RESUMEN
Recently, we found significantly reduced total superoxide dismutase (SOD) activity in the cartilage of patients with end-stage knee osteoarthritis (OA). In this study, we aimed to evaluate the SOD activity in serum, joint fluid, cartilage, and synovial membrane samples collected from 52 patients with end-stage knee OA who underwent total knee arthroplasty. The relationship between the total SOD activity in each tissue was evaluated using Spearman's rank correlation coefficient. The joint fluid total SOD activity was used as the objective variable, and its association with the serum, cartilage, and synovial total SOD activities was evaluated using multiple linear regression analysis. Univariate analysis revealed that joint fluid total SOD activity was positively correlated with synovial total SOD activity. Multiple linear regression analysis using joint fluid total SOD activity as the objective variable showed a positive association with synovial total SOD activity (ß = 0.493, adjusted R2 = 0.172, P < 0.01). In patients with end-stage knee OA, the state of the synovial total SOD activity is better reflected by the total SOD activity in the joint fluid than that in the cartilage. Joint fluid total SOD activity may serve as a biomarker for the treatment and prevention of synovitis.
Asunto(s)
Osteoartritis de la Rodilla , Superóxido Dismutasa , Líquido Sinovial , Membrana Sinovial , Humanos , Osteoartritis de la Rodilla/metabolismo , Osteoartritis de la Rodilla/enzimología , Osteoartritis de la Rodilla/patología , Masculino , Femenino , Líquido Sinovial/metabolismo , Superóxido Dismutasa/metabolismo , Membrana Sinovial/metabolismo , Membrana Sinovial/patología , Anciano , Persona de Mediana Edad , Biomarcadores , Cartílago Articular/patología , Cartílago Articular/metabolismo , Cartílago Articular/enzimología , Artroplastia de Reemplazo de RodillaRESUMEN
WNT ligands can activate several signalling cascades of pivotal importance during development and regenerative processes. Their de-regulation has been associated with the onset of different diseases. Here we investigated the role of the WNT/Calcium Calmodulin Kinase II (CaMKII) pathway in osteoarthritis. We identified Heme Oxygenase I (HMOX1) and Sox-9 as specific markers of the WNT/CaMKII signalling in articular chondrocytes through a microarray analysis. We showed that the expression of the activated form of CaMKII, phospho-CaMKII, was increased in human and murine osteoarthritis and the expression of HMOX1 was accordingly reduced, demonstrating the activation of the pathway during disease progression. To elucidate its function, we administered the CaMKII inhibitor KN93 to mice in which osteoarthritis was induced by resection of the anterior horn of the medial meniscus and of the medial collateral ligament in the knee joint. Pharmacological blockade of CaMKII exacerbated cartilage damage and bone remodelling. Finally, we showed that CaMKII inhibition in articular chondrocytes upregulated the expression of matrix remodelling enzymes alone and in combination with Interleukin 1. These results suggest an important homeostatic role of the WNT/CaMKII signalling in osteoarthritis which could be exploited in the future for therapeutic purposes.
Asunto(s)
Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Cartílago Articular/enzimología , Cartílago Articular/patología , Homeostasis , Osteoartritis/enzimología , Osteoartritis/patología , Anciano , Animales , Remodelación Ósea , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/antagonistas & inhibidores , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/genética , Bovinos , Condrocitos/metabolismo , Condrocitos/patología , Modelos Animales de Enfermedad , Femenino , Regulación Enzimológica de la Expresión Génica , Hemo-Oxigenasa 1/genética , Hemo-Oxigenasa 1/metabolismo , Humanos , Interleucina-1beta/metabolismo , Masculino , Ratones Endogámicos C57BL , Persona de Mediana Edad , Modelos Biológicos , Osteoartritis/genética , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Transcriptoma/genética , Regulación hacia Arriba , Proteína Wnt3/metabolismoRESUMEN
This article provides a brief review of the pathophysiology of osteoarthritis and the ontogeny of chondrocytes and details how physical exercise improves the health of osteoarthritic joints and enhances the potential of autologous chondrocyte implants, matrix-induced autologous chondrocyte implants, and mesenchymal stem cell implants for the successful treatment of damaged articular cartilage and subchondral bone. In response to exercise, articular chondrocytes increase their production of glycosaminoglycans, bone morphogenic proteins, and anti-inflammatory cytokines and decrease their production of proinflammatory cytokines and matrix-degrading metalloproteinases. These changes are associated with improvements in cartilage organization and reductions in cartilage degeneration. Studies in humans indicate that exercise enhances joint recruitment of bone marrow-derived mesenchymal stem cells and upregulates their expression of osteogenic and chondrogenic genes, osteogenic microRNAs, and osteogenic growth factors. Rodent experiments demonstrate that exercise enhances the osteogenic potential of bone marrow-derived mesenchymal stem cells while diminishing their adipogenic potential, and that exercise done after stem cell implantation may benefit stem cell transplant viability. Physical exercise also exerts a beneficial effect on the skeletal system by decreasing immune cell production of osteoclastogenic cytokines interleukin-1ß, tumor necrosis factor-α, and interferon-γ, while increasing their production of antiosteoclastogenic cytokines interleukin-10 and transforming growth factor-ß. In conclusion, physical exercise done both by bone marrow-derived mesenchymal stem cell donors and recipients and by autologous chondrocyte donor recipients may improve the outcome of osteochondral regeneration therapy and improve skeletal health by downregulating osteoclastogenic cytokine production and upregulating antiosteoclastogenic cytokine production by circulating immune cells.
