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1.
Int J Mol Sci ; 22(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34360771

RESUMO

Inflammation plays a central role in the pathogenesis of knee PTOA after knee trauma. While a comprehensive therapy capable of preventing or delaying post-traumatic osteoarthritis (PTOA) progression after knee joint injury does not yet clinically exist, current literature suggests that certain aspects of early post-traumatic pathology of the knee joint may be prevented or delayed by anti-inflammatory therapeutic interventions. We discuss multifaceted therapeutic approaches that may be capable of effectively reducing the continuous cycle of inflammation and concomitant processes that lead to cartilage degradation as well as those that can simultaneously promote intrinsic repair processes. Within this context, we focus on early disease prevention, the optimal timeframe of treatment and possible long-lasting sustained delivery local modes of treatments that could prevent knee joint-associated PTOA symptoms. Specifically, we identify anti-inflammatory candidates that are not only anti-inflammatory but also anti-degenerative, anti-apoptotic and pro-regenerative.


Assuntos
Anti-Inflamatórios/uso terapêutico , Traumatismos do Joelho , Osteoartrite do Joelho , Animais , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Humanos , Traumatismos do Joelho/complicações , Traumatismos do Joelho/tratamento farmacológico , Traumatismos do Joelho/metabolismo , Traumatismos do Joelho/patologia , Articulação do Joelho/metabolismo , Articulação do Joelho/patologia , Osteoartrite do Joelho/tratamento farmacológico , Osteoartrite do Joelho/etiologia , Osteoartrite do Joelho/metabolismo , Osteoartrite do Joelho/patologia
2.
Int J Mol Sci ; 22(15)2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34360640

RESUMO

Osteoarthritis (OA) is a major public health challenge that imposes a remarkable burden on the affected individuals and the healthcare system. Based on the clinical observation, males and females have different prevalence rates and severity levels of OA. Thus, sex-based differences may play essential roles in OA's prognosis and treatment outcomes. To date, the comprehensive understanding of the relationship between sex and OA is still largely lacking. In the current study, we analyzed a published transcriptome dataset of knee articular cartilage (GSE114007) from 18 healthy (five females, 13 males) and 20 OA (11 females, nine males) donors to provide a slight insight into this important but complex issue. First, comparing female healthy cartilage samples with those of males revealed 36 differential expression genes (DEGs), indicating the fundamental sex-related differences at the molecular level. Meanwhile, 923 DEGs were distinguished between OA and healthy female cartilage, which can be enriched to 15 Reactome pathways. On the other hand, when comparing OA and healthy male cartilage, there are only 419 DEGs were identified, and only six pathways were enriched against the Reactome database. The different signaling response to OA in the male and female cartilage was further enforced by recognizing 50 genes with significantly different OA-responsive expression fold changes in males and females. Particularly, 14 Reactome pathways, such as "Extracellular matrix organization", "Collagen biosynthesis and modifying enzymes", "Dissolution of fibrin clot", and "Platelet Aggregation (Plug formation)", can be noted from these 50 sex-dependent OA-responsive genes. Overall, the current study explores the Sex as a Biological Variable (SABV) at the transcriptomic level in the knee articular cartilage in both healthy status and OA event, which could help predict the differential OA prognosis and treatment outcome of males and female patients.


Assuntos
Cartilagem Articular/patologia , Redes Reguladoras de Genes , Osteoartrite do Joelho/patologia , Transcriptoma , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Cartilagem Articular/metabolismo , Estudos de Casos e Controles , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/genética , Osteoartrite do Joelho/metabolismo , Fatores Sexuais , Adulto Jovem
3.
Int J Mol Sci ; 22(13)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34281202

RESUMO

Autologous chondrocyte implantation (ACI) is a cell therapy for the treatment of focal cartilage defects. The ACI product that is currently approved for use in the European Union (EU) consists of spheroids of autologous matrix-associated chondrocytes. These spheroids are spherical aggregates of ex vivo expanded human autologous chondrocytes and their self-synthesized extracellular matrix. The aim is to provide an overview of the preclinical and nonclinical studies that have been performed to ensure reproducible quality, safety, and efficacy of the cell therapy, and to evaluate the clinical data on ACI with spheroids. A systematic review was performed to include all English publications on self-aggregated spheroids of chondrocytes cultured in autologous serum without other supplements. A total of 20 publications were included, 7 pre- and nonclinical and 13 clinical research publications. The pre- and nonclinical research publications describe the development from concept to in vivo efficacy and quality- and safety-related aspects such as biodistribution, tumorigenicity, genetic stability, and potency. The evaluation of clinical research shows short- to mid-term safety and efficacy for the ACI with spheroid-based treatment of cartilage defects in both randomized clinical trials with selected patients, as well as in routine treatment providing real-world data in more complex patients.


