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1.
PLoS One ; 16(1): e0245194, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33434210

RESUMO

Pharmacological treatment of osteoarthritis is still inadequate due to the low efficacy of the drugs used. Dexmedetomidine via the intra-articular (i.a.) route might be an option for the treatment of osteoarthritis-associated pain. The present study assessed the analgesic and anti-inflammatory effects of dexmedetomidine administered via the i.a. route in different doses in an experimental model of rat knee osteoarthritis induced with monosodium iodoacetate. Rats were allocated to four groups with 24 animals in each group. The OA (osteoarthritis), DEX-1 (dexmedetomidine in dose of 1µg/kg) and DEX-3 (dexmedetomidine in dose of 3µg/kg) groups were subjected to induction of osteoarthritis through injection of monosodium iodoacetate (MIA) via the i.a. route on the right knee; the control group was not subjected to osteoarthritis induction. Clinical assessment was performed on day 0 (before osteoarthritis induction) and then on days 5, 10, 14, 21 and 28 after induction. Treatment was performed on day 7 via the i.a. route, consisting of dexmedetomidine in doses of 1 and 3 µg/kg, while group OA received 0.9% normal saline. The animals were euthanized on days 7, 14, 21 and 28. Samples of the synovial membrane were collected for histopathological analysis, and the popliteal lymph nodes were collected for measurement of cytokines (interleukin [IL] IL-6, tumor necrosis factor alpha [TNF-α]). Dexmedetomidine (1 and 3 µg/kg) significantly reduced the animals' weight distribution deficit during the chronic-degenerative stage of osteoarthritis and improved the pain threshold throughout the entire experiment. Histological analysis showed that dexmedetomidine did not cause any additional damage to the synovial membrane. The TNF-α levels decreased significantly in the DEX-3 group on day 28 compared with the OA group. Dexmedetomidine reduced pain, as evidenced by clinical parameters of osteoarthritis in rats, but did not have an anti-inflammatory effect on histological evaluation.


Assuntos
Cartilagem Articular/imunologia , Dexmedetomidina/farmacologia , Interleucina-6/imunologia , Osteoartrite/tratamento farmacológico , Membrana Sinovial/imunologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Cartilagem Articular/patologia , Modelos Animais de Doenças , Injeções Intra-Articulares , Masculino , Osteoartrite/induzido quimicamente , Osteoartrite/imunologia , Osteoartrite/patologia , Ratos , Ratos Wistar , Membrana Sinovial/patologia
2.
Int J Mol Sci ; 21(24)2020 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-33322825

RESUMO

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.


Assuntos
Condrócitos/metabolismo , Exercício Físico/fisiologia , Células-Tronco Mesenquimais/metabolismo , Osteoartrite/fisiopatologia , Osteogênese , Condicionamento Físico Animal/fisiologia , Regeneração/genética , Animais , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/enzimologia , Cartilagem Articular/patologia , Citocinas/metabolismo , Glicosaminoglicanos/metabolismo , Humanos , Metaloproteases/metabolismo , Osteoartrite/enzimologia , Osteoartrite/imunologia , Osteoartrite/terapia , Osteogênese/genética , Osteogênese/imunologia , Osteogênese/fisiologia , Regeneração/imunologia , Regeneração/fisiologia , Transplante de Células-Tronco
3.
Life Sci ; 261: 118429, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32931797

RESUMO

AIMS: Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have been reported as the important regulators in osteoarthritis (OA). However, the detailed mechanism is implicated. The aim of this study is to reveal the functional mechanism of lncRNA ARFRP1 and miR-15a-5p in osteoarthritis. MATERIALS AND METHODS: The expression level of genes was detected by quantitative real time polymerase chain reaction (qRT-PCR) or western blot assay. Cell Counting Kit-8 (CCK-8) was used to assess cell viability. Cell apoptosis rate was analyzed by flow cytometry analysis. Furthermore, Enzyme-linked immunosorbent assay (ELISA) was performed to measure tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-1ß contents. The interaction between miR-15a-5p and ARFRP1 or Toll-like receptor 4 (TLR4) was predicted by miRcode or PITA, and then confirmed by the dual luciferase reporter assay or pull down assay. Besides, NF-κB-driven luciferase activity was determined using NF-κB luciferase reporter assay. KEY FINDINGS: ARFRP1 and TLR4 levels were increased and miR-15a-5p level was decreased in OA cartilage tissues and lipopolysaccharides (LPS)-induced chondrocytes. ARFRP1 knockdown inhibited LPS-induced the injury of chondrocytes. Interestingly, miR-15a-5p downregulated by ARFRP1 negatively modulated TLR4 expression through interaction. ARFRP1 mediated LPS-induced the injury of chondrocytes via regulating miR-15a-5p/TLR4 axis. Furthermore, ARFRP1 exerted function by modulation of NF-κB pathway. SIGNIFICANCE: Our findings confirmed that ARFRP1 mediated LPS-induced the injury of chondrocytes through regulating NF-κB pathway by modulation of miR-15a-5p/TLR4 axis, providing theoretical basis for the treatment of OA patients.


