Syndecan-4 is a Novel Therapeutic Target for Intervertebral Disc Degeneration via Suppressing JNK/p53 Pathway

Ge, Jun; Cheng, Xiaoqiang; Yuan, Chenxi; Qian, Jia; Wu, Chunshen; Cao, Cheng; Yang, Huilin; Zhou, Feng; Zou, Jun

doi:10.7150/ijbs.40189

Cited by 15 publications

(12 citation statements)

References 33 publications

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“…Stressors entail high glucose levels [ 256 ], hyperosmolarity [ 120 , 263 ], TNF-α and IL-1β exposure [ 250 , 251 , 255 ], syndecan-4 overexpression [ 264 ], and Propionibacterium acnes (P. acnes) infection [ 265 ]. Following activation, JNK regulates apoptosis [ 120 , 256 , 265 ], enhanced expression of MMP [ 250 ], DNA damage [ 263 ], and DD [ 264 ]. The pro-apoptotic mechanisms of JNK seem to be associated with p53 induction [ 266 ] and with toll-like receptor 2 activation [ 265 ].…”

Section: Ivd Regeneration Strategies: Biological Targets and Biomamentioning

confidence: 99%

Multiscale Regulation of the Intervertebral Disc: Achievements in Experimental, In Silico, and Regenerative Research

Baumgartner

Wuertz‐Kozak

Maitre

et al. 2021

IJMS

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Intervertebral disc (IVD) degeneration is a major risk factor of low back pain. It is defined by a progressive loss of the IVD structure and functionality, leading to severe impairments with restricted treatment options due to the highly demanding mechanical exposure of the IVD. Degenerative changes in the IVD usually increase with age but at an accelerated rate in some individuals. To understand the initiation and progression of this disease, it is crucial to identify key top-down and bottom-up regulations’ processes, across the cell, tissue, and organ levels, in health and disease. Owing to unremitting investigation of experimental research, the comprehension of detailed cell signaling pathways and their effect on matrix turnover significantly rose. Likewise, in silico research substantially contributed to a holistic understanding of spatiotemporal effects and complex, multifactorial interactions within the IVD. Together with important achievements in the research of biomaterials, manifold promising approaches for regenerative treatment options were presented over the last years. This review provides an integrative analysis of the current knowledge about (1) the multiscale function and regulation of the IVD in health and disease, (2) the possible regenerative strategies, and (3) the in silico models that shall eventually support the development of advanced therapies.

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Section: Ivd Regeneration Strategies: Biological Targets and Biomamentioning

confidence: 99%

Multiscale Regulation of the Intervertebral Disc: Achievements in Experimental, In Silico, and Regenerative Research

Baumgartner

Wuertz‐Kozak

Maitre

et al. 2021

IJMS

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“…In a previous study, the expression pattern of Col-X in intervertebral discs across different ages has been evaluated [ 26 ], and the researchers detected the expression of Col-X in both IDD and advanced disc herniation. Therefore, it can be stated that Col-II is negative, while Col-X is positive, correlated with the degree of degeneration in NP cells [ 27 ]. In the present study, the 25 ng/ml of IGF-1 treatment significantly increased the expression of Col-II in NP cells, and other concentrations did not make an obvious difference to Col-II expression.…”

