Jumonji domain containing-3 (JMJD3) inhibition attenuates IL-1ß-induced chondrocytes damage in vitro and protects osteoarthritis cartilage in vivo.
Inflamm Res
; 69(7): 657-666, 2020 Jul.
Article
en En
| MEDLINE
| ID: mdl-32394143
ABSTRACT
OBJECTIVES:
This study aimed to explore the effects and relative mechanism of JMJD3 on knee osteoarthritis (OA).METHODS:
In this study, we first analyzed the expression of JMJD3 in OA cartilage using western blot and immunohistochemistry. In an in vitro study, the effects of GSK-J4, JMJD3 inhibitor, on ATDC-5 chondrocytes were evaluated by CCK-8 assay. Real-time PCR and western blot were used to examine the inhibitory effect of GSK-J4 on the inflammation and ECM degradation of chondrocytes. NF-κB p65 phosphorylation and nuclear translocation were measured by western blot and immunofluorescence. In the animal study, twenty mice were randomized into four experimental groups sham group, DMM-induced OA + DMSO group, OA + low-dose GSK-J4 group, and OA + high-dose GSK-J4 group. After the treatment, hematoxylin-eosin and safranin O/fast green staining were used to evaluate cartilage degradation of knee joint, with OARSI scores for quantitative assessment of cartilage damage.RESULTS:
Our results revealed that JMJD3 was overexpressed in OA cartilage and GSK-J4 could suppress the IL-1ß-induced production of pro-inflammatory cytokines and catabolic enzymes, including IL-6, IL-8, MMP-9 and ADAMTS-5. Consistent with these findings, GSK-J4 could inhibit IL-1ß-induced degradation of collagen II and aggrecan. Mechanistically, GSK-J4 dramatically suppressed IL-1ß-stimulated NF-κB signal pathway activation. In vivo, GSK-J4 prevented cartilage damage in mouse DMM-induced OA model.CONCLUSIONS:
This study elucidates the important role of JMJD3 in cartilage degeneration in OA, and our results indicate that JDJM3 may become a novel therapeutic target in OA therapy.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Osteoartritis
/
Pirimidinas
/
Benzazepinas
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Cartílago
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Condrocitos
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Histona Demetilasas con Dominio de Jumonji
Tipo de estudio:
Clinical_trials
/
Prognostic_studies
Límite:
Animals
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Humans
Idioma:
En
Revista:
Inflamm Res
Asunto de la revista:
ALERGIA E IMUNOLOGIA
/
PATOLOGIA
Año:
2020
Tipo del documento:
Article