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1.
Nihon Shokakibyo Gakkai Zasshi ; 118(9): 840-850, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34511551

RESUMO

BACKGROUND & AIMS: Capsule endoscopy has revealed that nonsteroidal anti-inflammatory drugs may cause damage not only to the stomach but also to the small intestine, which has become one of the most serious issues in gastroenterology. However, few studies have reported the effect of ibuprofen (IBP), which is widely prescribed worldwide, on the small intestine, and it remains unclear whether IBP can cause small intestinal damage. We have previously shown that acetaminophen (APAP), which is used as an antipyretic/analgesic drug, inhibits IBP-induced gastric damage by suppressing matrix metalloprotease-13 (MMP-13) gene expression. In this study, we investigated the ability of IBP to induce small intestinal damage and the efficacy of APAP against IBP-induced small intestinal damage in rats. MAIN METHODS: Nonfasted male Sprague-Dawley rats were orally administered with IBP (200mg/kg) and then euthanized at various time points (0, 4, 8, 16, and 24h) after the administration. The small intestine, jejunum, and ileum were removed, and intestinal lesions were measured. To elucidate the efficacy of APAP against IBP-induced small intestinal damage, the rats were treated with IBP (200mg/kg) with or without APAP (200mg/kg), and small intestinal damage was evaluated 24h after the administration. Moreover, the expression levels of GAPDH, TNFα, iNOS, and MMP-13 genes were determined at various time points (8, 16, and 24h) by RT-qPCR. KEY FINDINGS: The oral administration of IBP induced obvious small intestinal damage, which was found to be significant at 24h (p<0.05 vs 0h, Dunnett's test). The coadministration of APAP significantly prevented IBP-induced damage (p<0.05, Student's t-test). In addition, the expression levels of TNFα and iNOS genes were significantly increased by IBP (p<0.01 and p<0.05 vs. vehicle, respectively, Tukey-Kramer test), whereas the cotreatment with APAP suppressed the increases at 8h. Moreover, compared with the vehicle, the IBP treatment significantly increased the expression level of the MMP-13 gene (p<0.01) at each time point (8, 16, and 24h, Tukey-Kramer test), whereas the APAP cotreatment significantly suppressed the increase (p<0.01 vs. IBP at 8h, p<0.05 vs. IBP at 16 and 24h, Tukey-Kramer test). CONCLUSIONS: This study suggested that a single administration of IBP was associated with the risk of inducing small intestinal ulcers in rats, and APAP could prevent IBP-induced small intestinal damage by suppressing the MMP-13 gene expression.


Assuntos
Acetaminofen , Doença Hepática Induzida por Substâncias e Drogas , Acetaminofen/toxicidade , Animais , Ibuprofeno/farmacologia , Intestino Delgado , Fígado , Masculino , Metaloproteinase 13 da Matriz/genética , Ratos , Ratos Sprague-Dawley
2.
Int J Mol Sci ; 22(18)2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34576138

RESUMO

Osteoarthritis is a degenerative disease, often resulting in chronic joint pain and commonly affecting elderly people. Current treatments with anti-inflammatory drugs are palliative, making the discovery of new treatments necessary. The inhibition of matrix metalloproteinase MMP-13 is a validated strategy to prevent the progression of this common joint disorder. We recently described polybrominated benzotriazole derivatives with nanomolar inhibitory activity and a promising selectivity profile against this collagenase. In this work, we have extended the study in order to explore the influence of bromine atoms and the nature of the S1' heterocyclic interacting moiety on the solubility/selectivity balance of this type of compound. Drug target interactions have been assessed through a combination of molecular modeling studies and NMR experiments. Compound 9a has been identified as a water-soluble and highly potent inhibitor with activity in MG-63 human osteosarcoma cells.


Assuntos
Desenho de Fármacos , Inibidores de Metaloproteinases de Matriz/farmacologia , Osteossarcoma/patologia , Água/química , Linhagem Celular Tumoral , Química Click , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Metaloproteinase 13 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz/síntese química , Inibidores de Metaloproteinases de Matriz/química , Modelos Moleculares , Solubilidade
3.
Nat Rev Rheumatol ; 17(11): 645, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34518672
4.
ACS Nano ; 15(9): 14475-14491, 2021 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-34409835

RESUMO

Post-traumatic osteoarthritis (PTOA) associated with joint injury triggers a degenerative cycle of matrix destruction and inflammatory signaling, leading to pain and loss of function. Here, prolonged RNA interference (RNAi) of matrix metalloproteinase 13 (MMP13) is tested as a PTOA disease modifying therapy. MMP13 is upregulated in PTOA and degrades the key cartilage structural protein type II collagen. Short interfering RNA (siRNA) loaded nanoparticles (siNPs) were encapsulated in shape-defined poly(lactic-co-glycolic acid) (PLGA) based microPlates (µPLs) to formulate siNP-µPLs that maintained siNPs in the joint significantly longer than delivery of free siNPs. Treatment with siNP-µPLs against MMP13 (siMMP13-µPLs) in a mechanical load-induced mouse model of PTOA maintained potent (65-75%) MMP13 gene expression knockdown and reduced MMP13 protein production in joint tissues throughout a 28-day study. MMP13 silencing reduced PTOA articular cartilage degradation/fibrillation, meniscal deterioration, synovial hyperplasia, osteophytes, and pro-inflammatory gene expression, supporting the therapeutic potential of long-lasting siMMP13-µPL therapy for PTOA.


