinoviocitos/metabolismo , Sinoviocitos/patología , Fibroblastos/metabolismo , Fibroblastos/patología , Ratones Endogámicos C57BL , Membrana Sinovial/patología , Membrana Sinovial/metabolismo , Masculino , Osteoartritis de la Rodilla/patología , Osteoartritis de la Rodilla/metabolismo , Modelos Animales de Enfermedad , Ratones , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Proteínas de Unión al ADN , Proteínas de NeoplasiasRESUMEN
OBJECTIVE: Osteoarthritis is a common and complex joint disorder that shows higher prevalence and greater disease severity in women. Here, we investigate genome-wide methylation profiles of primary chondrocytes from osteoarthritis patients. DESIGN: We compare genome-wide methylation profiles of macroscopically intact (low-grade) and degraded (high-grade) osteoarthritis cartilage samples matched from osteoarthritis patients undergoing knee replacement surgery. We perform an epigenome-wide association study for cartilage degeneration across 170 patients and separately in 96 women and 74 men. RESULTS: We reveal widespread epigenetic differences with enrichments of nervous system and apoptosis-related processes. We further identify substantial similarities between sexes, but also sex-specific markers and pathways. CONCLUSIONS: Together, we provide the largest genome-wide methylation profiles of primary cartilage to date with enhanced and sex-specific insights into epigenetic processes underlying osteoarthritis progression.
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Cartílago Articular , Condrocitos , Metilación de ADN , Epigénesis Genética , Estudio de Asociación del Genoma Completo , Osteoartritis de la Rodilla , Humanos , Femenino , Masculino , Cartílago Articular/metabolismo , Cartílago Articular/patología , Osteoartritis de la Rodilla/genética , Osteoartritis de la Rodilla/metabolismo , Osteoartritis de la Rodilla/patología , Persona de Mediana Edad , Anciano , Condrocitos/metabolismo , Condrocitos/patología , Epigenómica , Factores Sexuales , Índice de Severidad de la EnfermedadRESUMEN
Malalignment is one of the most critical risk factors for knee osteoarthritis (KOA). Biomechanical factors such as knee varus or valgus, hip-knee-ankle angle, and femoral anteversion affect KOA severity. In this study, we aimed to investigate KOA severity predictive factors based on hip and pelvic radiographic geometry. In this cross-sectional study, 125 patients with idiopathic KOA were enrolled. Two investigators evaluated the knee and pelvic radiographs of 125 patients, and 16 radiological parameters were measured separately. KOA severity was categorized based on the medial tibiofemoral joint space widths (JSW). Based on JSW measurements, 16% (nâ =â 40), 8.8% (nâ =â 22), 16.4% (nâ =â 41), and 56.8% (nâ =â 147) were defined as grades 0, 1, 2, 3, respectively. There were significant differences between the JSW groups with respect to hip axis length, femoral neck-axis length, acetabular width, neck shaft angle (NSA), outer pelvic diameter, midpelvis-caput distance, acetabular-acetabular distance, and femoral head to femoral head length (Pâ <â .05). Two different functions were obtained using machine learning classification and logistic regression, and the accuracy of predicting was 74.4% by using 1 and 89.6% by using both functions. Our findings revealed that some hip and pelvic geometry measurements could affect the severity of KOA. Furthermore, logistic functions using predictive factors of hip and pelvic geometry can predict the severity of KOA with acceptable accuracy, and it could be used in clinical decisions.