Assuntos
Condrócitos/patologia , MicroRNAs/genética , NF-kappa B/imunologia , RNA Longo não Codificante/genética , Receptor 4 Toll-Like/genética , Adulto , Idoso , Células Cultivadas , Condrócitos/imunologia , Condrócitos/metabolismo , Regulação para Baixo , Técnicas de Silenciamento de Genes , Humanos , Lipopolissacarídeos/imunologia , MicroRNAs/imunologia , Pessoa de Meia-Idade , Osteoartrite/genética , Osteoartrite/imunologia , Osteoartrite/patologia , RNA Longo não Codificante/imunologia , Receptor 4 Toll-Like/imunologia , Regulação para Cima
4.
Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi ; 34(7): 932-938, 2020 Jul 15.
Artigo em Chinês | MEDLINE | ID: mdl-32666741

RESUMO

Objective: To review and summarize the role of helper T cell (Th) in the pathogenesis of osteoarthritis (OA) and research progress of Th cell-related treatment for OA. Methods: The domestic and foreign literature in recent years was reviewed. The role of Th cells [Th1, Th2, Th9, Th17, Th22, and follicular helper T cell (Tfh)] and related cytokines in the pathogenesis of OA and the latest research progress of treatment were summarized. Results: Th cells play an important role in the pathogenesis of OA. Th1, Th9, and Th17 cells are more important than Th2, Th22, and Tfh cells in the pathogenesis of OA. Cytokines such as tumor necrosis factor α and interleukin 17 can cause damage to articular cartilage significantly. Conclusion: At present, the role of Th cells in the pathogenesis of OA has been played in the spotlight. The specific mechanism has not been clear. Regulating the Th cell-associated cytokines, intracellular and extracellular signals, and cellular metabolism is a potential method for prevention and treatment of OA.


Assuntos
Osteoartrite , Células Th17 , Citocinas , Humanos , Osteoartrite/imunologia , Osteoartrite/patologia
6.
J Vis Exp ; (158)2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32420987

RESUMO

Osteoarthritis (OA) is one of the most prevalent musculoskeletal diseases, affecting patients suffering from pain and physical limitations. Recent evidence indicates a potential inflammatory component of the disease, with both T-cells and monocytes/macrophages potentially associated with the pathogenesis of OA. Further studies postulated an important role for subsets of both inflammatory cell lineages, such as Th1, Th2, Th17, and T-regulatory lymphocytes, and M1, M2, and synovium-tissue-resident macrophages. However, the interaction between the local synovial and systemic inflammatory cellular response and the structural changes in the joint is unknown. To fully understand how T-cells and monocytes/macrophages contribute towards OA, it is important to be able to quantitively identify these cells and their subsets simultaneously in synovial tissue, secondary lymphatic organs and systemically (the spleen and bone marrow). Nowadays, the different inflammatory cell subsets can be identified by a combination of cell-surface markers making multi-color flow cytometry a powerful technique in investigating these cellular processes. In this protocol, we describe detailed steps regarding the harvest of synovial tissue and secondary lymphatic organs as well as generation of single cell suspensions. Furthermore, we present both an extracellular staining assay to identify monocytes/macrophages and their subsets as well as an extra- and intra-cellular staining assay to identify T-cells and their subsets within the murine spleen, bone marrow, lymph nodes and synovial tissue. Each step of this protocol was optimized and tested, resulting in a highly reproducible assay that can be utilized for other surgical and non-surgical OA mouse models.