Assuntos
Sistemas de Liberação de Medicamentos , Articulações/lesões , Metaloproteinase 13 da Matriz/administração & dosagem , Osteoartrite , Animais , Metaloproteinase 13 da Matriz/genética , Camundongos , Nanopartículas , Osteoartrite/terapia , RNA Interferente Pequeno
5.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201564

RESUMO

Obesity increases the risk of hip osteoarthritis (OA). Recent studies have shown that adipokine extracellular nicotinamide phosphoribosyltransferase (eNAMPT or visfatin) induces the production of IL-6 and matrix metalloproteases (MMPs) in chondrocytes, suggesting it may promote articular cartilage degradation. However, neither the functional effects of extracellular visfatin on human articular cartilage tissue, nor its expression in the joint of hip OA patients of varying BMI, have been reported. Hip OA joint tissues were collected from patients undergoing joint replacement surgery. Cartilage explants were stimulated with recombinant human visfatin. Pro-inflammatory cytokines and MMPs were measured by ELISA and Luminex. Localisation of visfatin expression in cartilage tissue was determined by immunohistochemistry. Cartilage matrix degradation was determined by quantifying proteoglycan release. Expression of visfatin was elevated in the synovial tissue of hip OA patients who were obese, and was co-localised with MMP-13 in areas of cartilage damage. Visfatin promoted the degradation of hip OA cartilage proteoglycan and induced the production of pro-inflammatory cytokines (IL-6, MCP-1, CCL20, and CCL4) and MMPs. The elevated expression of visfatin in the obese hip OA joint, and its functional effects on hip cartilage tissue, suggests it plays a central role in the loss of cartilage integrity in obese patients with hip OA.


Assuntos
Cartilagem Articular/patologia , Citocinas/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Osteoartrite do Quadril/metabolismo , Idoso , Idoso de 80 Anos ou mais , Cartilagem Articular/metabolismo , Quimiocinas/metabolismo , Condrócitos/metabolismo , Citocinas/sangue , Articulação do Quadril/metabolismo , Articulação do Quadril/fisiopatologia , Humanos , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinases da Matriz/metabolismo , Pessoa de Meia-Idade , NAD/metabolismo , Nicotinamida Fosforribosiltransferase/sangue , Obesidade/metabolismo , Técnicas de Cultura de Órgãos , Osteoartrite do Quadril/patologia , Proteoglicanas/metabolismo
6.
Biomed Pharmacother ; 138: 111537, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34311535

RESUMO

Aging of the skin is a complicated bioprocess that is affected by constant exposure to ultraviolet irradiation. The application of herbal-based anti-aging creams is still the best choice for treatment. In the present study, Citrus sinensis L. fruit peels ethanolic extract (CSPE) was formulated into lipid nanoparticles (LNPs) anti-aging cream. Eight different formulations of CSEP-LNPs were prepared and optimized using 23 full factorial designs. In vivo antiaging effect of the best formula was tested in Swiss albino mice where photo-aging was induced by exposure to UV radiation. HPLC-QToF-MS/MS metabolic profiling of CSPE led to the identification of twenty-nine metabolites. CSPE was standardized to a hesperidin content of 15.53 ± 0.152 mg% using RP-HPLC. It was suggested that the optimized formulation (F7) had (245 nm) particle size, (91.065%) EE, and (91.385%) occlusive effect with a spherical and smooth surface. The visible appearance of UV-induced photoaging in mice was significantly improved after topical application on CSPE-NLC cream for 5 weeks, levels of collagen and SOD were significantly increased in CSPE- NLC group, while levels of PGE2, COX2, JNK, MDA, and elastin was reduced. Finally, The prepared anti-aging CSPE-NLC cream represents a safe, convenient, and promising skincare cosmetic product.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Citrus sinensis , Metaloproteinase 13 da Matriz/metabolismo , Extratos Vegetais/administração & dosagem , Envelhecimento da Pele/efeitos dos fármacos , Creme para a Pele/administração & dosagem , Pele/efeitos dos fármacos , Administração Cutânea , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Antioxidantes/química , Antioxidantes/isolamento & purificação , Citrus sinensis/química , Colágeno/metabolismo , Regulação para Baixo , Composição de Medicamentos , Feminino , Frutas , Lipídeos/química , Metaloproteinase 13 da Matriz/genética , Camundongos , Nanopartículas , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Pele/enzimologia , Pele/patologia , Pele/efeitos da radiação , Creme para a Pele/química , Creme para a Pele/isolamento & purificação , Superóxido Dismutase/metabolismo , Raios Ultravioleta
7.
BMC Cancer ; 21(1): 816, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34266392