Asunto(s)
Condrocitos/metabolismo , Ejercicio Físico/fisiología , Células Madre Mesenquimatosas/metabolismo , Osteoartritis/fisiopatología , Osteogénesis , Condicionamiento Físico Animal/fisiología , Regeneración/genética , Animales , Cartílago Articular/efectos de los fármacos , Cartílago Articular/enzimología , Cartílago Articular/patología , Citocinas/metabolismo , Glicosaminoglicanos/metabolismo , Humanos , Metaloproteasas/metabolismo , Osteoartritis/enzimología , Osteoartritis/inmunología , Osteoartritis/terapia , Osteogénesis/genética , Osteogénesis/inmunología , Osteogénesis/fisiología , Regeneración/inmunología , Regeneración/fisiología , Trasplante de Células MadreRESUMEN
Osteoarthritis (OA) is a very common chronic joint dysfunction, and there is currently a poor understanding of its etiology and pathogenesis. Therefore, there are no active disease-modifying drugs currently available for clinical treatment. Several natural compounds have been shown to play a role in inhibiting OA progression. The present study is aimed at investigating the curative effects of acacetin, a natural flavonoid compound, against OA. Our results demonstrated that MMP-1, MMP-3, and MMP-13 were highly expressed in OA specimens. Acacetin inhibited the interleukin-1ß- (IL-1ß-) induced expression of MMP-1, MMP-3, and MMP-13in chondrocytes by blocking nuclear factor-κB (NF-κB) signaling pathways. Furthermore, we found that acacetin suppressed OA progression and inhibited the expression of MMP-1, MMP-3, and MMP-13 in ACLT-induced OA mice. Taken together, our study revealed that acacetin may serve as a potential drug for treating OA.
Asunto(s)
Condrocitos/enzimología , Flavonas/farmacología , Interleucina-1beta/efectos adversos , Metaloproteinasas de la Matriz/metabolismo , FN-kappa B/metabolismo , Osteoartritis/metabolismo , Osteoartritis/prevención & control , Transducción de Señal , Animales , Lesiones del Ligamento Cruzado Anterior/tratamiento farmacológico , Lesiones del Ligamento Cruzado Anterior/prevención & control , Cartílago Articular/efectos de los fármacos , Cartílago Articular/enzimología , Cartílago Articular/patología , Muerte Celular/efectos de los fármacos , Células Cultivadas , Condrocitos/efectos de los fármacos , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Flavonas/química , Flavonas/uso terapéutico , Humanos , Metaloproteinasas de la Matriz/farmacología , Ratones Endogámicos C57BL , Osteoartritis/tratamiento farmacológico , Osteoartritis/patologíaRESUMEN
Osteoarthritis (OA) is one of the most painful and widespread chronic degenerative joint diseases and is characterized by destructed articular cartilage and inflamed joints. Previously, our findings indicated that circular RNA ciRS-7 (ciRS-7)/microRNA 7 (miR-7) axis is abnormally expressed in OA, and regulates proliferation, inflammatory responses, and apoptosis of interleukin-1ß (IL-1ß)-stimulated chondrocytes. However, its underlying role in OA remains unknown. In this study, we first validated cartilage degradation and defection of autophagy in samples of OA patients. IL-1ß initially stimulated autophagy of chondrocytes, and ultimately significantly suppressed autophagy. Upregulated ciRS-7/down-regulated miR-7 aggravated IL-1ß-induced cartilage degradation, and restrained autophagy in vitro. Gene sequencing and bioinformatics analysis performed on a control group, IL-1ß group, and IL-1ß+miR-7-mimics group demonstrated that seven of the most significant mRNA candidates were enriched in the interleukin-17 (IL-17) signaling pathway. Increased IL-17A levels were also observed by qRT-PCR and ELISA. In addition, it was revealed that the ciRS-7/miR-7 axis ameliorated cartilage degradation and defection of autophagy by PI3K/AKT/mTOR activation in IL-1ß-induced chondrocytes. Furthermore, an OA model was established in rats with medial meniscus destabilization. miR-7-siRNA-expressing lentiviruses alleviated surgical resection-induced cartilage destruction of OA mice, whereas miR-7 mimics worsened the effects. Thus, these findings revealed that the mechanism of the ciRS-7/miR-7 axis involved regulating OA progression and provided valuable directions for OA treatment.
Asunto(s)
Autofagia , Cartílago Articular/enzimología , Condrocitos/enzimología , Interleucina-17/metabolismo , MicroARNs/metabolismo , Osteoartritis/enzimología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Largo no Codificante/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Animales , Autofagia/efectos de los fármacos , Cartílago Articular/efectos de los fármacos , Cartílago Articular/patología , Estudios de Casos y Controles , Línea Celular , Condrocitos/efectos de los fármacos , Condrocitos/patología , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Humanos , Interleucina-17/genética , Interleucina-1beta/farmacología , Masculino , MicroARNs/genética , Osteoartritis/genética , Osteoartritis/patología , ARN Largo no Codificante/genética , Ratas Sprague-Dawley , Transducción de Señal , TranscriptomaRESUMEN
Osteoarthritis (OA) is the most common type of arthritis that occurs in an aged population. It affects any joints in the body and degenerates the articular cartilage and the subchondral bone. Despite the pathophysiology of OA being different, cartilage resorption is still a symbol of osteoarthritis. Matrix metalloproteinases (MMPs) are important proteolytic enzymes that degrade extra-cellular matrix proteins (ECM) in the body. MMPs contribute to the turnover of cartilage and its break down; their levels have increased in the joint tissues of OA patients. Application of chondroprotective drugs neutralize the activities of MMPs. Natural products derived from herbs and plants developed as traditional medicine have been paid attention to, due to their potential biological effects. The therapeutic value of natural products in OA has increased in reputation due to their clinical impact and insignificant side effects. Several MMPs inhibitor have been used as therapeutic drugs, for a long time. Recently, different types of compounds were reviewed for their biological activities. In this review, we summarize numerous natural products for the development of MMPs inhibitors in arthritic diseases and describe the major signaling targets that were involved for the treatments of these destructive joint diseases.