Assuntos
Condrócitos/transplante , Animais , Doenças das Cartilagens/cirurgia , Doenças das Cartilagens/terapia , Cartilagem Articular/cirurgia , Terapia Baseada em Transplante de Células e Tecidos/métodos , Condrócitos/citologia , Condrócitos/metabolismo , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Humanos , Traumatismos do Joelho/cirurgia , Traumatismos do Joelho/terapia , Articulação do Joelho/metabolismo , Articulação do Joelho/patologia , Procedimentos Ortopédicos/métodos , Osteoartrite do Joelho/metabolismo , Osteoartrite do Joelho/patologia , Osteoartrite do Joelho/terapia , Esferoides Celulares , Transplante Autólogo
4.
Int J Mol Sci ; 22(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208719

RESUMO

Synovitis of the knee synovium is proven to be a precursor of knee osteoarthritis (OA), leading to a radiologically advanced stage of the disease. This study was conducted to elucidate the expression pattern of different inflammatory factors-NF-kB, iNOS, and MMP-9 in a subpopulation of synovial cells. Thirty synovial membrane intra-operative biopsies of patients (ten controls, ten with early OA, and ten with advanced OA, according to the Kellgren-Lawrence radiological score) were immunohistochemically stained for NF-kB, iNOS, and MMP9, and for different cell markers for macrophages, fibroblasts, leukocytes, lymphocytes, blood vessel endothelial cells, and blood vessel smooth muscle cells. The total number of CD68+/NF-kB+ cells/mm2 in the intima of early OA patients (median = 2359) was significantly higher compared to the total number of vimentin+/Nf-kB+ cells/mm2 (median = 1321) and LCA+/NF-kB+ cells/mm2 (median = 64) (p < 0.001 and p < 0.0001, respectively). The total number of LCA+/NF-kB+ cells/mm2 in the subintima of advanced OA patients (median = 2123) was significantly higher compared to the total number of vimentin+/NF-kB+ cells/mm2 (median = 14) and CD68+/NF-kB+ cells/mm2 (median = 29) (p < 0.0001). The total number of CD68+/iNOS+ cells/mm2 in the intima of both early and advanced OA patients was significantly higher compared to the total number of vimentin+/iNOS+ cells/mm2 and LCA+/iNOS+ cells/mm2 (p < 0.0001 and p < 0.001, respectively). The total number of CD68+/MMP-9+ cells/mm2 in the intima of both early and advanced OA patients was significantly higher compared to the total number of vimentin+/MMP-9+ cells/mm2 and CD5+/MMP-9+ cells/mm2 (p < 0.0001). Macrophages may have a leading role in OA progression through the NF-kB production of inflammatory factors (iNOS and MMP-9) in the intima, except in advanced OA, where leukocytes could have a dominant role through NF-kB production in subintima. The blocking of macrophageal and leukocyte NF-kB expression is a possible therapeutic target as a disease modifying drug.


Assuntos
NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Osteoartrite do Joelho/metabolismo , Osteoartrite do Joelho/patologia , Adulto , Biomarcadores , Feminino , Imunofluorescência , Humanos , Imuno-Histoquímica , Masculino , Metaloproteinases da Matriz/metabolismo , Osteoartrite do Joelho/etiologia , Índice de Gravidade de Doença , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia , Adulto Jovem
5.
Nat Commun ; 12(1): 4161, 2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34230488

RESUMO

Given the pleiotropic nature of coding sequences and that many loci exhibit multiple disease associations, it is within non-coding sequence that disease-specificity likely exists. Here, we focus on joint disorders, finding among replicated loci, that GDF5 exhibits over twenty distinct associations, and we identify causal variants for two of its strongest associations, hip dysplasia and knee osteoarthritis. By mapping regulatory regions in joint chondrocytes, we pinpoint two variants (rs4911178; rs6060369), on the same risk haplotype, which reside in anatomical site-specific enhancers. We show that both variants have clinical relevance, impacting disease by altering morphology. By modeling each variant in humanized mice, we observe joint-specific response, correlating with GDF5 expression. Thus, we uncouple separate regulatory variants on a common risk haplotype that cause joint-specific disease. By broadening our perspective, we finally find that patterns of modularity at GDF5 are also found at over three-quarters of loci with multiple GWAS disease associations.


Assuntos
Éxons , Luxação do Quadril/genética , Luxação do Quadril/metabolismo , Osteoartrite do Joelho/genética , Osteoartrite do Joelho/metabolismo , Animais , Condrócitos , Modelos Animais de Doenças , Regulação da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Fator 5 de Diferenciação de Crescimento/genética , Fator 5 de Diferenciação de Crescimento/metabolismo , Humanos , Camundongos , Fenótipo , Sequências Reguladoras de Ácido Nucleico
6.
Int J Mol Sci ; 22(14)2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34298911