RESUMO

BACKGROUND: A significant proportion of newly diagnosed patients with cutaneous squamous cell carcinoma (cSCC) have metastasis and eventually die of the disease, necessitating the exploration of novel biomarkers for early detection of cSCC aggressiveness, risk assessment and monitoring. Matrix metalloproteinase-13 (MMP-13) has been implicated in cSCC pathogenesis. Serum MMP-13 levels have been shown to predict survival in patients with esophageal SCC, but their diagnostic value for cSCC has not been explored. METHODS: We conducted a case-control study to examine serum MMP-13 as a biomarker for cSCC. Patients with cSCC undergoing surgical resection and health controls undergoing plastic surgery were recruited. ELISA for measurement of serum MMP-13 and immunohistochemistry for detection of tissue MMP-13 were performed, and the results were compared between the case and the control group, and among different patient groups. ROC curve analysis was performed to determine the diagnostic value of serum MMP-13 levels. RESULTS: The ratio of male to female, and the age between the case (n = 77) and the control group (n = 50) were not significantly different. Patients had significantly higher serum MMP-13 levels than healthy controls. Subjects with stage 3 cSCC had markedly higher serum MMP-13 levels than those with stage 1 and stage 2 cSCC. Patients with invasive cSCC had remarkably higher serum MMP-13 than those with cSCC in situ. Post-surgery serum MMP-13 measurement was done in 12 patients, and a significant MMP-13 decrease was observed after removal of cSCC. Tumor tissues had a remarkably higher level of MMP-13 than control tissues. Serum MMP-13 predicted the presence of invasive cSCC with an AUC of 0.87 (95% CI [0.78 to 0.95]) for sensitivity and specificity of 81.7 and 82.4%, respectively for a cut-off value of 290 pg/mL. Serum MMP-13 predicted lymph node involvement with an AUC of 0.94 (95% CI [0.88 to 0.99]) for sensitivity and specificity of 93.8 and 88.5%, respectively for a cut-off value of 430 pg/mL. CONCLUSION: Serum MMP-13 might serve as a valuable biomarker for early detection of cSCC invasiveness and monitoring of cSCC progression.


Assuntos
Biomarcadores Tumorais/sangue , Carcinoma de Células Escamosas/genética , Metaloproteinase 13 da Matriz/metabolismo , Neoplasias Cutâneas/genética , Carcinoma de Células Escamosas/patologia , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Cutâneas/patologia
8.
Eur J Med Chem ; 224: 113666, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34245949

RESUMO

Osteoarthritis (OA) is a chronic disorder that causes damage to the cartilage and surrounding tissues and is characterized by pain, stiffness, and loss of function. Current treatments for OA primarily involve providing only relief of symptoms but does not affect the overall trajectory of the disease. A major goal for treating OA has been to slow down or reverse disease progression. Matrix metalloproteinase-13 (MMP-13) is expressed by chondrocytes and synovial cells in human OA and is thought to play a critical role in cartilage destruction. Herein we report a new, allosteric MMP-13 inhibitor, AQU-019, that has been optimized for potency, metabolic stability, and oral bioavailability through a combination of structure activity relationship (SAR) and deuterium substitution as a potential disease modifying OA drug (DMOAD). The inhibitor was demonstrated to be chondroprotective when injected intraarticular (IA) in the monoiodoacetic acid (MIA) rat model of OA.


Assuntos
Metaloproteinase 13 da Matriz/química , Inibidores de Metaloproteinases de Matriz/uso terapêutico , Osteoartrite/tratamento farmacológico , Amidas/química , Amidas/metabolismo , Amidas/uso terapêutico , Animais , Modelos Animais de Doenças , Meia-Vida , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Articulações/patologia , Metaloproteinase 13 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz/química , Inibidores de Metaloproteinases de Matriz/farmacocinética , Osteoartrite/induzido quimicamente , Osteoartrite/patologia , Pirimidinas/química , Ratos , Relação Estrutura-Atividade
9.
Biomed Res Int ; 2021: 5544264, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34195267