Asunto(s)
Productos Biológicos/uso terapéutico , Inhibidores de la Metaloproteinasa de la Matriz/uso terapéutico , Osteoartritis/tratamiento farmacológico , Animales , Cartílago Articular/efectos de los fármacos , Cartílago Articular/enzimología , Cartílago Articular/patología , Condrocitos/efectos de los fármacos , Condrocitos/enzimología , Citocinas/fisiología , Evaluación Preclínica de Medicamentos , Proteínas de la Matriz Extracelular/metabolismo , Predicción , Humanos , Ácido Yodoacético/toxicidad , Modelos Animales , FN-kappa B/metabolismo , Osteoartritis/inducido químicamente , Osteoartritis/enzimología , Osteoartritis/patología , Ratas , Automedicación , Acetato de Tetradecanoilforbol/toxicidadRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Kyung-Bang Gumiganghwal-tang tablet (GMGHT) is a standardized Korean Medicine that could treat a cold, headache, arthralgia and fever. Although GMGHT has been used for arthritis-related diseases including a sprain, arthralgia, unspecified arthritis and knee arthritis, there is no pre-clinical evidence to treat osteoarthritis (OA). This study determined the drug dosage and the mechanisms of GMGHT for OA. METHODS: OA was induced by intra-articular monoiodoacetic acid (MIA) injection in Sprague-Dawley rats. As calculated from the human equivalent dose formula, GMGHT was orally administered at the doses of 9.86, 98.6 and 986 mg/kg for 4 weeks. The arthritis score was performed by a blind test, and histological changes in articular cartilage were indicated by hematoxylin and eosin, Safranin O and toluidine blue staining. SW1353 chondrocytes were stimulated by interleukin (IL)-1ß recombinant to analyze the expressions of Type II collagen, matrix metalloproteinases (MMPs) and nuclear factor (NF)-κB. RESULTS: Rough and punctate surfaces of the femoral condyle induced by MIA, were recovered by the GMGHT treatment. The arthritis score was significantly improved in the 968 mg/kg of GMGHT-treated cartilage. Loss of chondrocytes and proteoglycan were ameliorated at the deep zone of the subchondral bone plate by the GMGHT administration in OA rats. The expression of Type II collagen was increased, while MMP-1, -3 and -13 levels were decreased in the GMGHT-treated SW1353 chondrocytes. In addition, the GMGHT treatment regulated NF-κB activation along with IL-6, transforming growth factor-ß and IL-12 production. CONCLUSIONS: GMGHT promoted the recovery of articular cartilage damage by inhibiting MMPs, accompanied with its anti-inflammatory effects in OA. GMGHT might be an alternative therapeutic treatment for OA.
Asunto(s)
Artritis Experimental/prevención & control , Cartílago Articular/efectos de los fármacos , Articulaciones/efectos de los fármacos , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Metaloproteinasas de la Matriz Secretadas/antagonistas & inhibidores , Osteoartritis/prevención & control , Extractos Vegetales/farmacología , Animales , Artritis Experimental/inducido químicamente , Artritis Experimental/enzimología , Artritis Experimental/patología , Cartílago Articular/enzimología , Cartílago Articular/patología , Línea Celular Tumoral , Condrocitos/efectos de los fármacos , Condrocitos/enzimología , Condrocitos/patología , Colágeno Tipo II/metabolismo , Citocinas/metabolismo , Humanos , Mediadores de Inflamación/metabolismo , Ácido Yodoacético , Articulaciones/enzimología , Articulaciones/patología , Masculino , Metaloproteinasa 1 de la Matriz/metabolismo , Metaloproteinasa 13 de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/metabolismo , Metaloproteinasas de la Matriz Secretadas/genética , Metaloproteinasas de la Matriz Secretadas/metabolismo , Osteoartritis/inducido químicamente , Osteoartritis/enzimología , Osteoartritis/patología , Ratas Sprague-DawleyRESUMEN
BACKGROUND/AIMS: MicroRNAs (miRNAs) are involved in the pathogenesis of osteoarthritis (OA). The present study aimed to investigate the potential function of miR-122 in the development of OA and its potential molecular mechanisms. METHODS: The expression of miR-122, silent information regulator 1 (SIRT1), collagen II, aggrecan, matrix metalloproteinase (MMP) 13 (MMP13) and ADAMTS4 in OA cartilage was detected by RT-qPCR. Target gene prediction and screening, luciferase reporter assay were used to verify downstream target genes of miR-122. RESULTS: Compared with osteonecrosis, the expression of miR-122 was significantly increased in OA cartilage, while the expression of SIRT1 was significantly decreased. Overexpression of miR-122 increased the expression of extracellular matrix (ECM) catabolic factors, for example disintegrins, MMPs and metalloproteinases with platelet reaction protein motifs, and inhibited the expression of synthetic metabolic genes such as collagen II and aggregating proteoglycan. Inhibition of miR-122 expression had the opposite effect. Furthermore, SIRT1 was identified as a direct target of miR-122. SIRT1 was significantly inhibited by miR-122 overexpression. Knockdown of SIRT1 reversed the degradation of chondrocyte ECM by miR-122 inhibitors. CONCLUSION: The miR-122/SIRT1 axis can regulate the degradation of ECM in OA, thus providing new insights into the treatment of OA.
