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1.
Hematology ; 26(1): 684-690, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34493173

RESUMO

BACKGROUND: Sickle cell anaemia affects about 4 million people across the globe, making it an inherited disorder of public health importance. Red cell lysis consequent upon haemoglobin crystallization and repeated sickling leads to anaemia and a baseline strain on haemopoiesis. Vaso-occlusion and haemolysis underlies majority of the chronic complications of sickle cell. We evaluated the clinical and laboratory features observed across the various clinical phenotypes in adult sickle cell disease patients. METHODS: Steady state data collected prospectively in a cohort of adult sickle cell disease patients as out-patients between July 2010 and July 2020. The information included epidemiological, clinical and laboratory data. RESULTS: About 270 patients were captured in this study (165 males and 105 females). Their ages ranged from 16 to 55 years, with a median age of 25 years. Sixty-eight had leg ulcers, 43 of the males had priapism (erectile dysfunction in 8), 42 had AVN, 31 had nephropathy, 23 had osteomyelitis, 15 had osteoarthritis, 12 had cholelithiasis, 10 had stroke or other neurological impairment, 5 had pulmonary hypertension, while 23 had other complications. Frequency of crisis ranged from 0 to >10/year median of 2. Of the 219 recorded, 148 of the patients had been transfused in the past, while 71 had not. CONCLUSION: The prevalence of SLU, AVN, priapism, nephropathy and the other complications of SCD show some variations from other studies. This variation in the clinical parameters across different clinical phenotypes indicates an interplay between age, genetic and environmental factors.


Assuntos
Anemia Falciforme , Adolescente , Adulto , Anemia Falciforme/complicações , Anemia Falciforme/epidemiologia , Anemia Falciforme/metabolismo , Anemia Falciforme/patologia , Colelitíase/etiologia , Colelitíase/metabolismo , Colelitíase/patologia , Feminino , Humanos , Hipertensão Pulmonar/epidemiologia , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Nefropatias/epidemiologia , Nefropatias/etiologia , Nefropatias/metabolismo , Nefropatias/patologia , Úlcera da Perna/epidemiologia , Úlcera da Perna/etiologia , Úlcera da Perna/metabolismo , Úlcera da Perna/patologia , Masculino , Pessoa de Meia-Idade , Nigéria/epidemiologia , Osteoartrite/epidemiologia , Osteoartrite/etiologia , Osteoartrite/metabolismo , Osteomielite/epidemiologia , Osteomielite/etiologia , Osteomielite/metabolismo , Osteomielite/patologia , Priapismo/epidemiologia , Priapismo/etiologia , Priapismo/metabolismo , Priapismo/patologia , Estudos Prospectivos , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia
2.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360947

RESUMO

The distribution of differential extracellular matrix (ECM) in the lateral and medial menisci can contribute to knee instability, and changes in the meniscus tissue can lead to joint disease. Thus, deep proteomic identification of the lateral and medial meniscus cartilage is expected to provide important information for treatment and diagnosis of various knee joint diseases. We investigated the proteomic profiles of 12 lateral/medial meniscus pairs obtained from excess tissue of osteoarthritis patients who underwent knee arthroscopy surgery using mass spectrometry-based techniques and measured 75 ECM protein levels in the lesions using a multiple reaction monitoring (MRM) assay we developed. A total of 906 meniscus proteins with a 1% false discovery rate (FDR) was identified through a tandem mass tag (TMT) analysis showing that the lateral and medial menisci had similar protein expression profiles. A total of 131 ECM-related proteins was included in meniscus tissues such as collagen, fibronectin, and laminin. Our data showed that 14 ECM protein levels were differentially expressed in lateral and medial lesions (p < 0.05). We present the proteomic characterization of meniscal tissue with mass spectrometry-based comparative proteomic analysis and developed an MRM-based assay of ECM proteins correlated with tissue regeneration. The mass spectrometry dataset has been deposited to the MassIVE repository with the dataset identifier MSV000087753.