RESUMO

Osteoarthritis (OA) is the most common articular degenerative disease characterized by chronic pain, joint inflammation, and movement limitations, which are significantly influenced by aberrant epigenetic modifications of numerous OA-susceptible genes. Recent studies revealed that both the abnormal activation and differential expression of histone deacetylases (HDACs) might contribute to OA pathogenesis. In this study, we investigated the chondroprotective effects of a marine-derived HDAC inhibitor, panobinostat, on anterior cruciate ligament transection (ACLT)-induced experimental OA rats. The intra-articular administration of 2 or 10 µg of panobinostat (each group, n = 7) per week from the 6th to 17th week attenuates ACLT-induced nociceptive behaviors, including secondary mechanical allodynia and weight-bearing distribution. Histopathological and microcomputed tomography analysis showed that panobinostat significantly prevents cartilage degeneration after ACLT. Moreover, intra-articular panobinostat exerts hypertrophic effects in the chondrocytes of articular cartilage by regulating the protein expressions of HDAC4, HDAC6, HDAC7, runt-domain transcription factor-2, and matrix metalloproteinase-13. The study indicated that HDACs might have different modulations on the chondrocyte phenotype in the early stages of OA development. These results provide new evidence that panobinostat may be a potential therapeutic drug for OA.


Assuntos
Ligamento Cruzado Anterior/efeitos dos fármacos , Cartilagem Articular/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Osteoartrite do Joelho/tratamento farmacológico , Dor/tratamento farmacológico , Panobinostat/farmacologia , Animais , Ligamento Cruzado Anterior/metabolismo , Lesões do Ligamento Cruzado Anterior/tratamento farmacológico , Lesões do Ligamento Cruzado Anterior/metabolismo , Doenças das Cartilagens/tratamento farmacológico , Doenças das Cartilagens/metabolismo , Cartilagem Articular/metabolismo , Condrócitos/metabolismo , Modelos Animais de Doenças , Masculino , Osteoartrite do Joelho/metabolismo , Dor/metabolismo , Ratos , Ratos Wistar , Suporte de Carga
7.
Int J Mol Sci ; 22(14)2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34299030

RESUMO

Neutrophil-derived microvesicles (NDMVs) have the potential to exert anti-inflammatory effects. Our study aimed to explore the effects of NDMVs on proinflammatory cytokines expressed by tumor necrosis factor α (TNFα)-stimulated fibroblast-like synoviocytes (FLS). FLS were isolated from the synovium of knee osteoarthritis (OA) patients undergoing surgery. NDMVs, isolated from TNFα-stimulated healthy neutrophils, were characterized by electron microscopy and nanoparticle tracking analysis. MTT and scratch wound healing assays were used to measure FLS viability and migration after treatment with NDMVs, while internalization of fluorescently labeled NDMVs was appraised by flow cytometry and confocal microscopy. Levels of proinflammatory cytokines in supernatants were quantified by the Bio-Plex system. Incubation of FLS with NDMVs at a vesicle/cell ratio of 100 resulted in a time-dependent uptake, with 35% of synoviocytes containing microvesicles over a 6-24 h time period, with no significant change in cell viability. TNFα stimulated the cytokine expression in FLS, and NDMVs down-regulated TNFα-induced expression of IL-5, IL-6, IL-8, MCP-1, IFNγ and MIP-1ß. However, this down-regulation was selective, as NDMVs had no significant effects on TNFα-stimulated expression of IL-2 or IL-4. NDMVs were internalized by FLS to inhibit TNFα-stimulated broad-spectrum proinflammatory cytokine secretion. NDMVs, therefore, may exhibit an anti-inflammatory role in the regulation of the FLS function.


Assuntos
Micropartículas Derivadas de Células/metabolismo , Fibroblastos/metabolismo , Mediadores da Inflamação/metabolismo , Neutrófilos/metabolismo , Osteoartrite do Joelho/metabolismo , Sinoviócitos/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Micropartículas Derivadas de Células/patologia , Células Cultivadas , Fibroblastos/efeitos dos fármacos , Fibroblastos/imunologia , Fibroblastos/patologia , Humanos , Neutrófilos/patologia , Osteoartrite do Joelho/tratamento farmacológico , Osteoartrite do Joelho/imunologia , Osteoartrite do Joelho/patologia , Sinoviócitos/efeitos dos fármacos , Sinoviócitos/imunologia , Sinoviócitos/patologia
8.
Elife ; 102021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-34085927

RESUMO

Meniscal tears are associated with a high risk of osteoarthritis but currently have no disease-modifying therapies. Using a Gli1 reporter line, we found that Gli1+ cells contribute to the development of meniscus horns from 2 weeks of age. In adult mice, Gli1+ cells resided at the superficial layer of meniscus and expressed known mesenchymal progenitor markers. In culture, meniscal Gli1+ cells possessed high progenitor activities under the control of Hh signal. Meniscus injury at the anterior horn induced a quick expansion of Gli1-lineage cells. Normally, meniscal tissue healed slowly, leading to cartilage degeneration. Ablation of Gli1+ cells further hindered this repair process. Strikingly, intra-articular injection of Gli1+ meniscal cells or an Hh agonist right after injury accelerated the bridging of the interrupted ends and attenuated signs of osteoarthritis. Taken together, our work identified a novel progenitor population in meniscus and proposes a new treatment for repairing injured meniscus and preventing osteoarthritis.