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Osteoartritis de la Rodilla , Radiografía , Índice de Severidad de la Enfermedad , Humanos , Osteoartritis de la Rodilla/diagnóstico por imagen , Osteoartritis de la Rodilla/patología , Osteoartritis de la Rodilla/fisiopatología , Femenino , Masculino , Estudios Transversales , Persona de Mediana Edad , Anciano , Radiografía/métodos , Huesos Pélvicos/diagnóstico por imagen , Articulación de la Rodilla/diagnóstico por imagen , Articulación de la Rodilla/patología , Articulación de la Rodilla/fisiopatología , Factores de Riesgo , Pelvis/diagnóstico por imagen , Pelvis/patología , AdultoRESUMEN
OBJECTIVES: Adipose tissue has been associated with knee osteoarthritis (KOA) pathogenesis, but the longitudinal changes in adipose tissue with KOA progression have not been carefully evaluated. This study aimed to determine if longitudinal changes of systemic and local adipose tissue is associated with radiographic progression of KOA. METHODS: This case-control study used data from the Osteoarthritis Initiative (OAI) and included 315 cases (all the right knees with a minimum of Kellgren-Lawrence score (KL) of 0 and an increase of ≥ 1 KL from baseline to 48 months) and 315 controls matched by age, sex, race, and baseline KL. Cross sectional area of IPFP (IPFP CSA) and subcutaneous adipose tissue around the distal thigh (SCATthigh) were measured using MRI images at baseline and 24 months. Conditional logistic regression models were fitted to estimate associations of obesity markers, IPFP CSA, and SCATthigh with radiographic KOA progression. Mediation analysis was used to assess whether IPFP CSA or SCATthigh mediates the relationships between baseline BMI and radiographic KOA progression. RESULTS: 24-month changes of IPFP CSA (ΔIPFP CSA) and SCATthigh (ΔSCATthigh) were significantly greater in cases compared to controls, whereas Δ BMI and Δ abdominal circumference were similar in both groups during follow-up. Adjusted ORs for radiographic KOA progression were 9.299, 95% CI (5.357-16.141) per 1 SD increase of Δ IPFP CSA and 1.646, 95% CI (1.288-2.103) per 1 SD increase of Δ SCATthigh. ΔIPFP CSA mediated the association between baseline BMI and radiographic KOA progression (87%). CONCLUSIONS: Subjects with radiographic progression of KOA, had significant increases in IPFP CSA and subcutaneous adipose tissue while BMI and abdominal circumference remained stable. Additional studies are needed to confirm these associations.
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Tejido Adiposo , Progresión de la Enfermedad , Imagen por Resonancia Magnética , Osteoartritis de la Rodilla , Grasa Subcutánea , Humanos , Osteoartritis de la Rodilla/diagnóstico por imagen , Osteoartritis de la Rodilla/patología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Grasa Subcutánea/diagnóstico por imagen , Grasa Subcutánea/patología , Estudios de Casos y Controles , Imagen por Resonancia Magnética/métodos , Tejido Adiposo/diagnóstico por imagen , Tejido Adiposo/patología , Radiografía/métodos , Estudios LongitudinalesRESUMEN
Chondrocyte apoptosis is recognized as one of the pathological features involved in cartilage degeneration driving the onset and progression of knee osteoarthritis (OA). This study aimed to determine the molecular mechanism underlying the effect of clusterin (CLU), anti-apoptotic molecule, in human knee OA chondrocytes. Primary knee OA chondrocytes were isolated from the cartilage of knee OA patients and divided into five groups: (1) the cells treated with interleukin (IL)-1ß, (2) CLU alone, (3) a combination of IL-1ß and CLU, (4) LY294002 (PI3K inhibitor) along with IL-1ß and CLU, and (5) the untreated cells. Production of apoptotic, inflammatory, anabolic, and catabolic mediators in knee OA chondrocytes was determined after treatment for 24 h. Our in vitro study uncovered that CLU significantly suppressed the production of inflammatory mediators [nitric oxide (NO), IL6, and tumor necrosis factor (TNF)-α] and apoptotic molecule (caspase-3, CASP3). CLU significantly upregulated messenger ribonucleic acid (mRNA) expressions of anabolic factors [SRY-box transcription factor-9 (SOX9) and aggrecan (ACAN)], but significantly downregulated mRNA expressions of IL6, nuclear factor kappa-B (NF-κB), CASP3, and matrix metalloproteinase-13 (MMP13). Anti-apoptotic and anti-inflammatory effects of CLU were mediated through activating PI3K/Akt signaling pathway. The findings suggest that CLU might have beneficial effects on knee OA chondrocytes by exerting anti-apoptotic and anti-inflammatory functions via PI3K/Akt pathway, making CLU a promising target for potential therapeutic interventions in knee OA.