Assuntos
Medula Óssea/imunologia , Citometria de Fluxo/métodos , Linfonodos/imunologia , Osteoartrite/imunologia , Osteoartrite/patologia , Baço/imunologia , Membrana Sinovial/imunologia , Animais , Modelos Animais de Doenças , Humanos , Camundongos
7.
Inflamm Res ; 69(5): 533-543, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32200413

RESUMO

OBJECTIVE AND DESIGN: Estrogen is one of the important regulators of the balance between bone formation and bone resorption that can modulate the levels and activity of certain growth factors and cytokines. In this study, we investigated the effect of 17ß-estradiol (ED) on bone marrow (BM) cell differentiation in vivo and ex vivo in a mouse model of collagenase-induced osteoarthritis (CIOA). SUBJECT: ICR (CD-2) female mice were used in present experiments (total number = 75) and bone marrow cells were used for in vitro studies. TREATMENT: Mice were orally fed under different schemes with 17ß-estradiol at a dose of 2 µg or 4 µg for 30 days. METHODS: The effect of estradiol was estimated by histopathological, flow cytometry, and ELISA assays. Statistical differences were determined by one-way ANOVA. RESULTS: Estradiol treatment ameliorated cartilage destruction and osteophyte formation if started from day 0 of CIOA induction, attended with a decrease of uterine and ovarian weights. Long time treatment lowered the percentage of megakaryocyte/platelet (CD62P+) populations and osteoclast (RANK+) populations in BM. Cells obtained from estradiol-treated CIOA mice showed inhibited capacity to differentiate into RANK+ and mesenchymal cells under osteoclastogenic conditions in vitro. Estrogen decreased serum IL-6 levels. CONCLUSION: Results indicate a potential protective role for estrogen against the development of OA.


Assuntos
Células da Medula Óssea/efeitos dos fármacos , Estradiol/farmacologia , Osteoartrite/prevenção & controle , Animais , Células da Medula Óssea/citologia , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/patologia , Diferenciação Celular/efeitos dos fármacos , Colagenases , Feminino , Interleucina-6/sangue , Articulações/efeitos dos fármacos , Articulações/patologia , Camundongos Endogâmicos ICR , Osteoartrite/induzido quimicamente , Osteoartrite/imunologia , Osteoartrite/patologia , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos
8.
Inflamm Res ; 69(4): 385-400, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32112120

RESUMO

OBJECTIVE: Osteoarthritis (OA) is a degenerative articular cartilage disease accompanied by superfluous apoptosis of chondrocytes in the elderly. Celastrol is a potent bioactive medicine which can exert anti-inflammatory and anti-oxidative effects in various diseases. This study aimed to elucidate the possible role of celastrol in OA as well as the specific mechanism of celastrol in vitro and in vivo. METHODS: Autophagy-related biomarkers and apoptotic molecules were evaluated by PCR, Western blot and immunofluorescence staining. The level of autophagy was assessed by MDC staining and transmission electron microscopy. To study the downstream signaling pathway, nuclear factor kappa B (NF-κB) signaling pathway-related proteins were examined by Western blot. Moreover, an anterior cruciate ligament transection (ACLT) rat model was established to observe the protective effect of celastrol on rat cartilage. RESULTS: We found celastrol ameliorated IL-1ß-induced chondrocyte apoptosis and increased the expression of LC3-II and Beclin-1. In addition, the suppression of celastrol-induced autophagy by 3-methyladenine (3MA) prevented the protective effect of celastrol in chondrocytes. Moreover, celastrol decreased the IL-1ß-stimulated phosphorylation degree of IκBα and P65. We also found PDTC (a known NF-κB pathway inhibitor) can promote the activation of autophagy and attenuate the apoptosis of chondrocytes. Meanwhile, the results of rat ACLT model revealed the same effect as in vitro experiments. CONCLUSIONS: In summary, celastrol protected against chondrocyte apoptosis by promoting autophagy and inhibiting NF-κB signaling pathway in vitro and in vivo.


Assuntos
Anti-Inflamatórios/uso terapêutico , Autofagia/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Osteoartrite/tratamento farmacológico , Triterpenos/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Células Cultivadas , Interleucina-1beta/farmacologia , Masculino , NF-kappa B/imunologia , Osteoartrite/imunologia , Ratos Sprague-Dawley , Transdução de Sinais , Triterpenos/farmacologia
9.
Arthritis Res Ther ; 22(1): 29, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-32059749