Assuntos
Proteínas Hedgehog/metabolismo , Meniscos Tibiais/cirurgia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Osteoartrite do Joelho/prevenção & controle , Lesões do Menisco Tibial/cirurgia , Cicatrização , Proteína GLI1 em Dedos de Zinco/metabolismo , Animais , Linhagem da Célula , Proliferação de Células , Modelos Animais de Doenças , Proteínas Hedgehog/genética , Humanos , Masculino , Meniscos Tibiais/metabolismo , Meniscos Tibiais/patologia , Camundongos Knockout , Osteoartrite do Joelho/genética , Osteoartrite do Joelho/metabolismo , Osteoartrite do Joelho/patologia , Transdução de Sinais , Suínos , Porco Miniatura , Lesões do Menisco Tibial/genética , Lesões do Menisco Tibial/metabolismo , Lesões do Menisco Tibial/patologia , Fatores de Tempo , Proteína GLI1 em Dedos de Zinco/genética
9.
Int J Mol Sci ; 22(11)2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-34071929

RESUMO

Knee osteoarthritis (OA) is a degenerative knee joint disease that results from the breakdown of joint cartilage and underlying bone, affecting about 3.3% of the world's population. As OA is a multifactorial disease, the underlying pathological process is closely associated with genetic changes in articular cartilage and bone. Many studies have focused on the role of small noncoding RNAs in OA and identified numbers of microRNAs that play important roles in regulating bone and cartilage homeostasis. The connection between other types of small noncoding RNAs, especially tRNA-derived fragments and knee osteoarthritis is still elusive. The observation that there is limited information about small RNAs different than miRNAs in knee OA was very surprising to us, especially given the fact that tRNA fragments are known to participate in a plethora of human diseases and a portion of them are even more abundant than miRNAs. Inspired by these findings, in this review we have summarized the possible involvement of microRNAs and tRNA-derived fragments in the pathology of knee osteoarthritis.


Assuntos
Biomarcadores , Regulação da Expressão Gênica , Osteoartrite do Joelho/etiologia , Osteoartrite do Joelho/metabolismo , Pequeno RNA não Traduzido/genética , Animais , Suscetibilidade a Doenças , Perfilação da Expressão Gênica , Humanos , MicroRNAs , Técnicas de Diagnóstico Molecular , Osteoartrite do Joelho/diagnóstico , RNA de Transferência , Transcriptoma
10.
Clin Immunol ; 227: 108718, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33819576

RESUMO

BACKGROUND: Osteoarthritis (OA) is a common inflammatory disease characterized by articular cartilage degeneration and injury. Circular RNAs (circRNAs) are widely involved in the development of human diseases, including OA. The objective of this study was to investigate the function and functional mechanism of circ_0001103 in OA. METHODS: Cell model of OA was established by treating chondrocytes with interleukin-1ß (IL-1ß). The expression of circ_0001103, miR-375 and sirtuin 1 (SIRT1) mRNA was measured using quantitative real-time polymerase chain reaction (qRT-PCR). Cell viability was assessed using cell counting kit-8 (CCK-8) assay. Cell apoptosis was determined using flow cytometry assay. The expression levels of inflammatory factors were quantified by qRT-PCR. The expression of extracellular matrix (ECM) metabolism-related markers, including Collagen Type II Alpha 1 Chain (COL2A1) and A disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4), was detected by western blot. Predicted target relationship between miR-375 and circ_0001103 or SIRT1 by the bioinformatics tools was validated by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. RESULTS: Circ_0001103 was downregulated in OA tissues and IL-1ß-induced chondrocytes. Overexpression of circ_0001103 attenuated IL-1ß-induced chondrocyte apoptosis, inflammatory responses and ECM degradation. MiR-375 was targeted by circ_0001103, and miR-375 could bind to SIRT1. Circ_0001103 overexpression increased the expression of SIRT1 by suppressing miR-375. Rescue experiments suggested that miR-375 restoration reversed the effects of circ_0001103 overexpression, and SIRT1 knockdown overturned the effects of miR-375 inhibition. CONCLUSION: Circ_0001103 governed the miR-375/SIRT1 axis to ameliorate IL-1ß-induced chondrocyte injuries, implying that circ_0001103 was a promising biomarker in OA pathogenesis.