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Apoptosis , Condrocitos , Clusterina , Interleucina-1beta , Osteoartritis de la Rodilla , Humanos , Condrocitos/efectos de los fármacos , Condrocitos/metabolismo , Condrocitos/patología , Osteoartritis de la Rodilla/patología , Osteoartritis de la Rodilla/metabolismo , Apoptosis/efectos de los fármacos , Clusterina/metabolismo , Clusterina/genética , Interleucina-1beta/metabolismo , Transducción de Señal/efectos de los fármacos , Células Cultivadas , Masculino , Persona de Mediana Edad , Anciano , Inflamación/metabolismo , Inflamación/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Femenino , Fosfatidilinositol 3-Quinasas/metabolismo , Morfolinas/farmacología , Cromonas/farmacología , Factor de Transcripción SOX9/metabolismo , Factor de Transcripción SOX9/genética , Metaloproteinasa 13 de la Matriz/metabolismo , Mediadores de Inflamación/metabolismo , Óxido Nítrico/metabolismoRESUMEN
Knee osteoarthritis (OA) significantly impacts the quality of life of individuals globally. However, the interconnections between Achilles tendon thickness, knee symptoms/functions, and foot alignment remain understudied in knee OA patients. This study determines the relationships between Achilles tendon thickness (ATT), knee symptoms/functions, and foot alignment in knee OA patients, considering their interconnected biomechanical nature. In a cross-sectional analysis involving 122 knee OA patients, Knee injury and Osteoarthritis Outcome Score (KOOS) assessed knee function and symptoms. Forefoot, midfoot, and rearfoot alignment were measured using hallux valgus angle, navicular/foot ratio, and rearfoot angle. The navicular/foot ratio represented the ratio of navicular height to total foot length. ATT was measured using a digital calliper. Pearson correlations and stepwise multiple linear regression models were employed to explore relationships and determinants. Out of 122 participants, 88 (72.1%) were females. ATT correlated significantly with ankle range of motion, forefoot alignment, and midfoot alignment. In stepwise multivariable regression, ankle range of motion, navicular/foot ratio, and age were significantly associated with ATT (adjusted R2 = 0.44). Similarly, KOOS-Symptoms scores were linked to the OA severity, navicular/foot ratio, ankle range of motion, gastrocnemius strength, and age (adjusted R2 = 0.22). KOOS-Function scores were significantly associated with knee OA severity, gastrocnemius strength, ankle range of motion, and age (adjusted R2 = 0.19). Midfoot alignment was significantly associated with ATT and knee symptoms in patients with Knee OA. This suggests potential benefits of interventions targeting both Achilles tendon properties and foot alignment for improved knee OA outcomes.