Section: Discussionmentioning

confidence: 99%

Role of PI3K/AKT Signaling Pathway in Nucleus Pulposus Cells

Xiao¹,

Teng

Xu³

et al. 2021

BioMed Research International

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Objective. To investigate the role of PI3K/AKT signaling pathway in nucleus pulposus (NP) cells. Methods. Nucleus pulposus (NP) cells were isolated from SD rat, and thereafter, passage three (P3) NP cells were divided into the following experimental groups: control, PI3K/AKT agonist IGF-1 (25 ng/ml, 50 ng/ml, and 100 ng/ml), and PI3K/AKT inhibitor LY294002 (5 μM, 10 μM, and 20 μM). Flow cytometry and BrdU cell proliferation assays were performed to assess apoptosis and the proliferation rate of NP cells. Western blot analysis was performed to examine the protein expression level of Col II, Col X, Aggrecan, and MMP13. Results. PI3K/AKT inhibitor LY294002 increased the rate of apoptosis in NP cells when compared to the control and decreased the proliferation rate when compared to control. Moreover, LY294002 decreased the protein expression level of Col-II and Aggrecan in NP cells. At the same time, LY294002 increased the protein expression level of MMP13 and Col-X in NP cells. Through activating PI3K/AKT, IGF-1 increased the proliferation rate when compared to control and decreased the rate of apoptosis when compared to control. Additionally, IGF-1 decreased the protein expression level of MMP13 and Col-X and increased Col-II and Aggrecan in NP cells. Conclusion. The inhibition of PI3K/AKT signaling pathway accelerated the apoptosis of NP cells and facilitated the extracellular matrix degradation. However, the activation of PI3K/AKT pathway partly prevented the NP cell from apoptosis and promoted their proliferation. Meanwhile, its activation also delayed the loss of extracellular matrix.

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“…None of the animals exhibited signs of peritonitis, pain or discomfort. According to the modified Thompson classification ( 26 , 27 ), the discs in the T2-weighted images were scored from grade I to IV.…”

Section: Methodsmentioning

confidence: 99%

Myocardin‑related transcription factor A nuclear translocation contributes to mechanical overload‑induced nucleus pulposus fibrosis in rats with intervertebral disc degeneration

et al. 2021

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Previous studies have reported that the Ras homolog family member A (RhoA)/myocardin-related transcription factor A (MRTF-A) nuclear translocation axis positively regulates fibrogenesis induced by mechanical forces in various organ systems. The aim of the present study was to determine whether this signaling pathway was involved in the pathogenesis of nucleus pulposus (NP) fibrosis induced by mechanical overload during the progression of intervertebral disc degeneration (IVDD) and to confirm the alleviating effect of an MRTF-A inhibitor in the treatment of IVdd. NP cells (NPcs) were cultured on substrates of different stiffness (2.9 and 41.7 KPa), which mimicked normal and overloaded microenvironments, and were treated with an inhibitor of MRTF-A nuclear import, ccG-1423. In addition, bipedal rats were established by clipping the forelimbs of rats at 1 month and gradually elevating the feeding trough, and in order to establish a long-term overload-induced model of IVdd, and their intervertebral discs were injected with ccG-1423 in situ. cell viability was determined by cell counting Kit-8 assay, and protein expression was determined by western blotting, immunofluorescence and immunohistochemical staining. The results demonstrated that the viability of NPcs was not affected by the application of force or the inhibitor. In NPcs cultured on stiff matrices, MRTF-A was mostly localized in the nucleus, and the expression levels of fibrotic proteins, including type I collagen, connective tissue growth factor and α-smooth muscle cell actin, were upregulated compared with those in NPcs cultured on soft matrices. The levels of these proteins were reduced by ccG-1423 treatment. In rats, 6 months of upright posture activated MRTF-A nuclear-cytoplasmic trafficking and fibrogenesis in the NP and induced IVdd; these effects were alleviated by ccG-1423 treatment. In conclusion, the results of the present study demonstrated that the RhoA/MRTF-A translocation pathway may promote mechanical overload-induced fibrogenic activity in NP tissue and partially elucidated the molecular mechanisms underlying the occurrence of IVdd.

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Syndecan-4 is a Novel Therapeutic Target for Intervertebral Disc Degeneration via Suppressing JNK/p53 Pathway

Cited by 15 publications

References 33 publications

Multiscale Regulation of the Intervertebral Disc: Achievements in Experimental, In Silico, and Regenerative Research

Multiscale Regulation of the Intervertebral Disc: Achievements in Experimental, In Silico, and Regenerative Research

Role of PI3K/AKT Signaling Pathway in Nucleus Pulposus Cells

Myocardin‑related transcription factor A nuclear translocation contributes to mechanical overload‑induced nucleus pulposus fibrosis in rats with intervertebral disc degeneration

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