Assuntos
Apoptose/genética , Condrócitos/metabolismo , Inflamação/genética , MicroRNAs/genética , Osteoartrite do Joelho/genética , RNA Circular/genética , Sirtuína 1/genética , Cartilagem Articular/citologia , Cartilagem Articular/metabolismo , Estudos de Casos e Controles , Condrócitos/efeitos dos fármacos , Matriz Extracelular/metabolismo , Regulação da Expressão Gênica , Humanos , Inflamação/metabolismo , Interleucina-1beta/farmacologia , MicroRNAs/metabolismo , Osteoartrite do Joelho/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Sirtuína 1/metabolismo
11.
Bioorg Med Chem ; 38: 116132, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33872958

RESUMO

Since 2007, Metalloproteases (MMPs) have been considered potential targets for treating osteoarthritis (OA), for which the primary pathogenic event is the extensive degeneration of articular cartilage. MMP3 is an enzyme critical for these degenerative changes. However, problems of selectivity, low bioavailability and poor metabolic profile during clinical trials of MMPs inhibitors (MMPIs) led to limited beneficial effect and thus did not justify further pursuit of the clinical studies. In a previous work, a new alkyl derivative of hyaluronic acid (HA), HYADD4®, previously approved as intra-articular treatment for knee OA, was studied in vitro and in vivo as MMP3I. Molecular simulation studies confirmed the interaction between the alkyl side chain of this HA derivative and the additional S1' pocket of MMP3. However, the high MW and the polar HA backbone of HYADD4® imply a high desolvation energy cost, which can potentially decrease its inhibitory potency. In this study, a new class of MMP3Is based on a small peptide backbone (CGV) chemically derivatized with an alkyl chain was developed through interactive cycles of design, synthesis and screening, accompanied by computational evaluation and optimization. Two MMP3Is, e(I) and l(II), were selected because of their effective inhibitory activity (3.2 and 10.2 µM, respectively) and water solubility. Both MMPIs showed a broad range of inhibitory effects against almost all the MMPs tested. In an in vitro model of inflammatory OA, e(I) was the most effective MMPI: at the concentration of 93 µM, it reversed inflammatory outcomes. Moreover, because of its amphiphilic structure, the e(I) MMPI promoted stable micellar formulation at concentrations higher than 0.2 mg/mL in water. The findings were confirmed by TEM and Nile red staining analysis. Based on these results, the e(I) MMPI can be considered a good candidate for the intra-articular treatment of OA, and the micellar formulation of this peptide in an aqueous buffer can potentially increase the bioavailability and, thus, the efficacy of the MMPIs.


Assuntos
Inibidores Enzimáticos/farmacologia , Metaloproteinase 3 da Matriz/metabolismo , Osteoartrite do Joelho/tratamento farmacológico , Peptídeos/farmacologia , Tensoativos/farmacologia , Animais , Bovinos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Osteoartrite do Joelho/metabolismo , Peptídeos/síntese química , Peptídeos/química , Relação Estrutura-Atividade , Tensoativos/síntese química , Tensoativos/química
12.
Int J Mol Sci ; 22(6)2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33802838

RESUMO

Osteoarthritis (OA) is a multifactorial disease which is characterized by a change in the homeostasis of the extracellular matrix (ECM). The ECM is essential for the function of the articular cartilage and plays an important role in cartilage mechanotransduction. To provide a better understanding of the interaction between the ECM and the actin cytoskeleton, we investigated the localization and expression of the Ca2+-dependent proteins cartilage oligomeric matrix protein (COMP), thrombospondin-1 (TSP-1), plastin 3 (PLS3) and stromal interaction molecule 1 (STIM1). We investigated 16 patients who suffered from varus knee OA and performed a topographical analysis of the cartilage from the medial and lateral compartment of the proximal tibial plateau. In a varus knee, OA is more pronounced in the medial compared to the lateral compartment as a result of an overloading due to the malalignment. We detected a location-dependent staining of PLS3 and STIM1 in the articular cartilage tissue. The staining intensity for both proteins correlated with the degree of cartilage degeneration. The staining intensity of TSP-1 was clearly reduced in the cartilage of the more affected medial compartment, an observation that was confirmed in cartilage extracts by immunoblotting. The total amount of COMP was unchanged; however, slight changes were detected in the localization of the protein. Our results provide novel information on alterations in OA cartilage suggesting that Ca2+-dependent mechanotransduction between the ECM and the actin cytoskeleton might play an essential role in the pathomechanism of OA.


Assuntos
Cartilagem Articular/metabolismo , Articulação do Joelho/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas dos Microfilamentos/metabolismo , Osteoartrite do Joelho/metabolismo , Molécula 1 de Interação Estromal/metabolismo , Trombospondinas/metabolismo , Idoso , Idoso de 80 Anos ou mais , Proteína de Matriz Oligomérica de Cartilagem/metabolismo , Condrócitos/metabolismo , Feminino , Humanos , Articulação do Joelho/patologia , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/patologia , Transporte Proteico
13.
Int J Mol Sci ; 22(5)2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33807695

RESUMO

Osteoarthritis (OA) is a degenerative and chronic joint disease characterized by clinical symptoms and distortion of joint tissues. It primarily damages joint cartilage, causing pain, swelling, and stiffness around the joint. It is the major cause of disability and pain. The prevalence of OA is expected to increase gradually with the aging population and increasing prevalence of obesity. Many potential therapeutic advances have been made in recent years due to the improved understanding of the underlying mechanisms, diagnosis, and management of OA. Embryonic stem cells and induced pluripotent stem cells differentiate into chondrocytes or mesenchymal stem cells (MSCs) and can be used as a source of injectable treatments in the OA joint cavity. MSCs are known to be the most studied cell therapy products in cell-based OA therapy owing to their ability to differentiate into chondrocytes and their immunomodulatory properties. They have the potential to improve cartilage recovery and ultimately restore healthy joints. However, despite currently available therapies and advances in research, unfulfilled medical needs persist for OA treatment. In this review, we focused on the contents of non-cellular and cellular therapies for OA, and briefly summarized the results of clinical trials for cell-based OA therapy to lay a solid application basis for clinical research.