RESUMO

BACKGROUND: Synovitis is implicated in the severity and progression of pain and structural pathology of osteoarthritis (OA). Increases in inflammatory or immune cell subpopulations including macrophages and lymphocytes have been reported in OA synovium, but how the particular subpopulations influence symptomatic or structural OA disease progression is unclear. Two therapies, hyaluronan (HA) and mesenchymal stem cells (MSCs), have demonstrated efficacy in some clinical settings: HA acting as device to improve joint function and provide pain relief, while MSCs may have immunomodulatory and disease-modifying effects. We used these agents to investigate whether changes in pain sensitization or structural damage were linked to modulation of the synovial inflammatory response in post-traumatic OA. METHODS: Skeletally mature C57BL6 male mice underwent medial-meniscal destabilisation (DMM) surgery followed by intra-articular injection of saline, a hyaluronan hexadecylamide derivative (Hymovis), bone marrow-derived stem cells (MSCs), or MSC + Hymovis. We quantified the progression of OA-related cartilage, subchondral bone and synovial histopathology, and associated pain sensitization (tactile allodynia). Synovial lymphocytes, monocyte/macrophages and their subpopulations were quantified by fluorescent-activated cell sorting (FACS), and the expression of key inflammatory mediators and catabolic enzyme genes quantified by real-time polymerase chain reaction (PCR). RESULTS: MSC but not Hymovis significantly reduced late-stage (12-week post-DMM) cartilage proteoglycan loss and structural damage. Allodynia was initially reduced by both treatments but significantly better at 8 and 12 weeks by Hymovis. Chondroprotection by MSCs was not associated with specific changes in synovial inflammatory cell populations but rather regulation of post-injury synovial Adamts4, Adamts5, Mmp3, and Mmp9 expression. Reduced acute post-injury allodynia with all treatments coincided with decreased synovial macrophage and T cell numbers, while longer-term effect on pain sensitization with Hymovis was associated with increased M2c macrophages. CONCLUSIONS: This therapeutic study in mice demonstrated a poor correlation between cartilage, bone or synovium (histo)pathology, and pain sensitization. Changes in the specific synovial inflammatory cell subpopulations may be associated with chronic OA pain sensitization, and a novel target for symptomatic treatment.


Assuntos
Ácido Hialurônico/farmacologia , Transplante de Células-Tronco Mesenquimais/métodos , Osteoartrite/imunologia , Osteoartrite/patologia , Viscossuplementos/farmacologia , Animais , Artralgia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sinovite/imunologia , Sinovite/patologia , Linfócitos T/imunologia
10.
Eur J Pharmacol ; 872: 172971, 2020 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-32004526

RESUMO

Human melanocortin MC1 and MC3 receptors expressed on C-20/A4 chondrocytes exhibit chondroprotective and anti-inflammatory effects when activated by melanocortin peptides. Nearly 9 million people in the UK suffer from osteoarthritis, and bacterial infections play a role in its development. Here, we evaluate the effect of a panel of melanocortin peptides with different selectivity for human melanocortin MC1 (α-MSH, BMS-470539 dihydrochloride) and MC3 ([DTrp8]-γ-MSH, PG-990) receptors and C-terminal peptide α-MSH11-13(KPV), on inhibiting LPS-induced chondrocyte death, pro-inflammatory mediators and induction of anti-inflammatory proteins. C-20/A4 chondrocytes were treated with a panel of melanocortin peptides prophylactically and therapeutically in presence of LPS (0.1 µg/ml). The chondroprotective properties of these peptides determined by cell viability assay, RT-PCR, ELISA for detection of changes in inflammatory markers (IL-6, IL-8 and MMP-1, -3 and -13) and western blotting for expression of the anti-inflammatory protein heme-oxygenase-1. C-20/A4 expressed human melanocortin MC1 and MC3 receptors and melanocortin peptides elevated cAMP. LPS stimulation caused a reduction in C-20/A4 viability, attenuated by the human melanocortin MC1 receptor agonist BMS-470539 dihydrochloride, and MC3 receptor agonists PG-990 and [DTrp8]-γ-MSH. Prophylactic and therapeutic regimes of [DTrp8]-γ-MSH significantly inhibited LPS-induced modulation of cartilage-damaging IL-6, IL-8, MMPs -1,-3 and -13 mediators both prophylactically and therapeutically, whilst human melanocortin MC1 and MC3 receptor agonists promoted an increase in HO-1 production. In the presence of LPS, activation of human melanocortin MC1 and MC3 receptors provided potent chondroprotection, upregulation of anti-inflammatory proteins and downregulation of inflammatory and proteolytic mediators involved in cartilage degradation, suggesting a new avenue for osteoarthritis treatment.


Assuntos
Anti-Inflamatórios/farmacologia , Condrócitos/efeitos dos fármacos , Receptor Tipo 1 de Melanocortina/agonistas , Receptor Tipo 3 de Melanocortina/agonistas , Linhagem Celular , Condrócitos/imunologia , Condrócitos/metabolismo , Heme Oxigenase-1/metabolismo , Humanos , Imidazóis , Lipopolissacarídeos/imunologia , Osteoartrite/tratamento farmacológico , Osteoartrite/imunologia , Osteoartrite/patologia
11.
J Cell Physiol ; 235(1): 281-293, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31215024

