Preclinical development of a microRNA-based therapy for intervertebral disc degeneration

Ji, Ming-liang; Jiang, Hua; Zhang, Xuejun; Shi, Peiliang; Li, Chao; Wu, Hao; Wu, Xiaotao; Wang, Yuntao; Wang, Chen; Lü, Jun

doi:10.1038/s41467-018-07360-1

Cited by 189 publications

(198 citation statements)

References 65 publications

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“…And a syringe needle was vertically inserted into the lumbar disc through ventrally and rotated 180 degrees along the axis for 10 seconds. The 23‐G needle was inserted into the intervertebral disc 1.5 mm parallel to the endplate via AF to NP to decompress the nucleus . Mice are sacrificed at different time point to obtain intervertebral disc specimens.…”

Section: Methodsmentioning

confidence: 99%

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Inflammatory‐sensitive CHI3L1 protects nucleus pulposus via AKT3 signaling during intervertebral disc degeneration

Wang

Zhong

et al. 2020

FASEB j.

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Intervertebral disc degeneration (IDD) is the main cause of low back pain and the mechanism of which is far from fully revealed. Although inflammation directed nucleus pulposus (NP) extracellular matrix metabolism dysregulation is known to be the main cause of the degeneration process, few is known about the protective factors. Using high‐throughput label‐free proteomics, we found that inflammation‐related autocrine factor Chitinase‐3‐like protein 1 (CHI3L1, or YKL‐40) is highly expressed in the NP cells during degeneration. Immunohistochemical analysis show that the expression of CHI3L1 is NP tissue specific, and increase significantly during degeneration. Overexpression of CHI3L1 significantly decrease the catabolism, and increase the anabolism of extracellular matrix. Knockdown of CHI3L1 using siRNAs show the opposite results, which imply that the protective role of CHI3L1 in IDD. Using high‐throughput RNA sequencing and functional analyses, we find that AKT3 expression and its phosphorylation is mainly regulated by CHI3L1. And lastly, the mechanism of which is also validated using human and mouse degenerated NP tissues. In summary, our findings show that the inflammation‐related autocrine factor CHI3L1 is NP specific, and it protects IDD by promoting the AKT3 signaling, which may serve as a potential therapeutic target in intervertebral disc degeneration.

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Section: Methodsmentioning

confidence: 99%

“…The 23-G needle was inserted into the intervertebral disc 1.5 mm parallel to the endplate via AF to NP to decompress the nucleus. 2 Mice are sacrificed at different time point to obtain intervertebral disc specimens. Immunohistochemistry was performed to localize CHI3L1, AKT3, and OCN in human and mice NP samples.…”

Section: Immunohistochemistry Stainingmentioning

confidence: 99%

Inflammatory‐sensitive CHI3L1 protects nucleus pulposus via AKT3 signaling during intervertebral disc degeneration

Wang

Zhong

et al. 2020

FASEB j.

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“…More specifically, the cellularity and morphology of the AF, NP, and the border between the two structures were examined. 36 The scale is based on 5 categories of degenerative changes with scores ranging from 0 points (0 in each category) for a normal disc to 15 points (3 in each category) for a severely degenerated disc.…”

Section: Methodsmentioning

confidence: 99%

CircGLCE alleviates intervertebral disc degeneration by regulating apoptosis and matrix degradation through the targeting of miR-587/STAP1