RESUMO

Background: Rheumatoid arthritis (RA) is a chronic condition that manifests as inflammation of synovial joints, leading to joint destruction and deformity. Methods: We identified single-cell RNA-seq data of synovial fibroblasts from RA and osteoarthritis (OA) patients in GSE109449 dataset. RA- and OA-specific cellular subpopulations were identified, and enrichment analysis was performed. Further, key genes for RA and OA were obtained by combined analysis with differentially expressed genes (DEGs) between RA and OA in GSE56409 dataset. The diagnostic role of key genes for RA was predicted using receiver operating characteristic (ROC) curve. Finally, we identified differences in immune cell infiltration between RA and OA patients, and utilized flow cytometry, qRT-PCR, and Western blot were used to examine the immune cell and key genes in RA patients. Results: The cluster 0 matched OA and cluster 3 matched RA and significantly enriched for neutrophil-mediated immunity and ECM receptor interaction, respectively. We identified 478 DEGs. In the top 20 degrees of connection in the PPI network, the key genes for RA were obtained by comparing with the gene markers of cluster 0 and cluster 3, respectively. ROC curve showed that CCL2 and MMP13 might be diagnostic markers for RA. We found aberrant levels of CD8+T, neutrophil, and B cells in RA fibroblasts, which were validated in clinical samples. Importantly, we also validated the differential expression of key genes between RA and OA. Conclusion: High expression of CCL2 and MMP13 in RA may be a diagnostic and therapeutic target.


Assuntos
Artrite Reumatoide/metabolismo , Fibroblastos/metabolismo , Osteoartrite/metabolismo , Membrana Sinovial/metabolismo , Algoritmos , Linfócitos B/metabolismo , Biomarcadores/sangue , Linfócitos T CD8-Positivos/metabolismo , Quimiocina CCL2/sangue , Citometria de Fluxo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Marcadores Genéticos , Humanos , Sistema Imunitário , Inflamação , Metaloproteinase 13 da Matriz/sangue , Mapas de Interação de Proteínas/genética , Curva ROC
10.
Sci Rep ; 11(1): 15131, 2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34302034

RESUMO

Metabolic dysfunction in chondrocytes drives the pro-catabolic phenotype associated with osteoarthritic cartilage. In this study, substitution of galactose for glucose in culture media was used to promote a renewed dependence on mitochondrial respiration and oxidative phosphorylation. Galactose replacement alone blocked enhanced usage of the glycolysis pathway by IL1ß-activated chondrocytes as detected by real-time changes in the rates of proton acidification of the medium and changes in oxygen consumption. The change in mitochondrial activity due to galactose was visualized as a rescue of mitochondrial membrane potential but not an alteration in the number of mitochondria. Galactose-replacement reversed other markers of dysfunctional mitochondrial metabolism, including blocking the production of reactive oxygen species, nitric oxide, and the synthesis of inducible nitric oxide synthase. Of more clinical relevance, galactose-substitution blocked downstream functional features associated with osteoarthritis, including enhanced levels of MMP13 mRNA, MMP13 protein, and the degradative loss of proteoglycan from intact cartilage explants. Blocking baseline and IL1ß-enhanced MMP13 by galactose-replacement in human osteoarthritic chondrocyte cultures inversely paralleled increases in markers associated with mitochondrial recovery, phospho-AMPK, and PGC1α. Comparisons were made between galactose replacement and the glycolysis inhibitor 2-deoxyglucose. Targeting intermediary metabolism may provide a novel approach to osteoarthritis care.


Assuntos
Respiração Celular/fisiologia , Condrócitos/metabolismo , Mitocôndrias/metabolismo , Osteoartrite/metabolismo , Idoso , Animais , Cartilagem Articular/metabolismo , Bovinos , Células Cultivadas , Feminino , Glucose/metabolismo , Glicólise/fisiologia , Humanos , Interleucina-1beta/metabolismo , Masculino , Metaloproteinase 13 da Matriz/metabolismo , Óxido Nítrico/metabolismo , Fosforilação Oxidativa , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Espécies Reativas de Oxigênio/metabolismo
11.
Jt Dis Relat Surg ; 32(2): 299-305, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34145804

RESUMO

OBJECTIVES: The aim of this study was to investigate the relationship between MMP13 rs3819089, ADAM12 rs3740199 and rs1871054, and ADAMTS14 rs4747096 genotypes in patients with radiologically diagnosed knee osteoarthritis (OA). PATIENTS AND METHODS: A total of 300 patients (68 males, 232 females; mean age: 61.6 years; range, 25 to 89 years) who were admitted to the orthopedics and traumatology clinic and diagnosed with knee OA according to the 2000 American College of Rheumatology (ACR) criteria between October 2018 and March 2019 were prospectively analyzed. Patients with Grades III-IV OA according to the Kellgren-Lawrence (K-L) grading system were included in the patient group (n=150) and those without radiological features of knee OA (K-L Grades I-II) were included in the control group (n=150) voluntarily. The presence of single nucleotide polymorphisms (SNPs) in the targeted genes in both groups was assessed by real-time polymerase chain reaction in the peripheral blood sample. RESULTS: The most common nucleotides in both the control and patient groups were CG for rs3740199 and CT for rs1871054 in the ADAM12 gene, and the most common nucleotides in alleles were GG for MMP13 rs3819089 and AA for ADAMTS14 rs4747096. No statistically significant relationship was detected between the gene polymorphisms and advanced OA. CONCLUSION: The study results suggest that ADAM12 rs3740199 and rs1871054, MMP13 rs3819089, and ADAMTS14 rs4747096 polymorphisms have no relationship with knee OA susceptibility in the Turkish population. However, as this is the first study to investigate the relationship between the SNPs of ADAM12, ADAMTS14, and MMP13 genes and the development of OA in the Turkish population, it would contribute to our understanding of the molecular bases of OA.