RESUMO

The inflammatory microenvironment in the joints is one of the critical issues during osteoarthritis (OA) and also the main factor that may aggravate symptoms. Under inflammatory microenvironment, M1 macrophages are activated and produce large numbers of proinflammatory mediators, leading to the production of degradative enzymes, the disturbance of chondrocyte apoptosis and cartilage catabolic processes, and finally the deterioration of OA. In the present study, we reveal that the overexpression of osteopontin (OPN), a cytokine, and a matrix protein involved in arthritis and chondrocyte apoptosis in OA, could exacerbate the inflammatory microenvironment in OA via promoting the production of proinflammation cytokines and the levels of degradative enzymes in M1 macrophages, therefore, enhancing the cytotoxicity of M1 macrophage on chondrocytes. XIST expression significantly increases in OA tissue specimens. XIST serves as a competing endogenous RNA for miR-376c-5p to compete with OPN for miR-376c-5p binding, thus counteracting miR-376c-5p-mediated OPN suppression. XIST knockdown could improve the inflammatory microenvironment in OA via acting on M1 macrophages, subsequently affecting the apoptosis of cocultured chondrocytes. miR-376c-5p inhibition exerts an opposing effect on M1 macrophages and cocultured chondrocytes, as well as significantly reverses the effect of XIST knockdown. As a further confirmation, XIST and OPN mRNA expression significantly increased in OA tissues and was positively correlated in tissue samples. In summary, we provide a novel mechanism of macrophages and the inflammatory microenvironment affecting chondrocyte apoptosis. XIST and OPN might be potential targets for OA treatment, which needs further in vivo experimental confirmation.


Assuntos
Condrócitos/imunologia , Macrófagos/imunologia , MicroRNAs/genética , Osteoartrite/imunologia , Osteopontina/metabolismo , RNA Longo não Codificante/genética , Apoptose/imunologia , Células Cultivadas , Microambiente Celular/imunologia , Técnicas de Cocultura , Citocinas/biossíntese , Humanos , Macrófagos/citologia , Osteopontina/genética
12.
Int Immunopharmacol ; 78: 106043, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31837574

RESUMO

Protectin DX (PDX) has been reported to have extensive anti-inflammatory effects. However, it is unknown whether PDX acts as an anti-inflammatory agent in the context of osteoarthritis (OA). This study aimed to evaluate the anti-inflammatory activity of PDX in vitro and in vivo in a model of OA. Primary rat chondrocytes were preincubated with PDX 1 h prior to IL-1ß treatment for 24 h. We found that PDX was nontoxic, and pretreatment with PDX increased cell viability in IL-1ß-induced chondrocytes. Preincubation with PDX also efficiently inhibited the degradation of type II collagen dose-dependently. Additionally, the expression of MMP-3, MMP-13, ADAMTS4, iNOS, COX-2, NO, and PGE2 decreased after IL-1ß stimulation when cells were preincubated with PDX. Moreover, PDX inhibited the increase in phosphorylated NF-κB p65 and IκBα upon IL-1ß stimulation, and the negative effects of IL-1ß on chondrocytes were partially blocked by treatment with pyrrolidine dithiocarbamate (PDTC), a selective NF-κB inhibitor. In addition, we found that PDX increased AMPK phosphorylation in IL-1ß-mediated chondrocytes. The phosphorylation of AMPK could be inhibited by compound C, a classic AMPK inhibitor. Compound C also remarkably reversed the decrease in p65 phosphorylation and MMP-13 expression caused by PDX. Furthermore, nuclear translocation of NF-κB was visible by immunofluorescence after PDX-induced AMPK activation. Additionally, we verified that PDX ameliorated cartilage degradation in monosodium iodoacetate (MIA)-induced OA rats through histological evaluation and ELISA of TNF-α in the serum and intra-articular lavage fluid. In conclusion, we have shown that PDX suppresses inflammation in chondrocytes in vitro and in vivo, likely through the AMPK/NF-κB signaling pathway. Our results suggest that PDX could be a useful novel therapeutic agent for OA treatment.


Assuntos
Artrite Experimental/tratamento farmacológico , Condrócitos/efeitos dos fármacos , Ácidos Docosa-Hexaenoicos/farmacologia , Osteoartrite/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/imunologia , Artrite Experimental/patologia , Células Cultivadas , Condrócitos/imunologia , Progressão da Doença , Ácidos Docosa-Hexaenoicos/uso terapêutico , Humanos , Injeções Intra-Articulares , Ácido Iodoacético/administração & dosagem , Ácido Iodoacético/toxicidade , Masculino , Osteoartrite/induzido quimicamente , Osteoartrite/imunologia , Osteoartrite/patologia , Fosforilação/efeitos dos fármacos , Fosforilação/imunologia , Cultura Primária de Células , Ratos , Transdução de Sinais/imunologia , Fator de Transcrição RelA/metabolismo
13.
Biochem Biophys Res Commun ; 522(3): 783-791, 2020 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-31791577