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Tendón Calcáneo , Osteoartritis de la Rodilla , Humanos , Femenino , Tendón Calcáneo/fisiopatología , Tendón Calcáneo/patología , Masculino , Osteoartritis de la Rodilla/fisiopatología , Osteoartritis de la Rodilla/patología , Persona de Mediana Edad , Anciano , Estudios Transversales , Rango del Movimiento Articular , Articulación de la Rodilla/fisiopatología , Articulación de la Rodilla/patología , Pie/fisiopatología , Fenómenos BiomecánicosRESUMEN
Intra-articular injection of mesenchymal stem cells (MSCs) is envisioned as a solution for knee osteoarthritis (OA). Although synovial MSCs (SyMSCs) are promising for cartilage regeneration, the clinical choice is usually adipose MSCs (AdMSCs). However, the similarities/differences in the mode of action between SyMSCs and AdMSCs remain unclear. Here, we compared factors secreted by human SyMSCs and AdMSCs after injection into OA knees. Human SyMSCs or AdMSCs were injected into the knees of rat partial meniscectomy models. The next day, the knee joints were collected to analyze the distribution of injected MSCs and transcriptome changes in the human MSCs and rat synovium. Non-injected MSCs were mixed with rat synovium as a control. After injection, no difference was apparent in intra-articular distribution of the SyMSCs or AdMSCs. RNA sequencing demonstrated an enrichment of cytokine-cytokine receptor interaction-related genes in both human SyMSCs and AdMSCs after injection. Differentially expressed genes (DEGs) specific to SyMSCs were associated with cartilage matrix synthesis and homeostasis. PCR analysis of the matrisome-related DEGs showed significantly higher expression of PRG4 in SyMSCs than in AdMSCs after injection. Immunostaining also confirmed a significantly greater expression of lubricin by SyMSCs than by AdMSCs. These findings indicate that SyMSCs will be a more promising treatment for OA.
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Tejido Adiposo , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Osteoartritis de la Rodilla , Membrana Sinovial , Animales , Células Madre Mesenquimatosas/metabolismo , Humanos , Osteoartritis de la Rodilla/metabolismo , Osteoartritis de la Rodilla/terapia , Osteoartritis de la Rodilla/patología , Osteoartritis de la Rodilla/genética , Ratas , Membrana Sinovial/metabolismo , Membrana Sinovial/patología , Trasplante de Células Madre Mesenquimatosas/métodos , Tejido Adiposo/metabolismo , Tejido Adiposo/citología , Inyecciones Intraarticulares , Masculino , Ratas Sprague-Dawley , Glicoproteínas/metabolismo , Glicoproteínas/genética , Células Cultivadas , Proteoglicanos/metabolismo , Proteoglicanos/genéticaRESUMEN
Polygonatum sibiricum polysaccharides (PSP), the primary constituent of Polygonatum sibiricum, have been shown to exhibit a wide range of pharmacological effects, but their impact on osteoarthritis (OA) remains unclear. The objective of this study was to investigate the protective effects of PSP against OA and to elucidate its underlying molecular mechanism. In our in vitro experiments, PSP not only inhibited the IL-1ß-induced inflammatory responses and the nuclear factor kappa-B (NF-κB) signaling pathway in chondrocytes but also regulated the cartilage matrix metabolism. In addition, we detected 394 significantly differentially expressed genes through RNA-seq analysis on PSP-intervened chondrocytes, and the toll-like receptor 2 (TLR2) was identified as the most important feature by functional network analysis and qRT-PCR. It was also revealed that PSP treatment significantly reversed the IL-1-induced up-regulation of TLR2 expression in chondrocytes, while TLR2 overexpression partially inhibited the regulatory effects of PSP on inflammation, NF-κB signaling pathway and matrix metabolism. In our in vivo experiments, PSP treatment alleviated the development of destabilization of medial meniscus (DMM)-induced OA in mouse knee joints, inhibited the DMM-induced activation of the TLR2/NF-κB signaling pathway in mouse knee joint cartilage, and reduced the serum levels of inflammatory cytokines. In conclusion, PSP exerts its anti-inflammatory, matrix synthesis-promoting and matrix catabolism-suppressing effects in knee OA by inhibiting the TLR2/NF-κB signaling pathway, suggesting that PSP may be potentially targeted as a novel all-natural, low-toxicity drug for OA prevention and treatment.