Assuntos
Proteína ADAM12/genética , Proteínas ADAMTS/genética , Metaloproteinase 13 da Matriz/genética , Osteoartrite do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Radiografia , Reação em Cadeia da Polimerase em Tempo Real , Índice de Gravidade de Doença
12.
J Orthop Surg Res ; 16(1): 403, 2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34158084

RESUMO

BACKGROUND: The aim of this study was to investigate the effect of Iguratimod (T-614) on rat knee osteoarthritis (KOA) and further to explore its underlying mechanism. METHODS: In this study, papain-induced KOA model was constructed. Hematoxylin and eosin (H&E) staining was conducted to observe the pathological changes of cartilage tissue and Mankin scoring principle was used for quantitative scoring. Transmission electron microscopy (TEM) was applied to observe the ultrastructure of cartilage tissue. ELISA was used to measure the levels of matrix metalloproteinase 13 (MMP-13) and inflammatory factors (interleukin (IL)-6 and tumor necrosis factor a (TNF-a)) in serum. RT-qPCR and immunohistochemistry were conducted to detect mRNA expression and protein expression of key genes in Wnt/ß-catenin pathway. RESULTS: H&E, Mankin scoring, and TEM data confirmed that compared with model group, T-614 significantly improved the degeneration of articular cartilage. Besides, we observed that low, middle, and high doses of T-614 could decrease the levels of MMP13, TNF-α, and IL-6 in serum to different degrees. Mechanically, T-614 downregulated the mRNA and protein expression of ß-catenin and MMP13 in cartilage tissue via a dose-dependent manner, and on the contrary upregulated the mRNA and protein expression of glucogen synthase kinase-3 beta (GSK-3ß). CONCLUSION: Our results suggested that T-614 can reduce the level of its downstream target gene MMP-13 and downregulate the expression of inflammatory cytokines TNF-α and IL-6 by regulating the Wnt/ß-catenin signaling pathway, thereby inhibiting joint inflammation and controlling KOA degeneration of articular cartilage.


Assuntos
Benzopiranos/farmacologia , Cartilagem Articular/metabolismo , Cromonas/farmacologia , Regulação para Baixo/efeitos dos fármacos , Osteoartrite do Joelho/tratamento farmacológico , Sulfonamidas/farmacologia , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Glicogênio Sintase Quinase 3 beta/metabolismo , Interleucina-6/sangue , Metaloproteinase 13 da Matriz/sangue , Osteoartrite do Joelho/sangue , Osteoartrite do Joelho/induzido quimicamente , Papaína , Ratos , Fator de Necrose Tumoral alfa/sangue , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo
13.
Sci Rep ; 11(1): 13328, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34172768

RESUMO

Matrix metalloproteinase13 (MMP13) can be released by keratinocytes and fibroblasts and involved in the pathogenesis of skin disorders. Retinoic acid derivative drugs include tazarotene and acitretin. Tazarotene/acitretin and narrow-band ultraviolet B (NB-UVB) irradiation are common treatment options for psoriasis. However, their impact on MMP13 expression in the context of psoriasis has yet to be determined. The expression of MMP13 was analyzed in patients with psoriasis. The effects of tazarotene/acitretin and NB-UVB on MMP13 expression were also investigated in a mouse model of psoriasis. Human HaCaT keratinocytes were exposed to acitretin or NB-UVB and then assayed for cell proliferation and MMP13 expression levels. We showed that patients with psoriasis had increased levels of MMP13 protein in skin lesions and serum samples. Exposure to acitretin and NB-UVB irradiation alone or in combination led to reduction of cell proliferation and MMP13 expression in HaCaT cells. Consistently, tazarotene treatment or NB-UVB irradiation attenuated imiquimod-induced psoriasis-like dermatitis and decreased MMP13 expression in a mouse model. Based on these from HaCaT keratinocytes cells and animal experiments, we suggest that tazarotene/acitretin and NB-UVB irradiation can inhibit the expression of MMP13 in HaCaT keratinocytes and psoriasis mouse models. Blockade of MMP13 activity may have therapeutic potential in improving symptoms of psoriasis.