Asunto(s)
Cartílago Articular/enzimología , Condrocitos/enzimología , Matriz Extracelular/enzimología , Articulación de la Rodilla/enzimología , MicroARNs/metabolismo , Osteoartritis de la Rodilla/enzimología , Sirtuina 1/metabolismo , Anciano , Cartílago Articular/patología , Estudios de Casos y Controles , Línea Celular Tumoral , Condrocitos/patología , Matriz Extracelular/genética , Matriz Extracelular/patología , Femenino , Regulación Enzimológica de la Expresión Génica , Humanos , Articulación de la Rodilla/patología , Masculino , MicroARNs/genética , Persona de Mediana Edad , Osteoartritis de la Rodilla/genética , Osteoartritis de la Rodilla/patología , Proteolisis , Transducción de Señal , Sirtuina 1/genéticaRESUMEN
Reactive oxygen species (ROS) generated by the NADPH oxidase (Nox) enzymes are important short-range signaling molecules. They have been extensively studied in the physiology and pathophysiology of the cardiovascular system, where they have important roles in vascular inflammation, angiogenesis, hypertension, cardiac injury, stroke, and aging. Increasing evidence demonstrates that ROS and Nox enzymes also affect bone homeostasis and osteoporosis, and more recent studies implicate ROS and Nox enzymes in both inflammatory arthritis and osteoarthritis. Mechanistically, this connection may be through the effects of ROS on signal transduction. ROS affect both transforming growth factor-ß/Smad signaling, interleukin-1ß/nuclear factor-kappa B signaling, and the resulting changes in matrix metalloproteinase expression. The purpose of this review is to describe the role of Nox enzymes in the physiology and pathobiology of bone and joints and to highlight the potential of therapeutically targeting the Nox enzymes.
Asunto(s)
Huesos/enzimología , Cartílago Articular/enzimología , NADPH Oxidasas/metabolismo , Osteoartritis/enzimología , Animales , Homeostasis , Humanos , NADPH Oxidasas/antagonistas & inhibidores , NADPH Oxidasas/clasificaciónRESUMEN
A Disintegrin And Metalloproteinase with ThromboSpondin motif (ADAMTS)-5 was identified in 1999 as one of the enzymes responsible for cleaving aggrecan, the major proteoglycan in articular cartilage. Studies in vitro, ex vivo and in vivo have validated ADAMTS-5 as a target in osteoarthritis (OA), a disease characterized by extensive degradation of aggrecan. For this reason, it attracted the interest of many research groups aiming to develop a therapeutic treatment for OA patients. However, ADAMTS-5 proteoglycanase activity is not only involved in the dysregulated aggrecan proteolysis, which occurs in OA, but also in the physiological turnover of other related proteoglycans. In particular, versican, a major ADAMTS-5 substrate, plays an important structural role in heart and blood vessels and its proteolytic processing by ADAMTS-5 must be tightly regulated. On the occasion of the 20th anniversary of the discovery of ADAMTS-5, this review looks at the evidence for its detrimental role in OA, as well as its physiological turnover of cardiovascular proteoglycans. Moreover, the other potential functions of this enzyme are highlighted. Finally, challenges and emerging trends in ADAMTS-5 research are discussed.
Asunto(s)
Proteína ADAMTS5/metabolismo , Agrecanos/metabolismo , Enfermedades Cardiovasculares/enzimología , Sistema Cardiovascular/enzimología , Cartílago Articular/enzimología , Osteoartritis/enzimología , Versicanos/metabolismo , Proteína ADAMTS5/antagonistas & inhibidores , Animales , Enfermedades Cardiovasculares/patología , Sistema Cardiovascular/patología , Cartílago Articular/patología , Humanos , Osteoartritis/tratamiento farmacológico , Osteoartritis/patología , Inhibidores de Proteasas/uso terapéutico , Proteolisis , Especificidad por Sustrato , Remodelación VascularRESUMEN
OBJECTIVE: The aim of this study was to investigate cross-sectional associations between serum levels of citrate and knee structural changes and cartilage enzymes in patients with knee osteoarthritis (OA). METHOD: A total of 137 subjects with symptomatic knee OA (mean age 55.0 years, range 34-74, 84% female) were included. Knee radiography was used to assess knee osteophytes, joint space narrowing (JSN) and radiographic OA assessed by Kellgren-Lawrence (K-L) grading system. T2-weighted fat-suppressed fast spin echo magnetic resonance imaging (MRI) was used to determine knee cartilage defects, bone marrow lesions (BMLs) and infrapatellar fat pad (IPFP) signal intensity alternations. Colorimetric fluorescence was used to measure the serum levels of citrate. Enzyme-linked immunosorbent assay was used to measure the serum cartilage enzymes including matrix metalloproteinase (MMP)-3 and MMP-13. RESULTS: After adjustment for potential confounders (age, sex, body mass index), serum citrate was negatively associated with knee osteophytes at the femoral site, cartilage defects at medial femoral site, total cartilage defects, and total BMLs (odds ratio [OR] 0.17-0.30, all P < .05). Meanwhile, serum citrate was negatively associated with IPFP signal intensity alteration (OR 0.30, P = .05) in multivariable analyses. Serum citrate was significantly and negatively associated with MMP-13 (ß -3106.37, P < .05) after adjustment for potential confounders. However, citrate was not significantly associated with MMP-3 in patients with knee OA. CONCLUSION: Serum citrate was negatively associated with knee structural changes including femoral osteophytes, cartilage defects, and BMLs and also serum MMP-13 in patients with knee OA, suggesting that low serum citrate may be a potential indicator for advanced knee OA.