Assuntos
Proteínas da Matriz Extracelular/metabolismo , Menisco/metabolismo , Osteoartrite/metabolismo , Proteoma/metabolismo , Idoso , Idoso de 80 Anos ou mais , Proteínas da Matriz Extracelular/química , Feminino , Humanos , Masculino , Proteoma/química
3.
Int J Mol Sci ; 22(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34445661

RESUMO

Exogenous adenosine and its metabolite inosine exert anti-inflammatory effects in synoviocytes of osteoarthritis (OA) and rheumatoid arthritis (RA) patients. We analyzed whether these cells are able to synthesize adenosine/inosine and which adenosine receptors (ARs) contribute to anti-inflammatory effects. The functionality of synthesizing enzymes and ARs was tested using agonists/antagonists. Both OA and RA cells expressed CD39 (converts ATP to AMP), CD73 (converts AMP to adenosine), ADA (converts adenosine to inosine), ENT1/2 (adenosine transporters), all AR subtypes (A1, A2A, A2B and A3) and synthesized predominantly adenosine. The CD73 inhibitor AMPCP significantly increased IL-6 and decreased IL-10 in both cell types, while TNF only increased in RA cells. The ADA inhibitor DAA significantly reduced IL-6 and induced IL-10 in both OA and RA cells. The A2AAR agonist CGS 21680 significantly inhibited IL-6 and induced TNF and IL-10 only in RA, while the A2BAR agonist BAY 60-6583 had the same effect in both OA and RA. Taken together, OA and RA synoviocytes express the complete enzymatic machinery to synthesize adenosine/inosine; however, mainly adenosine is responsible for the anti- (IL-6 and IL-10) or pro-inflammatory (TNF) effects mediated by A2A- and A2BAR. Stimulating CD39/CD73 with simultaneous ADA blockage in addition to TNF inhibition might represent a promising therapeutic strategy.


Assuntos
Adenosina/farmacologia , Anti-Inflamatórios/farmacologia , Artrite Reumatoide/tratamento farmacológico , Osteoartrite/tratamento farmacológico , Membrana Sinovial/efeitos dos fármacos , Sinoviócitos/efeitos dos fármacos , Vasodilatadores/farmacologia , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Citocinas/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite/metabolismo , Osteoartrite/patologia , Sinoviócitos/metabolismo , Sinoviócitos/patologia
4.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360874

RESUMO

Osteoarthritis (OA) is still a recalcitrant musculoskeletal disease on account of its complex biochemistry and mechanical stimulations. Apart from stimulation by external mechanical forces, the regulation of intracellular mechanics in chondrocytes has also been linked to OA development. Recently, visfatin has received significant attention because of the clinical finding of the positive correlation between its serum/synovial level and OA progression. However, the precise mechanism involved is still unclear. This study determined the effect of visfatin on intracellular mechanics and catabolism in human primary chondrocytes isolated from patients. The intracellular stiffness of chondrocytes was analyzed by the particle-tracking microrheology method. It was shown that visfatin damages the microtubule and microfilament networks to influence intracellular mechanics to decrease the intracellular elasticity and viscosity via glycogen synthase kinase 3ß (GSK3ß) inactivation induced by p38 signaling. Further, microtubule network destruction in human primary chondrocytes is predominantly responsible for the catabolic effect of visfatin on the cyclooxygenase 2 upregulation. The present study shows a more comprehensive interpretation of OA development induced by visfatin through biochemical and biophysical perspectives. Finally, the role of GSK3ß inactivation, and subsequent regulation of intracellular mechanics, might be considered as theranostic targets for future drug development for OA.


Assuntos
Condrócitos , Citocinas/fisiologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Nicotinamida Fosforribosiltransferase/fisiologia , Osteoartrite , Citoesqueleto de Actina/metabolismo , Células Cultivadas , Condrócitos/metabolismo , Condrócitos/patologia , Humanos , Microtúbulos/metabolismo , Osteoartrite/metabolismo , Osteoartrite/patologia , Cultura Primária de Células
5.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360888

RESUMO

Osteoarthritis (OA) is a degenerative joint disease characterized by irreversible cartilage damage, inflammation and altered chondrocyte phenotype. Transforming growth factor-ß (TGF-ß) signaling via SMAD2/3 is crucial for blocking hypertrophy. The post-translational modifications of these SMAD proteins in the linker domain regulate their function and these can be triggered by inflammation through the activation of kinases or phosphatases. Therefore, we investigated if OA-related inflammation affects TGF-ß signaling via SMAD2/3 linker-modifications in chondrocytes. We found that both Interleukin (IL)-1ß and OA-synovium conditioned medium negated SMAD2/3 transcriptional activity in chondrocytes. This inhibition of TGF-ß signaling was enhanced if SMAD3 could not be phosphorylated on Ser213 in the linker region and the inhibition by IL-1ß was less if the SMAD3 linker could not be phosphorylated at Ser204. Our study shows evidence that inflammation inhibits SMAD2/3 signaling in chondrocytes via SMAD linker (de)-phosphorylation. The involvement of linker region modifications may represent a new therapeutic target for OA.