RESUMO

ΜiR-140-5p and miR-146a regulate inflammatory pathways including TLR4/NF-κB signaling and have been found to be involved in OA pathogenesis. In this study, we investigated the effect of the synergistic function of miR-140-5p and miR-146a on inflammation mediated by TLR4 in ΟΑ chondrocytes. Bioinformatics analysis revealed that TLR4 was the only common OA-related target gene of miR-140-5p and miR-146a, located in the sub-network with the highest MCODE score; it also showed that the target genes of miR-140-5p and miR-146a which located in MCODE sub-networks were enriched in OA-related biological processes and pathways. Overexpression of miR-140-5p or miR-146a and combined miR-140-5p/miR-146a overexpression in OA chondrocytes demonstrated that combined treatment had the strongest negative effect on TLR4 expression. Moreover, simultaneous overexpression of miR-140-5p and miR-146a resulted in the highest reduction of NF-κΒ phosphorylation levels, as well as IL-1b, IL-6 and TNFa expression levels in OA chondrocytes as compared to the reductions observed when either miR-140-5p or miR-146a was overexpressed. Our results, therefore, demonstrate for the first time, that the synergistic function of miR-140-5p and miR-146a have a strong protective effect against inflammatory mediators' production in OA chondrocytes through targeting the TLR4/NF-κB signaling.


Assuntos
Citocinas/genética , MicroRNAs/genética , Osteoartrite/genética , Receptor 4 Toll-Like/genética , Idoso , Células Cultivadas , Condrócitos/imunologia , Condrócitos/metabolismo , Citocinas/imunologia , Feminino , Regulação da Expressão Gênica , Humanos , Inflamação/genética , Inflamação/imunologia , Masculino , MicroRNAs/imunologia , Pessoa de Meia-Idade , Osteoartrite/imunologia , Mapas de Interação de Proteínas , Receptor 4 Toll-Like/imunologia , Regulação para Cima
14.
J Orthop Res ; 38(2): 253-257, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31469192

RESUMO

Understanding the molecular drivers and feedback loops of osteoarthritis (OA) may provide future therapeutic strategies to modulate the disease progression. The current paradigm of OA is evolving from a purely mechanical disease caused by cartilage wear toward a complex biological response connecting biomechanics, inflammation, and the immune system. The view of OA as a chronic wound highlights the role inflammation plays and also the body's attempts to repair an ongoing injury. Inflammatory signals, including cytokines such as interleukin-1 and tissue necrosis factor α, surface-expressed pattern recognition receptors such as toll-like receptors 2 and 4, complement factors such as C5, as well as pathogen-associated molecular patterns and damage-associated molecular patterns drive the enzymatic cascade that degrades cartilage matrix in OA. Considering the joint as an entire organ, interactions between the cells that reside in the synovium including macrophages and other immune cells, appear to drive enzymatic activity in cartilage, which, in turn, feeds signals back to the synovium that continues stimulating degradation in a feed-forward loop. This review will explore the potential roles of immune cells such as macrophages and T cells in the synovium in both stimulating and modulating the inflammatory response in OA. © 2019 Orthopedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:253-257, 2020.


Assuntos
Osteoartrite/imunologia , Imunidade Adaptativa , Animais , Humanos , Imunidade Inata , Macrófagos/fisiologia , Cicatrização
15.
BMC Musculoskelet Disord ; 20(1): 591, 2019 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-31812161

RESUMO

BACKGROUND: Fibroblast-like synoviocytes (FLS) are essential cellular components in inflammatory joint diseases such as osteoarthritis (OA) and rheumatoid arthritis (RA). Despite the growing use of FLS isolated from OA and RA patients, a detailed functional and parallel comparison of FLS from these two types of arthritis has not been performed. METHODS: In the present study, FLS were isolated from surgically removed synovial tissues from twenty-two patients with OA and RA to evaluate their basic cellular functions. RESULTS: Pure populations of FLS were isolated by a sorting strategy based on stringent marker expression (CD45-CD31-CD146-CD235a-CD90+PDPN+). OA FLS and RA FLS at the same passage (P2-P4) exhibited uniform fibroblast morphology. OA FLS and RA FLS expressed a similar profile of cell surface antigens, including the fibroblast markers VCAM1 and ICAM1. RA FLS showed a more sensitive inflammatory status than OA FLS with regard to proliferation, migration, apoptosis, inflammatory gene expression and pro-inflammatory cytokine secretion. In addition, the responses of OA FLS and RA FLS to both the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) and the anti-inflammatory drug methotrexate (MTX) were also evaluated here. CONCLUSION: The parallel comparison of OA FLS and RA FLS lays a foundation in preparation for when FLS are considered a potential therapeutic anti-inflammatory target for OA and RA.