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Cartílago Articular/enzimología , Ácido Cítrico/sangre , Articulación de la Rodilla/enzimología , Metaloproteinasa 13 de la Matriz/sangre , Osteoartritis de la Rodilla/sangre , Adulto , Anciano , Biomarcadores/sangre , Cartílago Articular/diagnóstico por imagen , Estudios Transversales , Femenino , Humanos , Articulación de la Rodilla/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Osteoartritis de la Rodilla/diagnóstico por imagen , Osteoartritis de la Rodilla/enzimología , PronósticoRESUMEN
The objective of this study is to investigate the expression of enzymes involved in the sulfation of articular cartilage from proximal metacarpophalangeal (PMC) joint cartilage and distal metacarpophalangeal (DMC) joint cartilage in children with Kashin-Beck disease (KBD). The finger cartilage samples of PMC and DMC were collected from KBD and normal children aged 5-14 years old. Hematoxylin and eosin staining as well as immunohistochemical staining were used to observe the morphology and quantitate the expression of carbohydrate sulfotransferase 3 (CHST-3), carbohydrate sulfotransferase 12 (CHST-12), carbohydrate sulfotransferase 13 (CHST-13), uronyl 2-O-sulfotransferase (UST), and aggrecan. In the results, the numbers of chondrocyte decreased in all three zones of PMC and DMC in the KBD group. Less positive staining cells for CHST-3, CHST-12, CHST-13, UST, and aggrecan were observed in almost all three zones of PMC and DMC in KBD. The positive staining cell rates of CHST-12 were higher in superficial and middle zones of PMC and DMC in KBD, and a significantly higher rate of CHST-13 was observed only in superficial zone of PMC in KBD. In conclusion, the abnormal expression of chondroitin sulfate sulfotransferases in chondrocytes of KBD children may provide an explanation for the cartilage damage, and provide therapeutic targets for the treatment.
Asunto(s)
Cartílago Articular/enzimología , Enfermedad de Kashin-Beck/enzimología , Sulfotransferasas/biosíntesis , Adolescente , Agrecanos/análisis , Agrecanos/biosíntesis , Cartílago Articular/metabolismo , Cartílago Articular/patología , Niño , Femenino , Humanos , Enfermedad de Kashin-Beck/metabolismo , Enfermedad de Kashin-Beck/patología , Masculino , Sulfotransferasas/análisis , Carbohidrato SulfotransferasasRESUMEN
Osteoarthritis is mainly caused by a degenerative joint disorder, which is characterized by the gradual degradation of articular cartilage and synovial inflammation. The chondrocyte, the unique resident cell type of articular cartilage, is crucial for the development of osteoarthritis. Previous studies revealed that P21-activated kinase-1 (PAK1) was responsible for the initiation of inflammation. The purpose of the present study was to determine the potential role of PAK1 in osteoarthritis. The level of PAK1 expression was measured by Western blot and quantitative real-time PCR in articular cartilage from osteoarthritis model rats and patients with osteoarthritis. In addition, the functional role of aberrant PAK1 expression was detected in the chondrocytes. We found that the expression of PAK1 was significantly increased in chondrocytes treated with osteoarthritis-related factors. Increased expression of PAK1 was also observed in knee articular cartilage samples from patients with osteoarthritis and osteoarthritis model rats. PAK1 was found to inhibit chondrocytes proliferation and to promote the production of inflammatory cytokines in cartilages chondrocytes. Furthermore, we found that PAK1 modulated the production of extracellular matrix and cartilage degrading enzymes in chondrocytes. Results of the present studies demonstrated that PAK1 might play an important role in the pathogenesis of osteoarthritis.