Assuntos
Condrócitos/metabolismo , Condrócitos/patologia , Osteoartrite/metabolismo , Transdução de Sinais/genética , Proteína Smad2/química , Proteína Smad2/metabolismo , Proteína Smad3/química , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Adulto , Animais , Bovinos , Linhagem Celular Tumoral , Humanos , Hipertrofia/metabolismo , Inflamação/metabolismo , Interleucina-1beta/farmacologia , Osteoartrite/genética , Osteoartrite/patologia , Fosforilação/efeitos dos fármacos , Fosforilação/genética , Domínios Proteicos/efeitos dos fármacos , Proteínas Recombinantes/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/genética , Proteína Smad3/genética , Membrana Sinovial/metabolismo , Transfecção , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/farmacologia
6.
Oxid Med Cell Longev ; 2021: 7385160, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34457118

RESUMO

Obesity is considered as a risk factor of osteoarthritis (OA), but the precise relationship is still poorly understood. Leptin, one of the most relevant factors secreted by adipose tissues, plays an important role in the pathogenesis of OA. Our aim was to investigate the regulation and molecular mechanism of the leptin signaling pathway in obesity-related OA. SD rats were fed with a high-fat diet (HFD) for 5, 15, and 27 weeks. The levels of leptin in serum increased from W5, while in the synovial fluid increased from W15. The histological evaluation showed that the pathological changes of OA occurred at 27 weeks rather than 5 or 15 weeks. We also found that leptin induced CD14/TLR4 activation by the JAK2-STAT3 signaling pathway to promote OA. Moreover, silencing SOCS3 enhanced leptin-induced JAK2-STAT3-CD14/TLR4 activation in rat primary chondrocytes. Our findings indicated that leptin may be one of the initiating factors of obesity-related OA. TLR4 is at least partially regulated by leptin through the JAK2-STAT3-CD14 pathway. Meanwhile, SOCS3 acting as a negative feedback inhibitor of leptin signaling presented a potential therapeutic prospect for obesity-related OA. Our study provided new evidence suggesting the key role of leptin in mediating obesity-related OA process and its underlying mechanisms.


Assuntos
Regulação da Expressão Gênica , Janus Quinase 2/metabolismo , Leptina/metabolismo , Obesidade/complicações , Osteoartrite/patologia , Fator de Transcrição STAT3/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Janus Quinase 2/genética , Masculino , Osteoartrite/etiologia , Osteoartrite/metabolismo , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT3/genética , Receptor 4 Toll-Like/genética
7.
Int J Mol Sci ; 22(15)2021 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-34361116

RESUMO

Along with cytokines, extracellular vesicles (EVs) released by immune cells in the joint contribute to osteoarthritis (OA) pathogenesis. By high-resolution flow cytometry, we characterized 18 surface markers and 4 proinflammatory cytokines carried by EVs of various sizes in plasma and synovial fluid (SF) from individuals with knee OA, with a primary focus on immune cells that play a major role in OA pathogenesis. By multiplex immunoassay, we also measured concentrations of cytokines within (endo) and outside (exo) EVs. EVs carrying HLA-DR, -DP and -DQ were the most enriched subpopulations in SF relative to plasma (25-50-fold higher depending on size), suggesting a major contribution to the SF EV pool from infiltrating immune cells in OA joints. In contrast, the CD34+ medium and small EVs, reflecting hematopoietic stem cells, progenitor cells, and endothelial cells, were the most significantly enriched subpopulations in plasma relative to SF (7.3- and 7.7-fold higher). Ratios of EVs derived from neutrophils and lymphocytes were highly correlated between SF and plasma, indicating that plasma EVs could reflect OA severity and serve as systemic biomarkers of OA joint pathogenesis. Select subsets of plasma EVs might also provide next generation autologous biological products for intra-articular therapy of OA joints.


Assuntos
Biomarcadores/metabolismo , Citocinas/metabolismo , Vesículas Extracelulares/metabolismo , Linfócitos/citologia , Neutrófilos/citologia , Osteoartrite/terapia , Líquido Sinovial/metabolismo , Idoso , Feminino , Antígenos HLA-DR/metabolismo , Humanos , Masculino , Osteoartrite/metabolismo , Osteoartrite/patologia
8.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204587

