Protein kinase B and extracellular signal‐regulated kinase contribute to the chondroprotective effect of morroniside on osteoarthritis chondrocytes

Cheng, Liang; Zeng, Guo-Qing; Liu, Zejun; Zhang, Bing; Cui, Xu; Zhao, Honghai; Zheng, Xiaomei; Song, Gang; Kang, Jian; Xia, Chun

doi:10.1111/jcmm.12559

Cited by 34 publications

(40 citation statements)

References 37 publications

(58 reference statements)

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“…This is in agreement with the results in Fan et al [ 14 ] data despite that it was not described. Furthermore, the up-regulation of ERK promoted matrix synthesis in OA chondrocytes, consistent with other authors’ studies, such that activated ERK signaling by pro-granulin elevated the levels of anabolic biomarkers in human chondrocyte [ 4 ], also there is our recent study that the activation of ERK by morroniside promotes matrix synthesis in human OA chondrocytes [ 15 ]. Based on these studies, it is inferred that ERK is a beneficial role in OA therapy.…”

Section: Discussionsupporting

confidence: 89%

The Involvement of Mutual Inhibition of ERK and mTOR in PLCγ1-Mediated MMP-13 Expression in Human Osteoarthritis Chondrocytes

Liu

Cai

Zheng

et al. 2015

IJMS

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The issue of whether ERK activation determines matrix synthesis or degradation in osteoarthritis (OA) pathogenesis currently remains controversial. Our previous study shows that PLCγ1 and mTOR are involved in the matrix metabolism of OA cartilage. Investigating the interplays of PLCγ1, mTOR and ERK in matrix degradation of OA will facilitate future attempts to manipulate ERK in OA prevention and therapy. Here, cultured human normal chondrocytes and OA chondrocytes were treated with different inhibitors or transfected with expression vectors, respectively. The levels of ERK, p-ERK, PLCγ1, p-PLCγ1, mTOR, p-mTOR and MMP-13 were then evaluated by Western blotting analysis. The results manifested that the expression level of ERK in human OA chondrocytes was lower than that in human normal articular chondrocytes, and the up-regulation of ERK could promote matrix synthesis, including the decrease in MMP-13 level and the increase in Aggrecan level in human OA chondrocytes. Furthermore, the PLCγ1/ERK axis and a mutual inhibition of mTOR and ERK were observed in human OA chondrocytes. Interestingly, activated ERK had no inhibitory effect on MMP-13 expression in PLCγ1-transformed OA chondrocytes. Combined with our previous study, the non-effective state of ERK activation by PLCγ1 on MMP-13 may be partly attributed to the inhibition of the PLCγ1/mTOR axis on the PLCγ1/ERK axis. Therefore, the study indicates that the mutual inhibition of ERK and mTOR is involved in PLCγ1-mediated MMP-13 expression in human OA chondrocytes, with important implication for the understanding of OA pathogenesis as well as for its prevention and therapy.

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Section: Discussionsupporting

confidence: 89%

The Involvement of Mutual Inhibition of ERK and mTOR in PLCγ1-Mediated MMP-13 Expression in Human Osteoarthritis Chondrocytes

Liu

Cai

Zheng

et al. 2015

IJMS

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“…The PIP3 then acts as a second messenger to trigger a downstream signaling cascade that is comprised of Akt, mTOR, and other proteins 22 23 . Other authors’ and our previous studies have shown that the alternation of those signal molecules is essential for OA development 24 25 26 27 28 . However, the role of miR-634 in OA pathogenesis is not revealed.…”

mentioning

confidence: 58%

“…Ginsenoside Rg1 protects chondrocyte from IL-1β-induced mitochondria-activated apoptosis through the PI3K/Akt pathway 40 . The promotion of Akt activity by morroniside could be beneficial to chondrocyte survival 28 . Therefore, the PI3K/Akt pathway could promote chondrocyte survival and matrix synthesis in OA pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of microRNA-634 suppresses survival and matrix synthesis of human osteoarthritis chondrocytes by targeting PIK3R1

