Self-amplifying loop of NF-κB and periostin initiated by PIEZO1 accelerates mechano-induced senescence of nucleus pulposus cells and intervertebral disc degeneration

Wu, Jinna; Chen, Yuyu; Liao, Zhiheng; Liu, Hengyu; Zhang, Shun; Zhong, Dongmei; Qiu, Xianjian; Chen, Taiqiu; Su, Deying; Ke, Xiaona; Wan, Yong; Zhou, Taifeng; Su, Peiqiang

doi:10.1016/j.ymthe.2022.05.021

Cited by 55 publications

(33 citation statements)

References 54 publications

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“…To further confirm the role of Piezo1 on mechanical signaling conduction, we treated chondrocytes with Yoda1, a synthetic chemical compound that contributes to activating Piezo1 [ 21 ]. We found that the effects of Yoda1 treatment were similar to mechanical strain, presenting high proportions of apoptotic cells, altered expression of BAX, BCL2, matrix metallopeptidase 3 (MMP3), matrix metallopeptidase 13 (MMP13), collagen type II alpha 1 chain (COL2A1), and Aggrecan ( Figure 3 a–h, p < 0.05).…”

Section: Resultsmentioning

confidence: 99%

Gsmtx4 Alleviated Osteoarthritis through Piezo1/Calcineurin/NFAT1 Signaling Axis under Excessive Mechanical Strain

Ren

Zhuang

et al. 2023

IJMS

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Excessive mechanical strain is the prominent risk factor for osteoarthritis (OA), causing cartilage destruction and degeneration. However, the underlying molecular mechanism contributing to mechanical signaling transduction remains unclear in OA. Piezo type mechanosensitive ion channel component 1 (Piezo1) is a calcium-permeable mechanosensitive ion channel and provides mechanosensitivity to cells, but its role in OA development has not been determined. Herein, we found up-regulated expression of Piezo1 in OA cartilage, and that its activation contributes to chondrocyte apoptosis. The knockdown of Piezo1 could protect chondrocytes from apoptosis and maintain the catabolic and anabolic balance under mechanical strain. In vivo, Gsmtx4, a Piezo1 inhibitor, markedly ameliorated the progression of OA, inhibited the chondrocyte apoptosis, and accelerated the production of the cartilage matrix. Mechanistically, we observed the elevated activity of calcineurin (CaN) and the nuclear transfection of nuclear factor of activated T cells 1 (NFAT1) under mechanical strain in chondrocytes. Inhibitors of CaN or NFAT1 rescued the pathologic changes induced by mechanical strain in chondrocytes. Overall, our findings revealed that Piezo1 was the essential molecule response to mechanical signals and regulated apoptosis and cartilage matrix metabolism via the CaN/NFAT1 signaling axis in chondrocytes, and that Gsmtx4 could be an attractive therapeutic drug for OA treatment.

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Section: Resultsmentioning

confidence: 99%

Gsmtx4 Alleviated Osteoarthritis through Piezo1/Calcineurin/NFAT1 Signaling Axis under Excessive Mechanical Strain

Ren

Zhuang

et al. 2023

IJMS

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“…In parallel to ECM degradation, cellular senescence is causally linked to the development of IDD [14,26]. Several studies have demonstrated that TNFα enhances β-gal activity and expression of senescence markers and promotes NPCs senescence [45][46][47].…”

Section: Discussionmentioning

confidence: 99%

“…NPC senescence [13], and excessive mechanical stretch [14]. NPCs are the major cell type in NP and play a pivotal role in maintaining the homeostasis of ECM.…”

Section: Introductionmentioning

confidence: 99%

Dihydroartemisinin Attenuated Intervertebral Disc Degeneration via Inhibiting PI3K/AKT and NF-κB Signaling Pathways