Assuntos
Queratinócitos/efeitos dos fármacos , Queratinócitos/efeitos da radiação , Metaloproteinase 13 da Matriz/metabolismo , Psoríase/tratamento farmacológico , Psoríase/radioterapia , Retinoides/farmacologia , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Modelos Animais de Doenças , Células HaCaT , Humanos , Imiquimode/farmacologia , Camundongos , Ácidos Nicotínicos/farmacologia , Psoríase/induzido quimicamente , Psoríase/metabolismo , Raios Ultravioleta , Terapia Ultravioleta/métodos
14.
Mol Med Rep ; 24(2)2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34165157

RESUMO

Excessive biomechanical loading is considered an important cause of osteoarthritis. Although the mechanical responses of chondrocytes and osteoblasts have been investigated, their communication during mechanical loading and the underlying molecular mechanisms are not yet fully known. The present study investigated the effects of excessive mechanically stretched osteoblasts on the metabolism and apoptosis of chondrocytes, and also assessed the involvement of the Wnt/ß­catenin signaling pathway. In the present study, rat chondrocytes and osteoblasts were subjected to mechanical tensile strain, and an indirect chondrocyte­osteoblast co­culture model was established. Reverse transcription­quantitative PCR and western blotting were performed to determine the expression levels of genes and proteins of interest. An ELISA was performed to investigate the levels of cytokines, including matrix metalloproteinase (MMP) 13, MMP 3, interleukin­6 (IL­6) and prostaglandin E2 (PG E2), released from osteoblasts. Flow cytometry was performed to detect the apoptosis of chondrocytes exposed to stretched osteoblast conditioned culture medium. The levels of MMP 13, IL­6 and PG E2 increased significantly in the supernatants of stretched osteoblasts compared with the un­stretched group. By contrast, the mRNA expression levels of Collagen 1a and alkaline phosphatase were significantly decreased in osteoblasts subjected to mechanical stretch compared with the un­stretched group. The mRNA expression level of Collagen 2a was significantly decreased, whereas the expression levels of MMP 13 and a disintegrin and metalloproteinase with thrombospondin­like motifs 5 were significantly increased in chondrocytes subjected to mechanical stretch compared with the un­stretched group. In the co­culture model, the results indicated that excessive mechanically stretched osteoblasts induced the catabolism and apoptosis of chondrocytes, which was partly inhibited by Wnt inhibitor XAV­939. The results of the present study demonstrated that excessive mechanical stretch led to chondrocyte degradation and inhibited osteoblast osteogenic differentiation; furthermore, excessive mechanically stretched osteoblasts induced the catabolism and apoptosis of chondrocytes via the Wnt/ß­catenin signaling pathway.


Assuntos
Apoptose , Condrócitos/metabolismo , Osteoblastos/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Citocinas/metabolismo , Dinoprostona/metabolismo , Modelos Animais de Doenças , Interleucina-6/metabolismo , Masculino , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , Osteoartrite/metabolismo , Ratos , Ratos Sprague-Dawley
15.
Theranostics ; 11(13): 6573-6591, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995677

RESUMO

Mesenchymal stem cells (MSCs) have been identified in many adult tissues. MSCs can regenerate through cell division or differentiate into adipocytes, osteoblasts and chondrocytes. As a result, MSCs have become an important source of cells in tissue engineering and regenerative medicine for bone tissue and cartilage. Several epigenetic factors are believed to play a role in MSCs differentiation. Among these, microRNA (miRNA) regulation is involved in the fine modulation of gene expression during osteogenic/chondrogenic differentiation. It has been reported that miRNAs are involved in bone homeostasis by modulating osteoblast gene expression. In addition, countless evidence has demonstrated that miRNAs dysregulation is involved in the development of osteoporosis and bone fractures. The deregulation of miRNAs expression has also been associated with several malignancies including bone cancer. In this context, bone-associated circulating miRNAs may be useful biomarkers for determining the predisposition, onset and development of osteoporosis, as well as in clinical applications to improve the diagnosis, follow-up and treatment of cancer and metastases. Overall, this review will provide an overview of how miRNAs activities participate in osteogenic/chondrogenic differentiation, while addressing the role of miRNA regulatory effects on target genes. Finally, the role of miRNAs in pathologies and therapies will be presented.


Assuntos
Doenças Ósseas/genética , Condrogênese/genética , Células-Tronco Mesenquimais/citologia , MicroRNAs/genética , Osteogênese/genética , Proteínas Morfogenéticas Ósseas/fisiologia , Subunidade alfa 1 de Fator de Ligação ao Core/fisiologia , Sistemas de Liberação de Medicamentos , Fraturas Ósseas/metabolismo , Histona Desacetilases/fisiologia , Humanos , Metaloproteinase 13 da Matriz/fisiologia , Proteínas Repressoras/fisiologia , Transdução de Sinais , Proteínas Smad/fisiologia , Fator de Transcrição Sp7/fisiologia , Fator de Crescimento Transformador beta/fisiologia , Fator A de Crescimento do Endotélio Vascular/fisiologia
16.
J Cell Mol Med ; 25(12): 5671-5680, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33942503