RESUMO

Structural disturbances of the subchondral bone are a hallmark of osteoarthritis (OA), including sclerotic changes, cystic lesions, and osteophyte formation. Osteocytes act as mechanosensory units for the micro-cracks in response to mechanical loading. Once stimulated, osteocytes initiate the reparative process by recruiting bone-resorbing cells and bone-forming cells to maintain bone homeostasis. Osteocyte-expressed sclerostin is known as a negative regulator of bone formation through Wnt signaling and the RANKL pathway. In this review, we will summarize current understandings of osteocytes at the crossroad of allometry and mechanobiology to exploit the relationship between osteocyte morphology and function in the context of joint aging and osteoarthritis. We also aimed to summarize the osteocyte dysfunction and its link with structural and functional disturbances of the osteoarthritic subchondral bone at the molecular level. Compared with normal bones, the osteoarthritic subchondral bone is characterized by a higher bone volume fraction, a larger trabecular bone number in the load-bearing region, and an increase in thickness of pre-existing trabeculae. This may relate to the aberrant expressions of sclerostin, periostin, dentin matrix protein 1, matrix extracellular phosphoglycoprotein, insulin-like growth factor 1, and transforming growth factor-beta, among others. The number of osteocyte lacunae embedded in OA bone is also significantly higher, yet the volume of individual lacuna is relatively smaller, which could suggest abnormal metabolism in association with allometry. The remarkably lower percentage of sclerostin-positive osteocytes, together with clustering of Runx-2 positive pre-osteoblasts, may suggest altered regulation of osteoblast differentiation and osteoblast-osteocyte transformation affected by both signaling molecules and the extracellular matrix. Aberrant osteocyte morphology and function, along with anomalies in molecular signaling mechanisms, might explain in part, if not all, the pre-osteoblast clustering and the uncoupled bone remodeling in OA subchondral bone.


Assuntos
Homeostase , Articulações/fisiologia , Osteoartrite/etiologia , Osteoartrite/metabolismo , Osteócitos/metabolismo , Animais , Biomarcadores , Remodelação Óssea , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Suscetibilidade a Doenças , Humanos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Osteoartrite/diagnóstico por imagem , Osteoartrite/patologia , Osteoblastos/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo
9.
Nat Rev Rheumatol ; 17(9): 533-549, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34316066

RESUMO

Osteoarthritis (OA) is a whole-joint disease characterized by subchondral bone perfusion abnormalities and neovascular invasion into the synovium and articular cartilage. In addition to local vascular disturbance, mounting evidence suggests a pivotal role for systemic vascular pathology in the aetiology of OA. This Review outlines the current understanding of the close relationship between high blood pressure (hypertension) and OA at the crossroads of epidemiology and molecular biology. As one of the most common comorbidities in patients with OA, hypertension can disrupt joint homeostasis both biophysically and biochemically. High blood pressure can increase intraosseous pressure and cause hypoxia, which in turn triggers subchondral bone and osteochondral junction remodelling. Furthermore, systemic activation of the renin-angiotensin and endothelin systems can affect the Wnt-ß-catenin signalling pathway locally to govern joint disease. The intimate relationship between hypertension and OA indicates that endothelium-targeted strategies, including re-purposed FDA-approved antihypertensive drugs, could be useful in the treatment of OA.


Assuntos
Hipertensão/complicações , Osteoartrite/complicações , Animais , Osso e Ossos/irrigação sanguínea , Humanos , Hipertensão/etiologia , Hipertensão/metabolismo , Articulações/irrigação sanguínea , Articulações/metabolismo , Articulações/patologia , Modelos Biológicos , Osteoartrite/etiologia , Osteoartrite/metabolismo , Membrana Sinovial/irrigação sanguínea
10.
Int J Mol Sci ; 22(14)2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34298867

RESUMO

The hexosamine biosynthetic pathway (HBP) is essential for the production of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), the building block of glycosaminoglycans, thus playing a crucial role in cartilage anabolism. Although O-GlcNAcylation represents a protective regulatory mechanism in cellular processes, it has been associated with degenerative diseases, including osteoarthritis (OA). The present study focuses on HBP-related processes as potential therapeutic targets after cartilage trauma. Human cartilage explants were traumatized and treated with GlcNAc or glucosamine sulfate (GS); PUGNAc, an inhibitor of O-GlcNAcase; or azaserine (AZA), an inhibitor of GFAT-1. After 7 days, cell viability and gene expression analysis of anabolic and catabolic markers, as well as HBP-related enzymes, were performed. Moreover, expression of catabolic enzymes and type II collagen (COL2) biosynthesis were determined. Proteoglycan content was assessed after 14 days. Cartilage trauma led to a dysbalanced expression of different HBP-related enzymes, comparable to the situation in highly degenerated tissue. While GlcNAc and PUGNAc resulted in significant cell protection after trauma, only PUGNAc increased COL2 biosynthesis. Moreover, PUGNAc and both glucosamine derivatives had anti-catabolic effects. In contrast, AZA increased catabolic processes. Overall, "fueling" the HBP by means of glucosamine derivatives or inhibition of deglycosylation turned out as cells and chondroprotectives after cartilage trauma.