Asunto(s)
Artritis Experimental/enzimología , Cartílago Articular/enzimología , Condrocitos/enzimología , Articulación de la Rodilla/enzimología , Osteoartritis de la Rodilla/enzimología , Quinasas p21 Activadas/metabolismo , Anciano , Anciano de 80 o más Años , Animales , Artritis Experimental/genética , Artritis Experimental/patología , Cartílago Articular/patología , Proliferación Celular , Células Cultivadas , Condrocitos/patología , Citocinas/metabolismo , Femenino , Humanos , Mediadores de Inflamación/metabolismo , Articulación de la Rodilla/patología , Masculino , Persona de Mediana Edad , Osteoartritis de la Rodilla/genética , Osteoartritis de la Rodilla/patología , Ratas Sprague-Dawley , Transducción de Señal , Regulación hacia Arriba , Quinasas p21 Activadas/genéticaRESUMEN
PURPOSE: Elevated synovial fluid (SF) concentrations of proinflammatory cytokines, degradative enzymes, and cartilage breakdown markers at the time of anterior cruciate ligament (ACL) reconstruction are associated with worse postoperative patient-reported outcomes and cartilage quality. However, it remains unclear if this is due to a more robust or dysregulated inflammatory response or is a function of a more severe injury. The objective of this study was to evaluate the association of the molecular composition of the SF, patient demographics, and injury characteristics to cartilage degradation after acute ACL injury. METHODS: We performed a cluster analysis of SF concentrations of proinflammatory and anti-inflammatory cytokines, and biomarkers of cartilage degradation, bony remodeling, and hemarthrosis. We evaluated the association of biomarker clusters with patient demographics, days between injury, Visual Analogue Scale pain, SF aspirate volumes, and bone bruise volumes measured on magnetic resonance imaging. RESULTS: Two clusters were identified from the 35 patients included in this analysis, dysregulated inflammation and low inflammation. The dysregulated inflammation cluster consisted of 10 patients and demonstrated significantly greater concentrations of biomarkers of cartilage degradation (P < 0.05) as well as a lower ratio of anti-inflammatory to proinflammatory cytokines (P = 0.053) when compared with the low inflammation cluster. Patient demographics, bone bruise volumes, SF aspirate volumes, pain, and concomitant injuries did not differ between clusters. CONCLUSIONS: A subset of patients exhibited dysregulation of the inflammatory response after acute ACL injury which may increase the risk of posttraumatic osteoarthritis. This response does not appear to be a function of injury severity.
Asunto(s)
Lesiones del Ligamento Cruzado Anterior/inmunología , Cartílago Articular/inmunología , Inflamación/inmunología , Líquido Sinovial/inmunología , Adolescente , Adulto , Lesiones del Ligamento Cruzado Anterior/metabolismo , Lesiones del Ligamento Cruzado Anterior/cirugía , Reconstrucción del Ligamento Cruzado Anterior , Biomarcadores/metabolismo , Remodelación Ósea/inmunología , Cartílago Articular/enzimología , Citocinas/metabolismo , Femenino , Hemartrosis/inmunología , Humanos , Masculino , Medición de Resultados Informados por el Paciente , Adulto JovenRESUMEN
Preserving the mature articular cartilage of joints is a critical focus in the prevention and treatment of osteoarthritis. We determined whether the genetic inactivation of high-temperature requirement A1 (HtrA1) can significantly attenuate the degradation of articular or condylar cartilage. Two types of mouse models of osteoarthritis were used, a spontaneous mutant mouse model [type XI collagen-haploinsufficient (Col11a1+/-) mice] and two post-traumatic mouse models [destabilization of the medial meniscus (DMM) on the knee and a partial discectomy (PDE) on the temporomandibular joint]. Three different groups of mice were generated: i) HtrA1 was genetically deleted from Col11a1+/- mice (HtrA1-/-;Col11a1+/-), ii) HtrA1-deficient mice (HtrA1-/-) were subjected to DMM, and iii) HtrA1-/- mice were subjected to PDE. Knee and temporomandibular joints from the mice were characterized for evidence of cartilage degeneration. The degradation of articular or condylar cartilage was significantly delayed in HtrA1-/-;Col11a1+/- mice and HtrA1-/- mice after DMM or PDE. The amount of collagen type VI was significantly higher in the articular cartilage in HtrA1-/-;Col11a1+/- mice, compared with that in Col11a1+/- mice. The genetic removal of HtrA1 may delay the degradation of articular or condylar cartilage in mice.
Asunto(s)
Serina Peptidasa A1 que Requiere Temperaturas Altas/metabolismo , Osteoartritis/enzimología , Animales , Cartílago Articular/enzimología , Cartílago Articular/patología , Colágeno Tipo X/genética , Colágeno Tipo X/metabolismo , Modelos Animales de Enfermedad , Serina Peptidasa A1 que Requiere Temperaturas Altas/genética , Articulación de la Rodilla/enzimología , Articulación de la Rodilla/patología , Cóndilo Mandibular/enzimología , Cóndilo Mandibular/patología , Ratones , Ratones Noqueados , Osteoartritis/genética , Osteoartritis/patologíaRESUMEN
PURPOSE: The aim of this study is to investigate which ADAMTS genes play a major role in the development of primary hip osteoarthritis, by comparing the tissue and blood samples in patients with hip osteoarthritis and a control group. MATERIAL AND METHODS: Human articular cartilage was obtained from femoral heads of 15 patients with end stage osteoarthritis undergoing total hip replacement. As the control group, the cartilages was obtained from femoral heads of 15 patients, who did not have osteoarthritis or degenerative changes in hip joint, undergoing hip replacement following the fracture of the femoral neck. After the cartilage samples were taken from the resection materials, the DNA polymorphisms in the patients' cartilage samples were tested by Polymerase Chain Reaction (PCR), the serum levels of aggrecanase genes were analyzed with Enzyme-Linked ImmunoSorbent Assay (ELISA). RESULTS: The level of ADAMTS5 and ADAMTS9 genes were found significantly lower as a result of ELISA analysis degenerative arthritis group than the control group (p < 0,05). ADAMTS 1, 4, 8, 15 were similar between the two groups in ELISA analysis (p > 0,05). As a result of quantitative real time RT-PCR analysis, the level of ADAMTS8 mRNA increased 3.5 fold in hip degenerative arthritis group when compared with femoral neck fractures group. ADAMTS1, ADAMTS4 and ADAMTS5 expression levels in hip degenerative arthritis group were decreased 2.5, 2 and 2.5 fold, respectively. ADAMTS9, 15 were found to be similar between two groups. CONCLUSON: As a result of this study on hip osteoarthritis, the ADAMTS8 levels was found to be significantly higher in the end stage of hip osteoarthritis. Unlike similar studies on knee osteoarthritis, ADAMTS1,4,5 levels were found to be lower.