RESUMO

Iron overload is common in elderly people which is implicated in the disease progression of osteoarthritis (OA), however, how iron homeostasis is regulated during the onset and progression of OA and how it contributes to the pathological transition of articular chondrocytes remain unknown. In the present study, we developed an in vitro approach to investigate the roles of iron homeostasis and iron overload mediated oxidative stress in chondrocytes under an inflammatory environment. We found that pro-inflammatory cytokines could disrupt chondrocytes iron homeostasis via upregulating iron influx transporter TfR1 and downregulating iron efflux transporter FPN, thus leading to chondrocytes iron overload. Iron overload would promote the expression of chondrocytes catabolic markers, MMP3 and MMP13 expression. In addition, we found that oxidative stress and mitochondrial dysfunction played important roles in iron overload-induced cartilage degeneration, reducing iron concentration using iron chelator or antioxidant drugs could inhibit iron overload-induced OA-related catabolic markers and mitochondrial dysfunction. Our results suggest that pro-inflammatory cytokines could disrupt chondrocytes iron homeostasis and promote iron influx, iron overload-induced oxidative stress and mitochondrial dysfunction play important roles in iron overload-induced cartilage degeneration.


Assuntos
Condrócitos/patologia , Citocinas/toxicidade , Mediadores da Inflamação/toxicidade , Inflamação/complicações , Sobrecarga de Ferro/complicações , Osteoartrite/patologia , Estresse Oxidativo , Animais , Células Cultivadas , Condrócitos/metabolismo , Masculino , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/genética , Metaloproteinase 3 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Osteoartrite/etiologia , Osteoartrite/metabolismo
17.
Tissue Eng Regen Med ; 18(5): 831-840, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34014552

RESUMO

BACKGROUND: Transforming growth factor beta 1 (TGFß1) plays an essential role in maintaining cartilage homeostasis. TGFß1 is known to upregulate anabolic processes in articular cartilage, but the role of TGFß1 in chondrocyte catabolism remains unclear. Thus, we examined whether TGFß1 increases catabolic processes in the osteoarthritic joint via transglutaminase 2 (TG2). In this study, we investigated whether interplay between TGFß1 and TG2 mediates chondrocyte catabolism and cartilage degeneration in osteoarthritis. METHODS: To investigate the role of TGFß1 and TG2 in osteoarthritis, we performed immunostaining to measure the levels of TGFß1 and TG2 in 6 human non-osteoarthritic and 16 osteoarthritic joints. We conducted quantitative reverse transcription polymerase chain reaction and western blot analysis to investigate the relationship between TGFß1 and TG2 in chondrocytes and determined whether TG2 regulates the expressions of matrix metalloproteinase (MMP)-13, type II, and type X collagen. We also examined the extent of cartilage degradation after performing anterior cruciate ligament transection (ACLT) and destabilization of the medial meniscus (DMM) surgery in TG2 knock-out mice. RESULTS: We confirmed the overexpression of TGFß1 and TG2 in human osteoarthritic cartilage compared with non-osteoarthritic cartilage. TGFß1 treatment significantly increased the expression of TG2 via p38 and ERK activation. TGFß1-induced TG2 also elevated the level of MMP-13 and type X collagen via NF-κB activation in chondrocytes. Cartilage damage after ACLT and DMM surgery was less severe in TG2 knock-out mice compared with wild-type mice. CONCLUSION: TGFß1 modulated catabolic processes in chondrocytes in a TG2-dependent manner. TGFß1-induced TG2 might be the therapeutic target for treating cartilage degeneration and osteoarthritis.


Assuntos
Cartilagem Articular , Condrócitos , Proteínas de Ligação ao GTP/genética , Metaloproteinase 13 da Matriz , Fator de Crescimento Transformador beta/genética , Transglutaminases/genética , Animais , Metaloproteinase 13 da Matriz/genética , Camundongos
18.
Cancer Lett ; 511: 15-25, 2021 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-33945837

RESUMO

Invasion of bladder cancer (BC) cells from the mucosa into the muscle layer is canonical for BC progression while phospholipase D isoform 1 (PLD1) is known to mediate development of cancer through phosphatidic acid (PA) production. We therefore used in silico, in vitro and in vivo approaches to detail the effect of PLD1 on BC invasion. In BC patients, higher levels of PLD1 expression were associated with poor prognoses. PLD1 knockdown significantly suppressed cellular invasion by human BC cells and matrix metalloproteinase-13 (MMP-13) was observed to mediate this effect. In our mouse bladder carcinogenesis model, the development of invasive BCs was suppressed by PLD1 knockout and a global transcriptomic analysis in this model indicated MMP-13 as a potential tumor invasion gene with NF-κB (nuclear factor-kB) as its transcriptional regulator. Furthermore, PA administration increased MMP-13 expression in line with NF-κB p65 phosphorylation levels. Collectively, we demonstrate that PLD1 promotes tumor invasion of BC by regulation of MMP-13 expression through the NF-κB signaling pathway and that PLD1 might be a potential therapeutic target to prevent clinical progression in BC patients.