Assuntos
Vias Biossintéticas/efeitos dos fármacos , Doenças das Cartilagens/tratamento farmacológico , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Glucosamina/farmacologia , Hexosaminas/metabolismo , Uridina Difosfato N-Acetilglicosamina/farmacologia , Biomarcadores/metabolismo , Cartilagem/efeitos dos fármacos , Cartilagem/metabolismo , Doenças das Cartilagens/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Colágeno Tipo II/metabolismo , Feminino , Expressão Gênica/efeitos dos fármacos , Glicosilação/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Fosforilação/efeitos dos fármacos
11.
Int J Mol Sci ; 22(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299305

RESUMO

Adenosine is a ubiquitous endogenous modulator with the main function of maintaining cellular and tissue homeostasis in pathological and stress conditions. It exerts its effect through the interaction with four G protein-coupled receptor (GPCR) subtypes referred as A1, A2A, A2B, and A3 adenosine receptors (ARs), each of which has a unique pharmacological profile and tissue distribution. Adenosine is a potent modulator of inflammation, and for this reason the adenosinergic system represents an excellent pharmacological target for the myriad of diseases in which inflammation represents a cause, a pathogenetic mechanism, a consequence, a manifestation, or a protective factor. The omnipresence of ARs in every cell of the immune system as well as in almost all cells in the body represents both an opportunity and an obstacle to the clinical use of AR ligands. This review offers an overview of the cardinal role of adenosine in the modulation of inflammation, showing how the stimulation or blocking of its receptors or agents capable of regulating its extracellular concentration can represent promising therapeutic strategies for the treatment of chronic inflammatory pathologies, neurodegenerative diseases, and cancer.


Assuntos
Adenosina/imunologia , Inflamação/imunologia , Adenosina/metabolismo , Animais , Humanos , Inflamação/metabolismo , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/metabolismo , Ligantes , Pneumopatias/imunologia , Pneumopatias/metabolismo , Modelos Biológicos , Modelos Imunológicos , Neoplasias/imunologia , Neoplasias/metabolismo , Neuroimunomodulação , Osteoartrite/imunologia , Osteoartrite/metabolismo , Receptores Purinérgicos P1/imunologia , Receptores Purinérgicos P1/metabolismo , Doenças Reumáticas/imunologia , Doenças Reumáticas/metabolismo
12.
Aging (Albany NY) ; 13(13): 17227-17236, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34198264

RESUMO

Osteoarthritis (OA) and rheumatoid arthritis (RA) are two of the most common types of arthritis. Both are characterized by the infiltration of a number of proinflammatory cytokines into the joint microenvironment. miRNAs play critical roles in the disease processes of arthritic disorders. However, little is known about the effects of miRNAs on critical inflammatory cytokine production with OA and RA progression. Here, we found higher levels of proinflammatory cytokines including interleukin 1 beta (IL-1ß), interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) in human OA and RA synovial fibroblasts (SFs) compared with normal SFs. Searches of open-source microRNA (miRNA) software determined that miR-let-7c-5p and miR-149-5p interfere with IL-1ß, IL-6 and TNF-α transcription; levels of all three proinflammatory cytokines were lower in human OA and RA patients compared with normal controls. Anti-inflammatory agents dexamethasone, celecoxib and indomethacin reduced proinflammatory cytokine production by promoting the expression of miR-let-7c-5p and miR-149-5p. Similarly, ibuprofen and methotrexate also enhanced miR-let-7c-5p and miR-149-5p expression in human SFs. The evidence suggests that increasing miR-let-7c-5p and miR-149-5p expression is a novel strategy for OA and RA.


Assuntos
Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Citocinas/biossíntese , Citocinas/genética , Fibroblastos/metabolismo , MicroRNAs/genética , Osteoartrite/genética , Osteoartrite/metabolismo , Membrana Sinovial/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Fibroblastos/efeitos dos fármacos , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , MicroRNAs/biossíntese , Membrana Sinovial/citologia , Membrana Sinovial/efeitos dos fármacos , Fator de Necrose Tumoral alfa
13.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209006