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Condrocitos , FN-kappa B , Osteoartritis de la Rodilla , Polygonatum , Polisacáridos , Transducción de Señal , Receptor Toll-Like 2 , Receptor Toll-Like 2/metabolismo , Animales , FN-kappa B/metabolismo , Transducción de Señal/efectos de los fármacos , Polisacáridos/farmacología , Polisacáridos/química , Ratones , Osteoartritis de la Rodilla/tratamiento farmacológico , Osteoartritis de la Rodilla/metabolismo , Osteoartritis de la Rodilla/prevención & control , Osteoartritis de la Rodilla/patología , Osteoartritis de la Rodilla/inducido químicamente , Condrocitos/efectos de los fármacos , Condrocitos/metabolismo , Polygonatum/química , Masculino , Regulación de la Expresión Génica/efectos de los fármacos , Modelos Animales de EnfermedadRESUMEN
Knee osteoarthritis (OA), characterized by multiple joint tissue degenerations, remains a significant clinical challenge. Recent evidence suggests that crosstalk within the osteochondral unit may drive OA progression. Although structural-biomechanical properties of bone and cartilage have been studied, potential interaction within the osteochondral unit in the context of OA has yet to be investigated. We performed comprehensive structural and biomechanical quantification of the cartilage, subchondral bone plate (SBP), and subchondral trabecular bone (STB) using 101 osteochondral cores collected from tibial plateaus of 12 control human cadavers (CT, 5 male/7 female) and 19 patients undergoing total knee replacement (OA, 6 male/13 female). For each sample, we quantified SBP microstructure, plate-and-rod morphological properties of the STB using individual trabecula segmentation, and morphological and compositional properties of the articular cartilage. We also performed indentation testing on each compartment of the osteochondral unit to extract the respective structural-mechanical properties. Cartilage thickness was lower in moderate and severe OA regions, while Osteoarthritis Research Society International score was higher only in severe OA regions. GAG content did not change in any OA region. Aggregate and shear moduli were lower only in severe OA regions, while permeability was lower only in moderate OA regions. In the SBP, thickness and tissue mineral density were higher in moderate and severe OA regions. Tissue modulus of STB was lower in moderate OA regions despite a thicker and more mineralized SBP; this deterioration was not observed in severe OA regions. Regression analysis revealed strong correlations between cartilage and STB properties in CT; these correlations were also found in moderate OA regions but were not observed in severe OA regions. In summary, our findings comprehensively characterize the human OA osteochondral unit. Importantly, uncoupling cartilage and subchondral bone structural-mechanical properties may be a hallmark of OA.
Knee osteoarthritis (OA) is a complex condition involving the degradation of joint tissues. To better understand OA progression, we investigated the interplay between different components of the joint. Our study focused on how cartilage, subchondral bone plate (SBP), and subchondral trabecular bone (STB) interact in human knee OA samples. We observed distinct changes in these tissues in moderate and severe OA regions compared with healthy joints. In moderate to severe OA, we found that cartilage thickness decreased, while the SBP thickened. Interestingly, the strength of the STB decreased only in moderate OA regions, not in severe OA. Moreover, our analysis revealed strong correlations between cartilage and STB properties in healthy joints and moderate OA regions. However, these correlations were absent in severe OA regions, indicating a disruption in the usual relationship between these tissues. Overall, our findings shed light on the structural and biomechanical changes occurring within the knee joint in OA. Understanding these changes may offer insights into potential therapeutic strategies for managing OA.