Cui

Wang

Cai

et al. 2016

Sci Rep

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Osteoarthritis (OA) is a degenerative disease characterized by deterioration of articular cartilage. Recent studies have demonstrated the importance of some microRNAs in cartilage damage. The aim of this study was to identify and characterize the expression of microRNA-634 (miR-634) in normal and OA chondrocytes, and to determine its role in OA pathogenesis. Human normal and OA chondrocytes obtained from patients were cultured in vitro. Transfection with miR-634 mimic or inhibitor was employed to investigate the effect of miR-634 on chondrocyte survival and matrix synthesis, and to identify miR-634 target. The results indicated that miR-634 was expressed at lower level in high grade OA chondrocyte compared with normal chondrocytes. Overexpression of miR-634 could inhibit cell survival and matrix synthesis in high grade OA chondrocytes. Furthermore, miR-634 targeted PIK3R1 gene that encodes the regulatory subunit 1 of class I PI3K (p85α) and exerted its inhibitory effect on the phosphorylation of Akt, mTOR, and S6 signal molecules in high grade OA chondrocytes. Therefore, the data suggested that miR-634 could suppress survival and matrix synthesis of high grade OA chondrocytes through targeting PIK3R1 gene to modulate the PI3K/Akt/S6 and PI3K/Akt/mTOR/S6 axes, with important implication for validating miR-634 as a potential target for OA therapy.

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“…Cells were seeded in 96-well plates and each well contained 100 μL of complete growth medium and cultured for the indicated time. The number of viable cells were measured by 3-(4, 5-Dimethylthiazol-2-y)-2,5-diphenyl-tetrazolium bromide (MTT) assay as described as previous studies [9,42].…”

Section: Mtt Assaymentioning

confidence: 99%

Phosphoinositide specific phospholipase Cγ1 inhibition-driven autophagy caused cell death in human lung adenocarcinoma A549 cells in vivo and in vitro

Lü¹,

Fu²,

Chen³

et al. 2020

Int. J. Biol. Sci.

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Our previous studies indicated that phosphoinositide specific phospholipase Cγ1 (PLCγ1) was involved in autophagy induction in colon and hepatic carcinoma cells. However, whether and how PLCγ1 regulation in human lung adenocarcinoma is linked to autophagy remains unclear. Here, we assessed the protein expression of PLCγ1 in human lung adenocarcinoma tissue using immunohistochemistry assay and the relationship between PLCG1 and autophagy in The Cancer Genome Atlas Network (TCGA) using Spearman correlation analysis and GSEA software. Furthermore, the interaction between PLCγ1 and autophagy-related signal molecules was investigated in human lung adenocarcinoma A549 cells treated with different inhibitors or transduction with lentivirus-mediated PLCγ1 gene short-hairpin RNA (shRNA) vectors using MTT, clonogenicity, Transwell migration, RT-PCR, Caspase-3, mitochondrial transmembrane potential, and western blotting assays, as well as transmission electron microscope technique. Additionally, the effect of shRNA/PLCγ1 alone or combined with autophagic activator Lithium Chloride (LiCl) on tumor growth and metastasis was measured using immunohistochemistry and assays in A549 xenograft nude mouse model. The results showed that increased PLCγ1 expression occurred frequently in human lung adenocarcinoma tissue with higher grades of T in TNM staging classification. PLCγ1 significantly enriched in autophagic process and regulation, which negatively regulating autophagy was enriched in higher expression of PLCγ1. PLCγ1 inhibition partially reduced cell proliferation and migration of A549 cells, with an increased autophagic flux involving alterations of AMPKα, mTOR, and ERK levels. However, PLCγ1 inhibition-driven autophagy led to cell death without depending on Caspase-3 and RIP1. Additionally, the abrogation of PLCγ1 signaling by shRNA and combination with autophagic activator LiCl could efficaciously suppress tumor growth and metastasis in A549 xenograft nude mice, in combination with a decrease in P62 level. These findings collectively suggest that reduction of cell proliferation and migration by PLCγ1 inhibition could be partially attributed to PLCγ1 inhibition-driven autophagic cell death (ACD). It highlights the potential role of a combination between targeting PLCγ1 and autophagy pathway in anti-tumor therapy, which may be an efficacious new strategy to overcome the autophagy addition of tumor and acquired resistance to current therapy.

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Protein kinase B and extracellular signal‐regulated kinase contribute to the chondroprotective effect of morroniside on osteoarthritis chondrocytes

Cited by 34 publications

References 37 publications

The Involvement of Mutual Inhibition of ERK and mTOR in PLCγ1-Mediated MMP-13 Expression in Human Osteoarthritis Chondrocytes

The Involvement of Mutual Inhibition of ERK and mTOR in PLCγ1-Mediated MMP-13 Expression in Human Osteoarthritis Chondrocytes

Overexpression of microRNA-634 suppresses survival and matrix synthesis of human osteoarthritis chondrocytes by targeting PIK3R1

Phosphoinositide specific phospholipase Cγ1 inhibition-driven autophagy caused cell death in human lung adenocarcinoma A549 cells in vivo and in vitro

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