Assuntos
Condrócitos , Osteoartrite do Joelho , Transplante de Células-Tronco , Células-Tronco , Condrócitos/metabolismo , Condrócitos/transplante , Humanos , Osteoartrite do Joelho/diagnóstico , Osteoartrite do Joelho/metabolismo , Osteoartrite do Joelho/fisiopatologia , Osteoartrite do Joelho/terapia , Células-Tronco/metabolismo , Células-Tronco/patologia
14.
Int J Mol Sci ; 22(6)2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33799588

RESUMO

We have been studying mesenchymal stem cells (MSCs) in synovial fluid and the intra-articular injection of synovial MSCs in osteoarthritis (OA) knees. Here, mainly based on our own findings, we overview the characteristics of endogenous MSCs in the synovial fluid of OA knees and their mode of action when injected exogenously into OA knees. Many MSCs similar to synovial MSCs were detected in the synovial fluid of human OA knees, and their number correlated with the radiological OA grade. Our suspended synovium culture model demonstrated the release of MSCs from the synovium through a medium into a non-contacting culture dish. In OA knees, endogenous MSCs possibly mobilize in a similar manner from the synovium through the synovial fluid and act protectively. However, the number of mobilized MSCs is limited; therefore, OA progresses in its natural course. Synovial MSC injections inhibited the progression of cartilage degeneration in a rat OA model. Injected synovial MSCs migrated into the synovium, maintained their MSC properties, and increased the gene expressions of TSG-6, PRG-4, and BMP-2. Exogenous synovial MSCs can promote anti-inflammation, lubrication, and cartilage matrix synthesis in OA knees. Based on our findings, we have initiated a human clinical study of synovial MSC injections in OA knees.


Assuntos
Condrogênese/genética , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/fisiologia , Osteoartrite do Joelho/terapia , Líquido Sinovial/fisiologia , Animais , Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 2/metabolismo , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Movimento Celular , Proliferação de Células , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Injeções Intra-Articulares , Células-Tronco Mesenquimais/citologia , Osteoartrite do Joelho/genética , Osteoartrite do Joelho/metabolismo , Osteoartrite do Joelho/patologia , Proteoglicanas/genética , Proteoglicanas/metabolismo , Ratos , Líquido Sinovial/citologia , Transplante Heterólogo , Resultado do Tratamento
15.
Int J Mol Sci ; 22(5)2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33804447

RESUMO

Interleukin (IL)-1ß is an important pro-inflammatory cytokine in the progression of osteoarthritis (OA), which impairs mitochondrial function and induces the production of nitric oxide (NO) in chondrocytes. The aim was to investigate if blockade of NO production prevents IL-1ß-induced mitochondrial dysfunction in chondrocytes and whether cAMP and AMP-activated protein kinase (AMPK) affects NO production and mitochondrial function. Isolated human OA chondrocytes were stimulated with IL-1ß in combination with/without forskolin, L-NIL, AMPK activator or inhibitor. The release of NO, IL-6, PGE2, MMP3, and the expression of iNOS were measured by ELISA or Western blot. Parameters of mitochondrial respiration were measured using a seahorse analyzer. IL-1ß significantly induced NO release and mitochondrial dysfunction. Inhibition of iNOS by L-NIL prevented IL-1ß-induced NO release and mitochondrial dysfunction but not IL-1ß-induced release of IL-6, PGE2, and MMP3. Enhancement of cAMP by forskolin reduced IL-1ß-induced NO release and prevented IL-1ß-induced mitochondrial impairment. Activation of AMPK increased IL-1ß-induced NO production and the negative impact of IL-1ß on mitochondrial respiration, whereas inhibition of AMPK had the opposite effects. NO is critically involved in the IL-1ß-induced impairment of mitochondrial respiration in human OA chondrocytes. Increased intracellular cAMP or inhibition of AMPK prevented both IL-1ß-induced NO release and mitochondrial dysfunction.