Liao

Liu

et al. 2022

Oxidative Medicine and Cellular Longevity

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Intervertebral disc degeneration (IDD) is the leading cause of low back pain (LBP). However, effective therapeutic drugs for IDD remain to be further explored. Inflammatory cytokines play a pivotal role in the onset and progression of IDD. Dihydroartemisinin (DHA) has been well reported to have powerful anti-inflammatory effects, but whether DHA could ameliorate the development of IDD remained unclear. In this study, the effects of DHA on extracellular matrix (ECM) metabolism and cellular senescence were firstly investigated in nucleus pulposus cells (NPCs) under tumor necrosis factor alpha (TNFα)-induced inflammation. Meanwhile, AKT agonist sc-79 was used to determine whether DHA exerted its actions through regulating PI3K/AKT and NF-κB signaling pathways. Next, the therapeutic effects of DHA were tested in a puncture-induced rat IDD model. Finally, we detected the activation of PI3K/AKT and NF-κB signaling pathways in clinical degenerative nucleus pulposus specimens. We demonstrated that DHA ameliorated the imbalance between anabolism and catabolism of extracellular matrix and alleviated NPCs senescence induced by TNFα in vitro. Further, we illustrated that DHA mitigated the IDD progression in a puncture-induced rat model. Mechanistically, DHA inhibited the activation of PI3K/AKT and NF-κB signaling pathways induced by TNFα, which was undermined by AKT agonist sc-79. Molecular docking predicted that DHA bound to the PI3K directly. Intriguingly, we also verified the activation of PI3K/AKT and NF-κB signaling pathways in clinical degenerative nucleus pulposus specimens, suggesting that DHA may qualify itself as a promising drug for mitigating IDD.

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“…Furthermore, dysfunction of biomechanics is a critical risk factor of IDD, and cellular senescence is also an essential pathological change in this process. Another study firstly revealed that a self‐amplifying loop of Nuclear factor kappa B (NF‐κB) and periostin could accelerate NPCs senescence initiated by the piezo1 under mechano‐stress (Wu et al, 2022). However, the potential role of the piezo1 activated by stiff ECM and the deep mechanism of mechanical transduction remain to be explored.…”

Section: Methodsmentioning

confidence: 99%

Role of the mechanosensitive piezo1 channel in intervertebral disc degeneration

Guo

Wang

Xiao

et al. 2022

Clin Physio Funct Imaging

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Intervertebral disc degeneration (IDD) is a multifactorial skeletal disease involving mechanical, genetic, systemic, and biological factors, and it is characterized by apoptosis of the nucleus pulposus cells and breakdown of the extracellular matrix (ECM), which will impair the structure and function of the intervertebral disc (IVD), and cause low back pain. Recently, the piezo1 is recognized as a critical mechanically activated ion channel of IDD. Numerous studies have reported that the piezo1 ion channel was aberrantly activated in the degenerated disc tissues and deeply participated in the pathogenesis of IDD. Inactivating or interfering with the piezo1 channel could effectively prevent the progression of IDD under the experimental conditions. It may be a promising target for the prevention and treatment of the disabling disease. Therefore, we have to make a comprehensive investigation and understanding of the mechanisms and functions of the piezo1 in the biomechanics of the spine. This study mainly elucidates the role of the piezo1 channel in IDD, which may facilitate the development of therapeutic targets for this disease.

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Self-amplifying loop of NF-κB and periostin initiated by PIEZO1 accelerates mechano-induced senescence of nucleus pulposus cells and intervertebral disc degeneration

Cited by 55 publications

References 54 publications

Gsmtx4 Alleviated Osteoarthritis through Piezo1/Calcineurin/NFAT1 Signaling Axis under Excessive Mechanical Strain

Gsmtx4 Alleviated Osteoarthritis through Piezo1/Calcineurin/NFAT1 Signaling Axis under Excessive Mechanical Strain

Dihydroartemisinin Attenuated Intervertebral Disc Degeneration via Inhibiting PI3K/AKT and NF-κB Signaling Pathways

Role of the mechanosensitive piezo1 channel in intervertebral disc degeneration

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