Asunto(s)
Proteínas ADAMTS/genética , Proteína ADAMTS1/genética , Cartílago Articular , Endopeptidasas , Osteoartritis de la Cadera , Proteínas ADAMTS/análisis , Anciano , Artroplastia de Reemplazo de Cadera/métodos , Cartílago Articular/enzimología , Cartílago Articular/patología , Correlación de Datos , Endopeptidasas/sangre , Endopeptidasas/genética , Femenino , Fracturas del Cuello Femoral/genética , Fracturas del Cuello Femoral/patología , Fracturas del Cuello Femoral/cirugía , Perfilación de la Expresión Génica/métodos , Humanos , Masculino , Persona de Mediana Edad , Osteoartritis de la Cadera/sangre , Osteoartritis de la Cadera/genética , Osteoartritis de la Cadera/patología , Osteoartritis de la Cadera/cirugíaRESUMEN
OBJECTIVE: Osteoarthritis (OA) appears to be associated with various metabolic disorders, but the potential contribution of amino acid metabolism to OA pathogenesis has not been clearly elucidated. Here, we explored whether alterations in the amino acid metabolism of chondrocytes could regulate OA pathogenesis. METHODS: Expression profiles of amino acid metabolism-regulating genes in primary-culture passage 0 mouse chondrocytes were examined by microarray analysis, and selected genes were further characterised in mouse OA chondrocytes and OA cartilage of human and mouse models. Experimental OA in mice was induced by destabilisation of the medial meniscus (DMM) or intra-articular (IA) injection of adenoviruses expressing catabolic regulators. The functional consequences of arginase II (Arg-II) were examined in Arg2-/- mice and those subjected to IA injection of an adenovirus encoding Arg-II (Ad-Arg-II). RESULTS: The gene encoding Arg-II, an arginine-metabolising enzyme, was specifically upregulated in chondrocytes under various pathological conditions and in OA cartilage from human patients with OA and various mouse models. Adenovirus-mediated overexpression of Arg-II in mouse joint tissues caused OA pathogenesis, whereas genetic ablation of Arg2 in mice (Arg2-/-) abolished all manifestations of DMM-induced OA. Mechanistically, Arg-II appears to cause OA cartilage destruction at least partly by upregulating the expression of matrix-degrading enzymes (matrix metalloproteinase 3 [MMP3] and MMP13) in chondrocytes via the nuclear factor (NF)-κB pathway. CONCLUSIONS: Our results indicate that Arg-II is a crucial regulator of OA pathogenesis in mice. Although chondrocytes of human and mouse do not identically, but similarly, respond to Arg-II, our results suggest that Arg-II could be a therapeutic target of OA pathogenesis.
Asunto(s)
Arginasa/fisiología , Artritis Experimental/enzimología , Cartílago Articular/enzimología , Condrocitos/enzimología , Osteoartritis/enzimología , Animales , Artritis Experimental/inducido químicamente , Modelos Animales de Enfermedad , Humanos , Metaloproteinasa 13 de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/metabolismo , Ratones , Osteoartritis/inducido químicamente , Regulación hacia ArribaRESUMEN
OBJECTIVE: We investigated the effects of 29-kDa amino-terminal fibronectin fragment (29-kDa FN-f) on xylosyltransferase-1 (XT-1), an essential anabolic enzyme that catalyzes the initial and rate-determining step in glycosaminoglycan chain synthesis, in human primary chondrocytes. METHODS: Proteoglycan and XT-1 expression in cartilage tissue was analyzed using safranin O staining and immunohistochemistry. The effects of 29-kDa FN-f on XT-1 expression and its relevant signaling pathway were analyzed by quantitative real-time-PCR, immunoblotting, chromatin immunoprecipitation, and immunoprecipitation assays. The receptors for 29-kDa FN-f were investigated using small interference RNA and blocking antibodies. RESULTS: The expression of XT-1 was significantly lower in human osteoarthritis cartilage than in normal cartilage. Intra-articular injection of 29-kDa FN-f reduced proteoglycan levels and XT-1 expression in murine cartilage. In addition, in 29-kDa FN-f-treated cells, XT-1 expression was significantly suppressed at both the mRNA and protein levels, modulated by the transcription factors specificity protein 1 (Sp1), Sp3, and activator protein 1 (AP-1). The 29-kDa FN-f suppressed the binding of Sp1 to the promoter region of XT-1 and enhanced the binding of Sp3 and AP-1. Inhibition of mitogen-activated protein kinase and nuclear factor kappa B signaling pathways restored the 29-kDa FN-f-inhibited XT-1 expression, along with the altered expression of Sp1 and Sp3. Blockading toll-like receptor 2 (TLR-2) and integrin α5ß1 via siRNA and blocking antibodies revealed that the effects of 29-kDa FN-f on XT-1 expression were mediated through the TLR-2 and integrin α5ß1 signaling pathways. CONCLUSION: These results demonstrate that 29-kDa FN-f negatively affects cartilage anabolism by regulating glycosaminoglycan formation through XT-1.