Assuntos
Condrócitos/efeitos dos fármacos , Inflamação/prevenção & controle , Interleucina-1beta/farmacologia , Mitocôndrias/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico/metabolismo , Osteoartrite do Joelho/prevenção & controle , Células Cultivadas , Condrócitos/metabolismo , Condrócitos/patologia , Feminino , Humanos , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Mitocôndrias/patologia , NF-kappa B/genética , NF-kappa B/metabolismo , Osteoartrite do Joelho/induzido quimicamente , Osteoartrite do Joelho/metabolismo , Osteoartrite do Joelho/patologia
16.
Knee ; 29: 365-373, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33690017

RESUMO

BACKGROUND: Chondrocyte transplantation to address cartilage damage is an established solution. Because hyaluronic acid (HA) is an essential component for homeostasis of the cartilage, in order to arrive at methodologies to utilize its advantages in cell-based therapies, we compared the HA retention capability of a thermoreversible gelation polymer scaffold-based environment (3D-TGP) with conventional in vitro cell culture methodologies. METHODS: Chondrocytes derived from osteoarthritis-affected knee joint cartilage of elderly patients were used and accomplished in three phases. In Phase I, the levels of HA secreted by chondrocytes were measured in culture supernatant. In Phase II, retention capacity of externally added HA was quantified indirectly by measuring the HA released in culture supernatant, and in Phase III, the expression of CD44 on cells was analysed by immunohistochemistry. RESULTS: In Phase I, the average HA in the 3D supernatant was 3% that of 2D. In phase II, 80% of externally added HA was detected in the 2D on day 7, while in 3D-TGP, only 0.1% was released until day 21. In Phase III, 2D yielded individual cells that started degenerating from the third week; in 3D-TGP cells grew for a longer duration, formed a tissue-like architecture with extracellular matrix with significantly intense staining of CD44 than 2D. CONCLUSION: The capability of the 3D-TGP culture environment to retain HA and support chondrocytes to grow with a tissue-like architecture expressing higher HA content is considered advantageous as it serves as an in vitro culture platform that enables tissue engineering of cartilage tissue with native hyaline phenotype and higher HA expression. The in vitro environment being conducive, based on this data, we also recommend that the TGP be tried as an encapsulation material in clinical studies of chondrocyte implantation for optimal clinical outcome.


Assuntos
Cartilagem Articular/citologia , Condrócitos/metabolismo , Ácido Hialurônico/metabolismo , Osteoartrite do Joelho/metabolismo , Tecidos Suporte , Idoso , Células Cultivadas , Humanos , Receptores de Hialuronatos/metabolismo , Imuno-Histoquímica
17.
Front Immunol ; 12: 609629, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33776996

RESUMO

Osteoarthritis (OA) is a chronic and debilitating disease of the knee joint. OA of the knee is initiated by physical damage and accumulated oxidative stress, followed by an exaggerated inflammation leading to cartilage damage. Currently, no effective and safe therapeutic option capable of restoring articular cartilage tissue and joint architecture is available. We here report a novel and highly bioavailable formulation of curcumin, labeled as Next Generation Ultrasol Curcumin (NGUC), which was 64.7 times more bioavailable than natural 95% curcumin extract as demonstrated in rat bioavailability studies. We further investigated the protective effect of NGUC against monosodium iodoacetate (MIA)-induced knee OA in rats. Analysis of X-ray and histopathological images revealed that NGUC supplementation restored joint architecture and reduced swelling of joints induced by MIA. NGUC treatment caused a significant reduction in the levels of inflammatory mediators such as TNF-α, IL-1ß, IL-6, COMP, and CRP, and expressions of MMP-3, 5-LOX, COX-2, and NFκB in synovial tissue of rats with MIA-induced OA. NGUC also decreased serum MDA level and increased the levels of antioxidant enzymes SOD, CAT, and GPX. Thus, our results indicate that a novel formulation of curcumin with enhanced bioavailability effectively ameliorates the pathophysiology of OA.


Assuntos
Curcumina/farmacologia , Mediadores da Inflamação/farmacologia , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Animais , Biomarcadores , Curcumina/química , Citocinas/metabolismo , Gerenciamento Clínico , Suscetibilidade a Doenças , Composição de Medicamentos , Feminino , Imuno-Histoquímica , Mediadores da Inflamação/química , Mediadores da Inflamação/metabolismo , Osteoartrite/diagnóstico , Osteoartrite/etiologia , Osteoartrite do Joelho/diagnóstico , Osteoartrite do Joelho/tratamento farmacológico , Osteoartrite do Joelho/etiologia , Osteoartrite do Joelho/metabolismo , Estresse Oxidativo , Radiografia , Ratos , Índice de Gravidade de Doença
18.
Biomolecules ; 11(3)2021 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-33652804

RESUMO

In recent years, the interest in oxygen-ozone (O2O3) therapy application has considerably increased in the field of rehabilitation. Despite its widespread use in common clinical practice, the biochemical effects of O2O3 are still far from being understood, although its chemical properties seem to play a pivotal role in exerting its positive effects on different pathological conditions. Indeed, the effectiveness of O2O3 therapy might be partly due to the moderate oxidative stress produced by O3 interactions with biological components. O2O3 therapy is widely used as an adjuvant therapeutic option in several pathological conditions characterized by chronic inflammatory processes and immune over-activation, and most musculoskeletal disorders share these pathophysiological processes. The present comprehensive review depicts the state-of-the-art on the mechanisms of action, safety and effectiveness of O2O3 therapy in the complex scenario of the management of musculoskeletal disorders. Taken together, our findings suggest that O2O3 therapy seems to reduce pain and improve functioning in patients affected by low back pain and knee osteoarthritis, as reported by several studies in the literature. However, to date, further studies are warranted to clearly investigate the therapeutic effects of this promising therapy on other musculoskeletal disorders in the field of rehabilitation.