Assuntos
Artrite Reumatoide/cirurgia , Osteoartrite/cirurgia , Membrana Sinovial/patologia , Sinoviócitos/imunologia , Apoptose/imunologia , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Movimento Celular/imunologia , Proliferação de Células , Células Cultivadas , Citometria de Fluxo , Humanos , Hiperplasia/patologia , Metotrexato/farmacologia , Osteoartrite/imunologia , Osteoartrite/patologia , Cultura Primária de Células , Membrana Sinovial/citologia , Membrana Sinovial/imunologia , Sinoviócitos/efeitos dos fármacos , Sinoviócitos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
16.
Int J Mol Sci ; 20(22)2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31731767

RESUMO

In this study, 34 Traditional Chinese Medicine (TCM) compounds were screened for potential anabolic and anti-inflammatory properties on human osteoarthritic (OA) chondrocytes. The anabolic effects were assessed by measuring the glycosaminoglycan (GAG) relative to the DNA content using a 3D pellet culture model. The most chondrogenic compounds were tested in an inflammatory model consisting of 3 days of treatment with cytokines (IL-1ß/TNF-α) with or without supplementation of TCM compounds. The anti-inflammatory effects were assessed transcriptionally, biochemically and histologically. From the 34 compounds, Vanilic acid (VA), Epimedin A (Epi A) and C (Epi C), 2''-O-rhamnosylicariside II (2-O-rhs II), Icariin, Psoralidin (PS), Protocatechuicaldehyde (PCA), 4-Hydroxybenzoic acid (4-HBA) and 5-Hydroxymethylfurfural (5-HMF) showed the most profound anabolic effects. After induction of inflammation, pro-inflammatory and catabolic genes were upregulated, and GAG/DNA was decreased. VA, Epi C, PS, PCA, 4-HBA and 5-HMF exhibited anti-catabolic and anti-inflammatory effects and prevented the up-regulation of pro-inflammatory markers including metalloproteinases and cyclooxygenase 2. After two weeks of treatment with TCM compounds, the GAG/DNA ratio was restored compared with the negative control group. Immunohistochemistry and Safranin-O staining confirmed superior amounts of cartilaginous matrix in treated pellets. In conclusion, VA, Epi C, PS, PCA, 4-HBA and 5-HMF showed promising anabolic and anti-inflammatory effects.


Assuntos
Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Osteoartrite/tratamento farmacológico , Osteoartrite/imunologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Interleucina-1beta/uso terapêutico , Medicina Tradicional Chinesa/métodos , Fator de Necrose Tumoral alfa/uso terapêutico
17.
Clin Exp Rheumatol ; 37 Suppl 120(5): 57-63, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31621560

RESUMO

Although osteoarthritis (OA) was historically referred to as the non-inflammatory arthritis, it is now considered a condition involving persistent low-grade inflammation and activation of innate inflammatory pathways. Synovitis increases the risk of OA onset and progression and involves the recruitment of monocytes, lymphocytes, and other leukocytes. In particular, macrophages are important mediators of synovial inflammatory activity and pathologic cartilage and bone responses that are characteristic of OA. Advances in understanding how damage-associated molecular patterns (DAMPs) trigger monocyte/macrophage recruitment and activation in joints provide opportunities for disease-modifying therapies. However, the complexity and plasticity of macrophage phenotypes that exist in vivo have thus far prevented the successful development of macrophage-targeted treatments. Current studies show that synovial macrophages are derived from distinct cellular lineages, which correspond to unique functional roles for maintaining joint homeostasis. An improved understanding of the aetiology of synovial inflammation in specific OA-subtypes, such as with obesity or genetic risk, is a potential strategy for developing patient selection criteria for future precision therapies.


