BRD4 inhibition alleviates mechanical stress-induced TMJ OA-like pathological changes and attenuates TREM1-mediated inflammatory response

Huang, Ziwei; Ren, Yang; Zhang, Lu; Zhu, Meiying; Zhang, Caixia; Wen, Juan; Huang, Li

doi:10.1186/s13148-021-01008-6

Cited by 18 publications

(15 citation statements)

References 44 publications

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“…For bone disease, increased BRD4 also mediates the inflammatory reactions and aberrant proliferation of cells [ 21 ]. BRD4 has been confirmed as a promising therapeutic target for osteoarthritis, and decreased BRD4 could effectively improve the inflammatory stress in osteoarthritis [ 22 ]. Moreover, this study also confirmed that BRD4 could effectively reverse the effects of miR-129-5p on RA-FLSs.…”

Section: Discussionmentioning

confidence: 99%

MiR-129-5p Inactivates NF-κB Pathway to Block Rheumatoid Arthritis Development via Targeting BRD4

Chen

2022

Journal of Healthcare Engineering

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Object. Rheumatoid arthritis (RA) is an osteoarticular disease which seriously affects the motor abilities of the patients. MicroRNA disorder has been confirmed as a biomarker event in RA development, and several studies have identified that miR-129-5p is related with the progression of multiple bone diseases. The study attempted to investigate the regulation mechanism of miR-129-5p in RA development. Methods. The abundance of miR-129-5p was detected in the samples including normal tissues and RA tissues and cell lines including human fibroblast-like synoviocytes (hFLSs) and human rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs). The CCK-8 assay, flow cytometry, Transwell, and ELISA were used to observe the effects of miR-129-5p on the phenotype of RA-FLSs. Moreover, the potential targets of miR-129-5p were identified with TargetScan and dual-luciferase reporter gene assay. Besides, the abundances of the proteins were analyzed with western blot. Results. Decreased miR-129-5p was observed in RA tissues and cells. Increased miR-129-5p obviously blocked the proliferation, inflammatory stress, and migration and remarkably promoted cellular apoptosis. Moreover, BRD4 was confirmed as targets of miR-129-5p, and BRD4 upregulation could partly rescue the inhibition of miR-129-5p on aggressive behaviors of RA-FLSs. Besides, the finding of this study also proved that upregulated miR-129-5p could impede the NF-κB pathway via targeting BRD4. Conclusion. This study suggests that miR-129-5p suppresses the activation of NF-κB pathway to block the progression of RA via targeting BRD4.

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Section: Discussionmentioning

confidence: 99%

MiR-129-5p Inactivates NF-κB Pathway to Block Rheumatoid Arthritis Development via Targeting BRD4

Chen

2022

Journal of Healthcare Engineering

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“… 45 In addition, it was reported that excessive mechanical stress increased the binding of BRD4 to H3K27ac on the promoter region of Trem1, leading to TMJ OA-like pathological changes. 46 These findings provided evidences for targeting BRD4 as a promising strategy for OA therapy. In the present study, we explored the potential epigenetic regulation mechanism during aberrant force-induced OA.…”

Section: Discussionmentioning

confidence: 82%

Histone demethylase JMJD3 downregulation protects against aberrant force-induced osteoarthritis through epigenetic control of NR4A1

Liu

et al. 2022

Int J Oral Sci

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Osteoarthritis (OA) is a prevalent joint disease with no effective treatment strategies. Aberrant mechanical stimuli was demonstrated to be an essential factor for OA pathogenesis. Although multiple studies have detected potential regulatory mechanisms underlying OA and have concentrated on developing novel treatment strategies, the epigenetic control of OA remains unclear. Histone demethylase JMJD3 has been reported to mediate multiple physiological and pathological processes, including cell differentiation, proliferation, autophagy, and apoptosis. However, the regulation of JMJD3 in aberrant force-related OA and its mediatory effect on disease progression are still unknown. In this work, we confirmed the upregulation of JMJD3 in aberrant force-induced cartilage injury in vitro and in vivo. Functionally, inhibition of JMJD3 by its inhibitor, GSK-J4, or downregulation of JMJD3 by adenovirus infection of sh-JMJD3 could alleviate the aberrant force-induced chondrocyte injury. Mechanistic investigation illustrated that aberrant force induces JMJD3 expression and then demethylates H3K27me3 at the NR4A1 promoter to promote its expression. Further experiments indicated that NR4A1 can regulate chondrocyte apoptosis, cartilage degeneration, extracellular matrix degradation, and inflammatory responses. In vivo, anterior cruciate ligament transection (ACLT) was performed to construct an OA model, and the therapeutic effect of GSK-J4 was validated. More importantly, we adopted a peptide-siRNA nanoplatform to deliver si-JMJD3 into articular cartilage, and the severity of joint degeneration was remarkably mitigated. Taken together, our findings demonstrated that JMJD3 is flow-responsive and epigenetically regulates OA progression. Our work provides evidences for JMJD3 inhibition as an innovative epigenetic therapy approach for joint diseases by utilizing p5RHH-siRNA nanocomplexes.