Assuntos
Metaloproteinase 13 da Matriz/metabolismo , NF-kappa B/metabolismo , Fosfolipase D/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Animais , Feminino , Humanos , Camundongos , Fosfolipase D/farmacologia , Transdução de Sinais , Neoplasias da Bexiga Urinária/patologia
19.
Int J Mol Sci ; 22(6)2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33804203

RESUMO

Osteoarthritis (OA) is a common degenerative disease that results in joint inflammation as well as pain and stiffness. A previous study has reported that Cornus officinalis (CO) extract inhibits oxidant activities and oxidative stress in RAW 264.7 cells. In the present study, we isolated bioactive compound(s) by fractionating the CO extract to elucidate its antiosteoarthritic effects. A single bioactive component, morroniside, was identified as a potential candidate. The CO extract and morroniside exhibited antiosteoarthritic effects by downregulating factors associated with cartilage degradation, including cyclooxygenase-2 (Cox-2), matrix metalloproteinase 3 (Mmp-3), and matrix metalloproteinase 13 (Mmp-13), in interleukin-1 beta (IL-1ß)-induced chondrocytes. Furthermore, morroniside prevented prostaglandin E2 (PGE2) and collagenase secretion in IL-1ß-induced chondrocytes. In the destabilization of the medial meniscus (DMM)-induced mouse osteoarthritic model, morroniside administration attenuated cartilage destruction by decreasing expression of inflammatory mediators, such as Cox-2, Mmp3, and Mmp13, in the articular cartilage. Transverse microcomputed tomography analysis revealed that morroniside reduced DMM-induced sclerosis in the subchondral bone plate. These findings suggest that morroniside may be a potential protective bioactive compound against OA pathogenesis.


Assuntos
Cornus/química , Glicosídeos/farmacologia , Inflamação/tratamento farmacológico , Meniscos Tibiais/efeitos dos fármacos , Osteoartrite/tratamento farmacológico , Animais , Cartilagem Articular/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Ciclo-Oxigenase 2/genética , Dinoprostona/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Glicosídeos/química , Humanos , Interleucina-1beta/genética , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 3 da Matriz/genética , Meniscos Tibiais/patologia , Meniscos Tibiais/cirurgia , Camundongos , Osteoartrite/genética , Osteoartrite/patologia , Osteoartrite/cirurgia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Cultura Primária de Células , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos
20.
Chin Med J (Engl) ; 134(8): 963-970, 2021 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-33840739

RESUMO

BACKGROUND: Histone deacetylase 4 (HDAC4) regulates chondrocyte hypertrophy and bone formation. The aim of the present study was to explore the effects of HDAC4 on Interleukin 1 beta (IL-1ß)-induced chondrocyte extracellular matrix degradation and whether it is regulated through the WNT family member 3A (WNT3A)/ß-catenin signaling pathway. METHODS: Primary chondrocytes (CC) and human chondrosarcoma cells (SW1353 cells) were treated with IL-1ß and the level of HDAC4 was assayed using Western blotting. Then, HDAC4 expression in the SW1353 cells was silenced using small interfering RNA to detect the effect of HDAC4 knockdown on the levels of matrix metalloproteinase 3 (MMP3) and MMP13 induced by IL-1ß. After transfection with HDAC4 plasmids, the overexpression efficiency was examined using Real-time quantitative polymerase chain reaction (qRT-PCR) and the levels of MMP3 and MMP13 were assayed using Western blotting. After incubation with IL-1ß, the translocation of ß-catenin into the nucleus was observed using immunofluorescence staining in SW1353 cells to investigate the activation of the WNT3A/ß-catenin signaling pathway. Finally, treatment with WNT3A and transfection with glycogen synthase kinase 3 beta (GSK3ß) plasmids were assessed for their effects on HDAC4 levels using Western blotting. RESULTS: IL-1ß downregulated HDAC4 levels in chondrocytes and SW1353 cells. Furthermore, HDAC4 knockdown increased the levels of MMP3 and MMP13, which contributed to the degradation of the extracellular matrix. Overexpression of HDAC4 inhibited IL-1ß-induced increases in MMP3 and MMP13. IL-1ß upregulated the levels of WNT3A, and WNT3A reduced HDAC4 levels in SW1353 cells. GSK-3ß rescued IL-1ß-induced downregulation of HDAC4 in SW1353 cells. CONCLUSION: HDAC4 exerted an inhibitory effect on IL-1ß-induced extracellular matrix degradation and was regulated partially by the WNT3A/ß-catenin signaling pathway.


Assuntos
Condrócitos , Histona Desacetilases , Via de Sinalização Wnt , beta Catenina , Linhagem Celular Tumoral , Células Cultivadas , Condrócitos/metabolismo , Glicogênio Sintase Quinase 3 beta/genética , Histona Desacetilases/genética , Humanos , Interleucina-1beta/farmacologia , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 3 da Matriz , Proteínas Repressoras , Proteína Wnt3A/genética , beta Catenina/genética , beta Catenina/metabolismo
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