Asunto(s)
Cartílago Articular/enzimología , Condrocitos/enzimología , Inhibidores Enzimáticos/farmacología , Fibronectinas/farmacología , Osteoartritis de la Rodilla/enzimología , Pentosiltransferasa/antagonistas & inhibidores , Anciano , Animales , Cartílago Articular/efectos de los fármacos , Cartílago Articular/patología , Células Cultivadas , Condrocitos/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Femenino , Humanos , Masculino , Ratones Endogámicos C57BL , Persona de Mediana Edad , Osteoartritis de la Rodilla/genética , Osteoartritis de la Rodilla/patología , Pentosiltransferasa/biosíntesis , Pentosiltransferasa/genética , Pentosiltransferasa/metabolismo , Fragmentos de Péptidos/farmacología , ARN Mensajero/genética , Transducción de Señal/efectos de los fármacos , Factor de Transcripción Sp1/genética , Factor de Transcripción Sp1/metabolismo , Factor de Transcripción Sp3/genética , Factor de Transcripción Sp3/metabolismo , Factor de Transcripción AP-1/genética , Factor de Transcripción AP-1/metabolismo , Transcripción Genética , UDP Xilosa Proteína XilosiltransferasaRESUMEN
The etiology of joint tissue degeneration following rotator cuff tear remains unclear. Thus, the purpose of this study was to understand the timeline of protease activity in the soft tissues of the shoulder (tendon, muscle, and cartilage) that may lead to down-stream degeneration following rotator cuff tear. A well-established rat model involving suprascapular nerve denervation and supraspinatus/infraspinatus tendon transection was employed. Histological staining and/or micro-computed tomography (µCT) were used to observe structural damage in the supraspinatus tendon and muscle, humeral head cartilage, and subchondral bone. Multiplex gelatin zymography was utilized to assess protease activity in the supraspinatus tendon and muscle, and humeral head cartilage. Zymography analysis demonstrated that cathepsins were upregulated in the first week in all tissues, while MMP-2 maintained prolonged activity in supraspinatus tendon between 1 and 3 weeks and increased only at 3 weeks in supraspinatus muscle. In supraspinatus tendon, increased cathepsin L and MMP-2 activity in the first week was concurrent with matrix disorganization and infiltration of inflammatory cells. In contrast, significant upregulation of cathepsin L and K activity in supraspinatus muscle and humeral head cartilage did not correspond to any visible tissue damage at 1 week. However, focal defects developed in half of all animals' humeral head cartilage by 12 weeks (volume: 0.12 ± 0.09 mm3 ). This work provides a more comprehensive understanding of biochemical changes to joint tissue over time following rotator cuff tear. Overall, this provides insight into potential therapeutic targets and will better inform ideal intervention times and treatments for each tissue. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:490-502, 2019.
Asunto(s)
Catepsinas/metabolismo , Metaloproteinasas de la Matriz/metabolismo , Lesiones del Manguito de los Rotadores/enzimología , Manguito de los Rotadores/enzimología , Articulación del Hombro/enzimología , Animales , Hueso Esponjoso/diagnóstico por imagen , Cartílago Articular/diagnóstico por imagen , Cartílago Articular/enzimología , Masculino , Ratas Sprague-Dawley , Manguito de los Rotadores/patología , Lesiones del Manguito de los Rotadores/diagnóstico por imagen , Lesiones del Manguito de los Rotadores/patología , Articulación del Hombro/diagnóstico por imagen , Factores de Tiempo , Microtomografía por Rayos XRESUMEN
OBJECTIVE: Cartilage destruction in osteoarthritis (OA) is mediated mainly by matrix metalloproteinases (MMPs) and ADAMTS. The therapeutic candidature of targeting aggrecanases has not yet been defined in joints in which spontaneous OA arises from genetic susceptibility, as in the case of the STR/Ort mouse, without a traumatic or load-induced etiology. In addition, we do not know the long-term effect of aggrecanase inhibition on bone. We undertook this study to assess the potential aggrecanase selectivity of a variant of tissue inhibitor of metalloproteinases 3 (TIMP-3), called [-1A]TIMP-3, on spontaneous OA development and bone formation in STR/Ort mice. METHODS: Using the background of STR/Ort mice, which develop spontaneous OA, we generated transgenic mice that overexpress [-1A]TIMP-3, either ubiquitously or conditionally in chondrocytes. [-1A]TIMP-3 has an extra alanine at the N-terminus that selectively inhibits ADAMTS but not MMPs. We analyzed a range of OA-related measures in all mice at age 40 weeks. RESULTS: Mice expressing high levels of [-1A]TIMP-3 were protected against development of OA, while those expressing low levels were not. Interestingly, we also found that high levels of [-1A]TIMP-3 transgene overexpression resulted in increased bone mass, particularly in females. This regulation of bone mass was at least partly direct, as adult mouse primary osteoblasts infected with [-1A]TIMP-3 in vitro showed elevated rates of mineralization. CONCLUSION: The results provide evidence that [-1A]TIMP-3-mediated inhibition of aggrecanases can protect against cartilage degradation in a naturally occurring mouse model of OA, and they highlight a novel role that aggrecanase inhibition may play in increased bone mass.