RESUMO

Osteoarthritis (OA) is a common chronic disease with increasing prevalence in societies with more aging populations, therefore, it is causing more concern. S-Equol, a kind of isoflavones, was reported to be bioavailable and beneficial to humans in many aspects, such as improving menopausal symptoms, osteoporosis and prevention of cardiovascular disease. This study investigated the effects of S-Equol on OA progress in which rat primary chondrocytes were treated with sodium nitroprusside (SNP) to mimic OA progress with or without the co-addition of S-Equol for the evaluation of S-Equol's efficacy on OA. Results showed treatment of 0.8 mM SNP caused cell death, and increased oxidative stress (NO and H2O2), apoptosis, and proteoglycan loss. Furthermore, the expressions of MMPs of MMP-2, MMP-3, MMP-9, and MMP-13 and p53 were increased. The addition of 30 µM S-Equol could lessen those caused by SNP. Moreover, S-Equol activates the PI3K/Akt pathway, which is an upstream regulation of p53 and NO production and is associated with apoptosis and matrix degradation. As a pretreatment of phosphoinositide 3-kinases (PI3K) inhibitor, all S-Equol protective functions against SNP decrease or disappear. In conclusion, through PI3K/Akt activation, S-Equol can protect chondrocytes against SNP-induced matrix degradation and apoptosis, which are commonly found in OA, suggesting S-Equol is a potential for OA prevention.


Assuntos
Condrócitos/citologia , Equol/farmacologia , Nitroprussiato/efeitos adversos , Osteoartrite/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Condrócitos/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Modelos Biológicos , Osteoartrite/induzido quimicamente , Osteoartrite/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos
14.
Int J Mol Sci ; 22(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208590

RESUMO

Osteoarthritis (OA) is the most common musculoskeletal disorder causing a great disability and a reduction in the quality of life. In OA, articular chondrocytes (AC) and synovial fibroblasts (SF) release innate-derived immune mediators that initiate and perpetuate inflammation, inducing cartilage extracellular matrix (ECM) degradation. Given the lack of therapies for the treatment of OA, in this study, we explore biomarkers that enable the development of new therapeutical approaches. We analyze the set of secreted proteins in AC and SF co-cultures by stable isotope labeling with amino acids (SILAC). We describe, for the first time, 115 proteins detected in SF-AC co-cultures stimulated by fibronectin fragments (Fn-fs). We also study the role of the vasoactive intestinal peptide (VIP) in this secretome, providing new proteins involved in the main events of OA, confirmed by ELISA and multiplex analyses. VIP decreases proteins involved in the inflammatory process (CHI3L1, PTX3), complement activation (C1r, C3), and cartilage ECM degradation (DCN, CTSB and MMP2), key events in the initiation and progression of OA. Our results support the anti-inflammatory and anti-catabolic properties of VIP in rheumatic diseases and provide potential new targets for OA treatment.


Assuntos
Condrócitos/metabolismo , Fibroblastos/metabolismo , Osteoartrite/metabolismo , Proteoma , Proteômica , Membrana Sinovial/citologia , Peptídeo Intestinal Vasoativo/metabolismo , Biomarcadores , Condrócitos/efeitos dos fármacos , Técnicas de Cocultura , Citocinas/metabolismo , Suscetibilidade a Doenças , Matriz Extracelular/metabolismo , Fibroblastos/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Osteoartrite/etiologia , Osteoartrite/patologia , Proteômica/métodos , Peptídeo Intestinal Vasoativo/farmacologia
15.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299264

RESUMO

Inflammation has a fundamental impact on the pathophysiology of osteoarthritis (OA), a common form of degenerative arthritis. It has previously been established that curcumin, a component of turmeric (Curcuma longa), has anti-inflammatory properties. This research evaluates the potentials of curcumin on the pathophysiology of OA in vitro. To explore the anti-inflammatory efficacy of curcumin in an inflamed joint, an osteoarthritic environment (OA-EN) model consisting of fibroblasts, T-lymphocytes, 3D-chondrocytes is constructed and co-incubated with TNF-α, antisense oligonucleotides targeting NF-kB (ASO-NF-kB), or an IkB-kinase (IKK) inhibitor (BMS-345541). Our results show that OA-EN, similar to TNF-α, suppresses chondrocyte viability, which is accompanied by a significant decrease in cartilage-specific proteins (collagen II, CSPG, Sox9) and an increase in NF-kB-driven gene proteins participating in inflammation, apoptosis, and breakdown (NF-kB, MMP-9, Cox-2, Caspase-3). Conversely, similar to knockdown of NF-kB at the mRNA level or at the IKK level, curcumin suppresses NF-kB activation, NF-kB-promotes gene proteins derived from the OA-EN, and stimulates collagen II, CSPG, and Sox9 expression. Furthermore, co-immunoprecipitation assay shows that curcumin reduces OA-EN-mediated inflammation and chondrocyte apoptosis, with concomitant chondroprotective effects, due to modulation of Sox-9/NF-kB signaling axis. Finally, curcumin selectively hinders the interaction of p-NF-kB-p65 directly with DNA-this association is disrupted through DTT. These results suggest that curcumin suppresses inflammation in OA-EN via modulating NF-kB-Sox9 coupling and is essential for maintaining homeostasis in OA by balancing chondrocyte survival and inflammatory responses. This may contribute to the alternative treatment of OA with respect to the efficacy of curcumin.