Chen

Zhang

Deng

et al. 2020

Preprint

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BackgroundIntervertebral disc degeneration (IDD) can induce profound global socioeconomic burdens. Recent studies have suggested that circular RNAs might have crucial functions in the progression of IDD. The purpose of this study was to identify a specific circular RNA and to investigate its regulatory mechanism in IDD.MethodsCircGLCE was selected after microarray analyses and was further analysed by RT-qPCR and FISH. After silencing CircGLCE, its function was assessed with RT-qPCR, immunofluorescence analysis and flow cytometry. Based on Sanger sequencing, miR-587 was identified as a direct target of CircGLCE, and it was further examined with RNA pulldown assays, RT-qPCR, dual luciferase assays and FISH. After silencing CircGLCE or miR-587, western blotting, immunofluorescence analysis, and flow cytometry were conducted. STAP1 was assessed by RT-qPCR and luciferase assay, and experiments with silenced and overexpressed miR-587 were performed. A rescue experiment was also included. In an IDD rat model, the in vivo effects of overexpressing CircGLCE on IDD were analysed with imaging techniques, TUNEL staining, FISH, western blotting, H&E staining and immunohistochemistry.ResultsCircGLCE was found to stably exist in the cytoplasm of nucleus pulposus (NP) cells. It was downregulated in IDD. Knockdown of CircGLCE promoted apoptosis and induced the expression of matrix-degrading enzymes in NP cells. CircGLCE served as a miR-587 sponge in NP cells. Inhibiting miR-587 counteracted the IDD-enhancing effect caused by silencing CircGLCE. STAP1 served as the miRNA target that mediated the functions of miR-587. Overexpressing CircGLCE alleviated IDD in vivo.ConclusionsCircGLCE attenuates IDD by regulating the apoptosis of NP cells and by regulating ECM degradation through the targeting of miR-587/STAP1. CircGLCE may be a potential therapeutic target for IDD treatments.

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“…[1][2][3][4][5][6] LBP is a multifactorial disease, 7 and the disorder is strongly associated with intervertebral disc degeneration (IVDD), which is characterized by a homeostatic imbalance between anabolism and catabolism, including extracellular matrix (ECM) degradation 8,9 or nucleus pulposus (NP) cell survival. [10][11][12] The intervertebral disc (IVD) is a special organ that consists of an outer fibrocartilaginous annulus fibrosus (AF) and an inner gel-like NP. 13,14 Inflammatory responses, which are induced by inflammatory cytokine overexpression, are a primary and important cause of IVDD.…”

Section: Introductionmentioning

confidence: 99%

Melatonin alleviates intervertebral disc degeneration by disrupting the IL-1β/NF-κB-NLRP3 inflammasome positive feedback loop

et al. 2020

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The inflammatory response is induced by the overexpression of inflammatory cytokines, mainly interleukin (IL)-1β, and is one of the main causes of intervertebral disc degeneration (IVDD). NLR pyrin domain containing 3 (NLRP3) inflammasome activation is an important source of IL-1β. As an anti-inflammatory neuroendocrine hormone, melatonin plays various roles in different pathophysiological conditions. However, its roles in IVDD are still not well understood and require more examination. First, we demonstrated that melatonin delayed the progression of IVDD and relieved IVDD-related low back pain in a rat needle puncture IVDD model; moreover, NLRP3 inflammasome activation (NLRP3, p20, and IL-1β levels) was significantly upregulated in severely degenerated human discs and a rat IVDD model. Subsequently, an IL-1β/NF-κB-NLRP3 inflammasome activation positive feedback loop was found in nucleus pulposus (NP) cells that were treated with IL-1β. In these cells, expression of NLRP3 and p20 was significantly increased, NF-κB signaling was involved in this regulation, and mitochondrial reactive oxygen species (mtROS) production increased. Furthermore, we found that melatonin disrupted the IL-1β/NF-κB-NLRP3 inflammasome activation positive feedback loop in vitro and in vivo. Melatonin treatment decreased NLRP3, p20, and IL-1β levels by inhibiting NF-κB signaling and downregulating mtROS production. Finally, we showed that melatonin mediated the disruption of the positive feedback loop of IL-1β in vivo. In this study, we showed for the first time that IL-1β promotes its own expression by upregulating NLRP3 inflammasome activation. Furthermore, melatonin disrupts the IL-1β positive feedback loop and may be a potential therapeutic agent for IVDD.

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Preclinical development of a microRNA-based therapy for intervertebral disc degeneration

Cited by 189 publications

References 65 publications

Inflammatory‐sensitive CHI3L1 protects nucleus pulposus via AKT3 signaling during intervertebral disc degeneration

Inflammatory‐sensitive CHI3L1 protects nucleus pulposus via AKT3 signaling during intervertebral disc degeneration

CircGLCE alleviates intervertebral disc degeneration by regulating apoptosis and matrix degradation through the targeting of miR-587/STAP1

Melatonin alleviates intervertebral disc degeneration by disrupting the IL-1β/NF-κB-NLRP3 inflammasome positive feedback loop

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