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“…The chondrocyte nucleus was blue and other tissues were pink. For detecting p-NF-κB expression in the cartilage, immunohistochemistry was carried out according to the previous study [ 21 ]. The primary antibody was the Anti-Rabbit NF-kB p65 (phospho S276) antibody (ab194726, Abcam) and the secondary antibody is Goat Anti-Rabbit IgG H&L (HRP) (ab205718, Abcam).…”

Section: Methodsmentioning

confidence: 99%

NF-κB inducible miR-30b-5p aggravates joint pain and loss of articular cartilage via targeting SIRT1-FoxO3a-mediated NLRP3 inflammasome

Zhang

Shi

et al. 2021

Aging

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MicroRNAs (miRNAs) contribute to osteoarthritis (OA) development. Nevertheless, the function and mechanism of miR-30b-5p in OA are unclear. In the present article, we gauged the miR-30b-5p level in OA patients and analyzed its correlation with OA stages. Then, we conducted in-vivo and in-vitro gain-of-function assays to determine the function of miR-30b-5p, silent information regulator 2 homolog 1 (SIRT1) and Fox. Cell counting Kit-8 (CCK-8) assay, BrdU assay and flow cytometry were utilized to gauge cell viability and apoptosis of human chondrocyte (HC-A). The targeting association between miR-30b-5p and SIRT1 was validated through the dual-luciferase reporter assay and RNA immunoprecipitation (RIP) experiment. The results signified that miR-30b-5p was up-regulated in OA patients, OA rats and interleukin-1β (IL-1β)-induced chondrocytes. The higher miR-30b-5p expression brought about progressive stages of OA patients and enhanced levels of pro-inflammatory mediators in the synovial fluid. Functionally, overexpressing miR-30b-5p hampered cell viability, aggravated chondrocyte apoptosis and NLRP3 inflammasome activation induced by IL-1β, while down-regulating miR-30b-5p exerted the reverse effects. The in-vivo experiment exhibited that down-regulating miR-30b-5p improved joint pain and loss of articular cartilage in the rats with restrained inflammation and NLRP3 inflammasome activation. Mechanistically, miR-30b-5p targeted the 3’-non-translated region (3’UTR) of SIRT1, and miR-30b-5p was inducible with NF-κB phosphorylation enhancement. Overexpressing SIRT1 or inhibiting NF-κB relieved miR-30b-5p-induced apoptosis and NLRP3 inflammasome activation by promoting FoxO3a, while down-regulating SIRT1 or FoxO3a reversed miR-30b-5p-in-induced anti-inflammatory and apoptosis-suppressive effects. Collectively, NF-κB-induced miR-30b-5p modulates chondrocyte apoptosis and OA progression by regulating the SIRT1-FoxO3a-mediated NLRP3 inflammasome.

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BRD4 inhibition alleviates mechanical stress-induced TMJ OA-like pathological changes and attenuates TREM1-mediated inflammatory response

Cited by 18 publications

References 44 publications

MiR-129-5p Inactivates NF-κB Pathway to Block Rheumatoid Arthritis Development via Targeting BRD4

MiR-129-5p Inactivates NF-κB Pathway to Block Rheumatoid Arthritis Development via Targeting BRD4

Histone demethylase JMJD3 downregulation protects against aberrant force-induced osteoarthritis through epigenetic control of NR4A1

NF-κB inducible miR-30b-5p aggravates joint pain and loss of articular cartilage via targeting SIRT1-FoxO3a-mediated NLRP3 inflammasome

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