Assuntos
Doenças Musculoesqueléticas/tratamento farmacológico , Doenças Musculoesqueléticas/metabolismo , Osteoartrite do Joelho/tratamento farmacológico , Osteoartrite do Joelho/metabolismo , Oxigênio/uso terapêutico , Ozônio/uso terapêutico , Animais , Fibromialgia/tratamento farmacológico , Fibromialgia/metabolismo , Humanos , Dor Lombar/tratamento farmacológico , Dor Lombar/metabolismo , Cervicalgia/tratamento farmacológico , Cervicalgia/metabolismo
19.
DNA Cell Biol ; 40(4): 629-637, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33646053

RESUMO

Our study aimed at validating the effect of WISP1 on osteoarthritis (OA) and the pathway involved in the WISP1-induced protection against OA. The expression of WISP1 was measured by immunohistochemical analyses. We found that WISP1 expression was shown to be upregulated within human OA cartilage compared with controls. WISP1 expression was related to knee OA severity. rhWISP1 inhibited OA chondrocyte senescence and apoptosis in vitro, which was reversed by the αvß3 antibody and PI3K/Akt inhibitor LY294002. WISP1 overexpression induced by knee injection of LiCI could also prevent the senescence and apoptosis of rat chondrocytes. Safranin-O staining and Mankin score revealed that WISP1 overexpression can protect rat chondrocytes from degeneration. Nearly opposite results were obtained in the treatment of ICG-001 and siRNA-WISP1 in vivo. These data strongly suggest that WISP1 can protect against the senescence and apoptosis of chondrocytes via modulating the αvß3 receptor and PI3K/Akt signaling pathway within OA. Therefore, the development of specific activators of WISP1 may present the value of an underlying OA treatment.


Assuntos
Proteínas de Sinalização Intercelular CCN/metabolismo , Condrócitos/metabolismo , Osteoartrite do Joelho/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Adulto , Envelhecimento/fisiologia , Animais , Apoptose/fisiologia , Proteínas de Sinalização Intercelular CCN/fisiologia , Cartilagem Articular/metabolismo , Feminino , Humanos , Integrina alfaVbeta3/metabolismo , Interleucina-1beta/metabolismo , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Osteoartrite/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas/fisiologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
20.
PLoS One ; 16(2): e0247191, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33617578

RESUMO

Whether osteoarthritis (OA) is a systemic metabolic disorder remains controversial. The aim of this study was to investigate the metabolic characteristics between plasma and knee joint fluid (JF) of patients with advanced OA using a differential correlation metabolic (DCM) networks approach. Plasma and JF were collected during the joint replacement surgery of patients with knee OA. The biological samples were pretreated with standard procedures for metabolite analysis. The metabolic profiling was conducted by means of liquid mass spectrometry coupled with a AbsoluteIDQ kit. A DCM network approach was adopted for analyzing the metabolomics data between the plasma and JF. The variation in the correlation of the pairwise metabolites was quantified across the plasma and JF samples, and networks analysis was used to characterize the difference in the correlations of the metabolites from the two sample types. Core metabolites that played an important role in the DCM networks were identified via topological analysis. One hundred advanced OA patients (50 men and 50 women) were included in this study, with an average age of 65.0 ± 7.6 years (65.6 ± 7.1 years for females and 64.4 ± 8.1 years for males) and a mean BMI of 32.6 ± 5.8 kg/m2 (33.4 ± 6.3 kg/m2 for females and 31.7 ± 5.3 kg/m2 for males). Age and BMI matched between the male and female groups. One hundred and forty-five nodes, 567 edges, and 131 nodes, 407 edges were found in the DCM networks (p < 0.05) of the female and male groups, respectively. Six metabolites in the female group and 5 metabolites in the male group were identified as key nodes in the network. There was a significant difference in the differential correlation metabolism networks of plasma and JF that may be related to local joint metabolism. Focusing on these key metabolites may help uncover the pathogenesis of knee OA. In addition, the differential metabolic correlation between plasma and JF mostly overlapped, indicating that these common correlations of pairwise metabolites may be a reflection of systemic characteristics of JF and that most significant correlation variations were just a result of "housekeeping" biological reactions.


Assuntos
Articulação do Joelho/metabolismo , Redes e Vias Metabólicas , Osteoartrite do Joelho/metabolismo , Líquido Sinovial/metabolismo , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/sangue
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