Assuntos
Curcumina/farmacologia , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Apoptose/efeitos dos fármacos , Cartilagem/metabolismo , Células Cultivadas , Condrócitos/metabolismo , Curcuma/metabolismo , Curcumina/metabolismo , Ciclo-Oxigenase 2/metabolismo , Humanos , Quinase I-kappa B/antagonistas & inibidores , Quinase I-kappa B/metabolismo , Imidazóis/farmacologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-1beta/metabolismo , NF-kappa B/metabolismo , Osteoartrite/fisiopatologia , Cultura Primária de Células , Quinoxalinas/farmacologia , Fatores de Transcrição SOX9/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
16.
ACS Appl Mater Interfaces ; 13(27): 31379-31392, 2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34197081

RESUMO

Osteoarthritis (OA) is treated with the intra-articular injection of steroids such as dexamethasone (DEX) to provide short-term pain management. However, DEX treatment suffers from rapid joint clearance. Here, 20 × 10 µm, shape-defined poly(d,l-lactide-co-glycolide)acid microPlates (µPLs) are created and intra-articularly deposited for the sustained release of DEX. Under confined conditions, DEX release is projected to persist for several months, with only ∼20% released in the first month. In a highly rigorous murine knee overload injury model (post-traumatic osteoarthritis), a single intra-articular injection of Cy5-µPLs is detected in the cartilage surface, infrapatellar fat pad/synovium, joint capsule, and posterior joint space up to 30 days. One intra-articular injection of DEX-µPL (1 mg kg-1) decreased the expression of interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, IL-6, and matrix metalloproteinase (MMP)-13 by approximately half compared to free DEX at 4 weeks post-treatment. DEX-µPL also reduced load-induced histological changes in the articular cartilage and synovial tissues relative to saline or free DEX. In sum, the µPLs provide sustained drug release along with the capability to precisely control particle geometry and mechanical properties, yielding long-lasting benefits in overload-induced OA. This work motivates further study and development of particles that provide combined pharmacological and mechanical benefits.


Assuntos
Cartilagem Articular/metabolismo , Dexametasona/química , Dexametasona/metabolismo , Portadores de Fármacos/química , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Animais , Biomarcadores/metabolismo , Preparações de Ação Retardada , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Injeções Intra-Articulares , Camundongos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Estresse Mecânico
17.
Int J Mol Sci ; 22(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34073090

RESUMO

Nuclear magnetic resonance therapy (NMRT) is discussed as a participant in repair processes regarding cartilage and as an influence in pain signaling. To substantiate the application of NMRT, the underlying mechanisms at the cellular level were studied. In this study microRNA (miR) was extracted from human primary healthy and osteoarthritis (OA) chondrocytes after NMR treatment and was sequenced by the Ion PI Hi-Q™ Sequencing 200 system. In addition, T/C-28a2 chondrocytes grown under hypoxic conditions were studied for IL-1ß induced changes in expression on RNA and protein level. HDAC activity an NAD(+)/NADH was measured by luminescence detection. In OA chondrocytes miR-106a, miR-27a, miR-34b, miR-365a and miR-424 were downregulated. This downregulation was reversed by NMRT. miR-365a-5p is known to directly target HDAC and NF-ĸB, and a decrease in HDAC activity by NMRT was detected. NAD+/NADH was reduced by NMR treatment in OA chondrocytes. Under hypoxic conditions NMRT changed the expression profile of HIF1, HIF2, IGF2, MMP3, MMP13, and RUNX1. We conclude that NMRT changes the miR profile and modulates the HDAC and the NAD(+)/NADH signaling in human chondrocytes. These findings underline once more that NMRT counteracts IL-1ß induced changes by reducing catabolic effects, thereby decreasing inflammatory mechanisms under OA by changing NF-ĸB signaling.