Assuntos
Macrófagos/imunologia , Osteoartrite , Sinovite , Humanos , Inflamação , Monócitos , Osteoartrite/imunologia , Osteoartrite/patologia , Sinovite/imunologia , Sinovite/patologia
18.
Clin Exp Rheumatol ; 37 Suppl 120(5): 48-56, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31621566

RESUMO

Osteoarthritis (OA) is the most common age-related chronic and disabling joint disease. Long considered to be a "wear and tear" disease, OA is now seen as a low-grade inflammation disease that affects all tissues of the joint, involving cartilage degradation, bone remodelling, osteophytes, and synovitis. The process, called inflammaging, is characterised by the association of low-grade inflammation, profound changes in intra-cellular mechanisms, and the decreased efficiency of the immune system with ageing. The activation of innate immunity plays a critical role in the development and progression of OA. Innate immunity, including inflammasome activation, is triggered by small endogenous molecules called alarmins or damage-associated molecular patterns (DAMPs). These molecules are released in the extracellular media after cell stress or damage, bind to pathogen-recognition receptors (PRRs), such as Toll-like receptors (TLRs) and the receptor for advanced glycation end products (RAGE), and activate the secretion of pro-inflammatory factors, leading to joint inflammation. Moreover, such sterile inflammation triggers cell senescence, characterised by a senescence-associated secretory phenotype (SASP). Understanding the substantial age-related changes of joint tissues that influence the pathogenesis of OA is critical to improving the quality of life of elderly people in the context of increased life expectancy. This review will focus on age-related sterile inflammation in OA and highlight the various innovative and promising therapies targeting the mechanisms of aging.


Assuntos
Osteoartrite , Qualidade de Vida , Idoso , Envelhecimento , Humanos , Inflamação/imunologia , Osteoartrite/imunologia , Osteoartrite/patologia , Osteoartrite/terapia , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Receptores Toll-Like/metabolismo
19.
Clin Exp Rheumatol ; 37 Suppl 120(5): 130-134, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31621572

RESUMO

From the time of their discovery in 1999, the aggrecanases, and ADAMTS-5 in particular, have been heavily investigated as targets for disease-modifying osteoarthritis drug (DMOAD) development. Here, we provide a brief narrative review of the discovery efforts to target these enzymes, and how this led to the current ongoing programmes that hold promise for the future. We discuss a comparison of inhibition of collagen breakdown versus inhibition of aggrecan breakdown. We then summarise existing programmes that target ADAMTS-5, including small molecule inhibitors, monoclonal neutralising antibodies and nanobodies, and gene editing technologies. We also briefly discuss the potential analgesic effects this strategy may offer in addition to its joint-protective effects.


Assuntos
Proteínas ADAM , Endopeptidases/metabolismo , Osteoartrite/enzimologia , Pró-Colágeno N-Endopeptidase , Proteínas ADAM/antagonistas & inibidores , Proteínas ADAM/imunologia , Proteína ADAMTS4 , Agrecanas/metabolismo , Humanos , Osteoartrite/tratamento farmacológico , Osteoartrite/imunologia
20.
BMC Complement Altern Med ; 19(1): 264, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31590658

RESUMO

BACKGROUND: Osteoarthritis (OA) is a common degenerative disease of synovial joints caused by inflammation. Acteoside (ACT), a major component and lipase inhibitor from the Chinese tea Ligustrum purpurascens kudingcha, has been reported to regulate the inflammation and immune response. The study aims to investigate the effects of ACT on inflammatory responses and joint protection in OA rats. METHODS: Cell proliferation was examined by MTT and colony formation assay. Apoptosis was analyzed using flow cytometry with Annexin V/PI staining. ELISA was employed to examine the concentration of inflammatory cytokines. OA rat model was established by surgery stimulation. RESULTS: ACT treatment significantly inhibited the upregulation of inflammatory cytokines induced by IL-1ß in primary chondrocytes, including IL-6, IL-12, TNF-α and IFN-γ. ACT stimulation also enhanced the cell proliferation, while inhibited cell apoptosis in IL-1ß-treated chondrocytes. Consistently, ACT treatment led to downregulation of cleaved-caspase-3 and apoptosis regulator Bax, and upregulation of Bcl-2. Furthermore, ACT treatment inhibited IL-1ß-induced activation of JAK/STAT pathway. The results were confirmed in surgery-induced OA rat model. Moreover, ACT treatment significantly inhibited synovial inflammation and articular chondrocyte apoptosis in OA rats. CONCLUSION: Our findings indicate that ACT has the potential therapeutic effect on OA through inhibiting the inflammatory responses via inactivating JAK/STAT signaling pathway.


Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , Glucosídeos/administração & dosagem , Ligustrum/química , Osteoartrite/tratamento farmacológico , Fenóis/administração & dosagem , Animais , Proliferação de Células/efeitos dos fármacos , Condrócitos , Modelos Animais de Doenças , Humanos , Interferon gama/genética , Interferon gama/imunologia , Janus Quinases/genética , Janus Quinases/imunologia , Masculino , Osteoartrite/genética , Osteoartrite/imunologia , Ratos , Ratos Sprague-Dawley , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/imunologia , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
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