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Cartílago Articular , Osteoartritis de la Rodilla , Humanos , Cartílago Articular/patología , Cartílago Articular/diagnóstico por imagen , Cartílago Articular/fisiopatología , Masculino , Femenino , Osteoartritis de la Rodilla/patología , Osteoartritis de la Rodilla/fisiopatología , Anciano , Fenómenos Biomecánicos , Persona de Mediana Edad , Anciano de 80 o más Años , Hueso Esponjoso/patología , Hueso Esponjoso/diagnóstico por imagen , Hueso Esponjoso/fisiopatologíaRESUMEN
Excessive growth hormone (GH) has been shown to promote joint degeneration in both preclinical and clinical studies. Little is known about the effect of disrupted GH or GH receptor (GHR) on joint health. The goal of this study is to investigate joint pathology in mice with either germline (GHR-/-) or adult inducible (iGHR-/-) GHR deficiency. Knee joints from male and female GHR-/- and WT mice at 24 months of age were processed for histological analysis. Also, knee joints from male and female iGHR-/- and WT mice at 22 months of age were scanned by micro-CT (µCT) for subchondral bone changes and characterized via histology for cartilage degeneration. Joint sections were also stained for the chondrocyte hypertrophy marker, COLX, and the cartilage degeneration marker, ADAMTS-5, using immunohistochemistry. Compared to WT mice, GHR-/- mice had remarkably smooth articular joint surfaces and an even distribution of proteoglycan with no signs of degeneration. Quantitatively, GHR-/- mice had lower OARSI and Mankin scores compared to WT controls. By contrast, iGHR-/- mice were only moderately protected from developing aging-associated OA. iGHR-/- mice had a significantly lower Mankin score compared to WT. However, Mankin scores were not significantly different between iGHR-/- and WT when males and females were analyzed separately. OARSI scores did not differ significantly between WT and iGHR-/- in either individual or combined sex analyses. Both GHR-/- and iGHR-/- mice had fewer COLX+ hypertrophic chondrocytes compared to WT, while no significant difference was observed in ADAMTS-5 staining. Compared to WT, a significantly lower trabecular thickness in the subchondral bone was observed in the iGHR-/- male mice but not in the female mice. However, there were no significant differences between WT and iGHR-/- mice in the bone volume to total tissue volume (BV/TV), bone mineral density (BMD), and trabecular number in either sex. This study identified that both germline and adult-induced GHR deficiency protected mice from developing aging-associated OA with more effective protection in GHR-/- mice.
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Condrocitos , Hipertrofia , Receptores de Somatotropina , Animales , Femenino , Condrocitos/metabolismo , Condrocitos/patología , Masculino , Ratones , Receptores de Somatotropina/genética , Receptores de Somatotropina/metabolismo , Ratones Noqueados , Microtomografía por Rayos X , Cartílago Articular/patología , Cartílago Articular/metabolismo , Modelos Animales de Enfermedad , Osteoartritis de la Rodilla/patología , Osteoartritis de la Rodilla/metabolismo , Osteoartritis de la Rodilla/genética , Osteoartritis/metabolismo , Osteoartritis/patologíaRESUMEN
OBJECTIVE: Synovial pathology has been linked to osteoarthritis (OA) pain in patients. Microscopic grading systems for synovial changes in human OA have been described, but a standardized approach for murine models of OA is needed. We sought to develop a reproducible approach and set of minimum recommendations for reporting of synovial histopathology in mouse models of OA. METHODS: Coronal and sagittal sections from male mouse knee joints subjected to destabilization of medial meniscus (DMM) or partial meniscectomy (PMX) were collected as part of other studies. Stains included Hematoxylin and Eosin (H&E), Toluidine Blue (T-Blue), and Safranin O/Fast Green (Saf-O). Four blinded readers graded pathological features (hyperplasia, cellularity, and fibrosis) at specific anatomic locations. Inter-reader agreement of each feature score was determined. RESULTS: There was acceptable to very good agreement when using 3-4 individual readers. After DMM and PMX, expected medial predominant changes in hyperplasia and cellularity were observed, with fibrosis noted at 12 weeks post-PMX. Synovial changes were consistent from section to section in the mid-joint area. When comparing stains, H&E and T-blue resulted in better agreement compared to Saf-O stain. CONCLUSIONS: To account for the pathologic and anatomic variability in synovial pathology and allow for a more standardized evaluation that can be compared across studies, we recommend evaluating a minimum set of 3 pathological features at standardized anatomic areas. Further, we suggest reporting individual feature scores separately before relying on a single summed "synovitis" score. H&E or T-blue are preferred, inter-reader agreement for each feature should be considered.