Assuntos
Condrócitos , Espectroscopia de Ressonância Magnética/métodos , MicroRNAs/metabolismo , Osteoartrite , Linhagem Celular , Condrócitos/citologia , Condrócitos/metabolismo , Condrócitos/patologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Osteoartrite/metabolismo , Osteoartrite/terapia , Cultura Primária de Células
18.
Bone ; 152: 116076, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34174501

RESUMO

Cholesterol homeostasis plays a significant role in skeletal development and the dysregulation of cholesterol-related mechanism has been shown to be involved in the development of cartilage diseases including osteoarthritis (OA). Epidemiological studies have shown an association between elevated serum cholesterol levels and OA. Furthermore, abnormal lipid accumulation in chondrocytes as a result of abnormal regulation of cholesterol homeostasis has been demonstrated to be involved in the development of OA. Although, many in vivo and in vitro studies support the connection between cholesterol and cartilage degradation, the mechanisms underlying the complex interactions between lipid metabolism, especially HDL cholesterol metabolism, and OA remain unclear. The current review aims to address this problem and focuses on key molecular players of the HDL metabolism pathway and their role in ΟΑ pathogenesis. Understanding the complexity of biological processes implicated in OA pathogenesis, such as cholesterol metabolism, may lead to new targets for drug therapy of OA patients.


Assuntos
Cartilagem Articular , Osteoartrite , Cartilagem , Cartilagem Articular/metabolismo , Colesterol/metabolismo , Condrócitos , Humanos , Metabolismo dos Lipídeos/genética , Osteoartrite/genética , Osteoartrite/metabolismo
19.
Int J Mol Sci ; 22(11)2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-34072015

RESUMO

Osteoarthritis (OA) is a painful and disabling disease that affects millions of patients. Its etiology is largely unknown, but it is most likely multifactorial. OA pathogenesis involves the catabolism of the cartilage extracellular matrix and is supported by inflammatory and oxidative signaling pathways and marked epigenetic changes. To delay OA progression, a wide range of exercise programs and naturally derived compounds have been suggested. This literature review aims to analyze the main signaling pathways and the evidence about the synergistic effects of these two interventions to counter OA. The converging nutrigenomic and physiogenomic intervention could slow down and reduce the complex pathological features of OA. This review provides a comprehensive picture of a possible signaling approach for targeting OA molecular pathways, initiation, and progression.


Assuntos
Suplementos Nutricionais , Suscetibilidade a Doenças , Osteoartrite/etiologia , Osteoartrite/metabolismo , Transdução de Sinais , Animais , Antioxidantes , Biomarcadores , Condrócitos/metabolismo , Gerenciamento Clínico , Exercício Físico , Humanos , Nutrigenômica/métodos , Osteoartrite/diagnóstico , Osteoartrite/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
20.
Ann Rheum Dis ; 80(9): 1209-1219, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34039624

RESUMO

OBJECTIVES: Circular RNAs (circRNAs) have emerged as significant biological regulators. Herein, we aimed to elucidate the role of an unidentified circRNA (circPDE4B) that is reportedly downregulated in osteoarthritis (OA) tissues. METHODS: The effects of circPDE4B were explored in human and mouse chondrocytes in vitro. Specifically, RNA pull-down (RPD)-mass spectrometry analysis (MS), immunoprecipitation, glutathione-S-transferase (GST) pull-down, RNA immunoprecipitation and RPD assays were performed to verify the interactions between circPDE4B and the RIC8 guanine nucleotide exchange factor A (RIC8A)/midline 1 (MID1) complex. A mouse model of OA was also employed to confirm the role of circPDE4B in OA pathogenesis in vivo. RESULTS: circPDE4B regulates chondrocyte cell viability and extracellular matrix metabolism. Mechanistically, FUS RNA binding protein (FUS) was found to promote the splicing of circPDE4B, while downregulation of circPDE4B in OA is partially caused by upstream inhibition of FUS. Moreover, circPDE4B facilitates the association between RIC8A and MID1 by acting as a scaffold to promote RIC8A degradation through proteasomal degradation. Furthermore, ubiquitination of RIC8A at K415 abrogates RIC8A degradation. The circPDE4B-RIC8A axis was observed to play an important role in regulating downstream p38 mitogen-activated protein kinase (MAPK) signalling. Furthermore, delivery of a circPDE4B adeno-associated virus (AAV) abrogates the breakdown of cartilage matrix by medial meniscus destabilisation in mice, whereas a RIC8A AAV induces the opposite effect. CONCLUSION: This work highlights the function of the circPDE4B-RIC8A axis in OA joints, as well as its regulation of MAPK-p38, suggesting this axis as a potential therapeutic target for OA.


Assuntos
Cartilagem Articular/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Osteoartrite/genética , RNA Circular , Regeneração/genética , Animais , Cartilagem Articular/citologia , Cartilagem Articular/fisiologia , Sobrevivência Celular/genética , Condrócitos/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Humanos , Camundongos , Osteoartrite/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Processamento de Proteína Pós-Traducional , Proteólise , Proteína FUS de Ligação a RNA/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
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