Crosstalk between Smad2/3 and specific isoforms of ERK in TGF‐β1‐induced TIMP‐3 expression in rat chondrocytes

Zhu, Yanhui; Gu, Jianhua; Zhu, Tong; Chen, Jin; Hu, Xiaopeng; Wang, Xiang

doi:10.1111/jcmm.13099

Cited by 28 publications

(28 citation statements)

References 38 publications

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“…We demonstrated that knockdown of Smad2 or Smad3 effectively reduced expression levels of ERK1, but knockdown of Smad4 did not. However, knockdown of ERK1 or ERK2 did not result in positive feedback, consistent with data reported previously [22].…”

Section: Discussionsupporting

confidence: 92%

“…Crosstalk between the ERK and TGF-b/SMAD pathways has been demonstrated in many cell types [21,22], but crosstalk between the pathways to promote proliferation of stem cells The results revealed that ERK1 knockdown significantly suppressed melatonin-induced ERK1/2 and Smad2/3 expression (p < .01), but ERK2 knockdown did not do so (p > .05). Smad2/3 knockdown also significantly suppressed melatonin-induced ERK1/2 and Smad2/3 expression (p < .01), but Smad4 knockdown did not (p > .05).…”

Section: Crosstalk Between the Erk And Tgf-b/smad Pathways In Melatonmentioning

confidence: 97%

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Melatonin promotes self-renewal of nestin-positive pancreatic stem cells through activation of the MT2/ERK/SMAD/nestin axis

Bai

Gao

Zhang

et al. 2017

Artificial Cells, Nanomedicine, and Biotechnology

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Although melatonin has been shown to exhibit a wide variety of biological functions, its effects on promotion of self-renewal in pancreatic stem cells remain unknown. In this study, we incubated murine pancreatic stem cells (PSCs) with various concentrations of melatonin (0.01, 0.1, 1, 10 or 100 μM) to screen for the optimum culture medium for increasing cell proliferation. We found that 10 μM melatonin can significantly increase proliferation and enhance expression of a stem cell marker, nestin, in PSCs via melatonin receptor 2 (MT2). Thus, we used 10 μM melatonin to study the melatonin-mediated molecular mechanisms of cell proliferation in PSCs. We applied extracellular signal-regulated kinase (ERK) pathway inhibitor SCH772984 and transforming growth factor beta (TGF-β) pathway inhibitor SB431542, along with interfering RNAs siERK1, siERK2, siSmad2, siSmad3, siSmad4 and siNestin, to melatonin-treated PSCs to research the roles of these genes in self-renewal. The results revealed a novel molecular mechanism by which melatonin promotes self-renewal of PSCs: a chain reaction in the MT2/ERK/SMAD/nestin axis promoted the aforementioned self-renewal as well as inhibited differentiation. In addition, upregulation of nestin created a positive feedback loop in the regulation of the transforming growth factor beta 1 (TGF-β1)/SMADs pathway by promoting expression of Smad4. Conversely, knockdown of nestin significantly suppressed the proliferative effect in melatonin-treated PSCs. These are all novel mechanisms through which the ERK pathway cooperatively crosstalks with the SMAD pathway to regulate nestin expression, thereby enhancing self-renewal in PSCs.

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Section: Discussionsupporting

confidence: 92%

Section: Crosstalk Between the Erk And Tgf-b/smad Pathways In Melatonmentioning

confidence: 97%

Melatonin promotes self-renewal of nestin-positive pancreatic stem cells through activation of the MT2/ERK/SMAD/nestin axis

Bai

Gao

Zhang

et al. 2017

Artificial Cells, Nanomedicine, and Biotechnology

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“…ERK has been demonstrated to be involved in renal brosis, but its role has been controversial. Majority of studies have shown that ERK acts as a pro-brotic factor important for in ammatory responses [47], TGF-β/Smad signaling [48], ECM and myo broblast accumulation [49,50]. In addition, ERK has recently been shown to participate in EMT progression, and inhibition of ERK ameliorates renal interstitial brosis by suppressing tubular EMT [51,52].…”

Section: Discussionmentioning

confidence: 99%

NMDA Receptor-mediated CaMKII/ERK Activation Contributes to Renal Fibrosis

Zhou

Liu

Guo

et al. 2020

Preprint

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Background: Renal fibrosis (RF) results in renal function impairment and eventually kidney failure. We found that N-methyl-D-aspartate receptor (NMDAR) played an important role during RF. However, its mechanism of action is yet to be deciphered. Methods: Acute RF was induced in mice by unilateral ureteral obstruction (UUO). NR1, which is the functional subunit of NMDAR, was downregulated using lentiviral vector-mediated shRNA interference. Histological changes were observed by Masson’s trichrome staining. Expression of NR1, fibrotic and EMT markers were measured by immunohistochemistry and western blot analysis. HK-2 cells were incubated with TGF-β, and NMDAR antagonist MK-801 and Ca2+/calmodulin-dependent protein kinase II (CaMKII) antagonist KN-93 administration were further included in this study for pathway determination. Expression of NR1, total and phosphorylated CaMKII, total and phosphorylated ERK were measured using western blot and immunofluorescent assays. Chronic renal fibrosis was introduced by sublethal ischemia-reperfusion injury in mice, and oral NMDAR inhibitor dextromethorphan (DXM) administration was performed. Results: NR1 expressions were upregulated in both obstructed kidneys and TGF-β treated HK-2 cells. NR1 knockdown, MK801 and KN93 reduced the fibrotic morphology in vivo and in vitro respectively, and companied with the downregulated ERK activation, while KN93 administration had no effect on NR1 and CaMKII levels. Mice in the DXM group had better preservation of kidney structures and corticomedullary volumes. Conclusions: NMDAR participates in both acute and chronic renal fibrogenesis via CaMKII/ERK activation, and is a potential therapeutic target for renal fibrosis.

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“…However, studies have reported that miR-15a played a protective role in osteoarticular cartilage [5,6], but its specific molecular mechanism remains undefined. TGF-beta/SMAD pathway played an important role in chondrocyte [7,8], in which Smad 2/3 played a key role [9,10]. However, the regulation mechanism of SMAD2 in osteoarthritic chondrocytes is not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of miR-15a regulating the growth and apoptosis of human knee joint chondrocytes by targeting SMAD2

Ma¹,

Cheng

Tan

2019

Artificial Cells, Nanomedicine, and Biotechnology

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Objective: To investigate the effects of miR-15a on proliferation and apoptosis of human knee articular chondrocytes and explore its underlying mechanism. Methods: qRT-PCR was used to detect the expression of miR-15a in normal chondrocytes and knee arthritic chondrocytes; miR-con (transfected miR-con), miR-15a (transfected miR-15a mimics), anti-miRcon group (transfected anti-miR-con), anti-miR-15a group (transfected anti-miR-15a mimics), pcDNA group (transfected pcDNA), pcDNA-SMAD2 group (transfected pcDNA-SMAD2), the miR-15a þ pcDNA group (co-transfected miR-15a and pcDNA), miR-15a þ pcDNA-SMAD2 group (co-transfected miR-15a mimics and pcDNA-SMAD2), were transfected into knee articular chondrocytes by liposome method, respectively. The cell proliferation and apoptosis of each group were detected by MTT assay and flow cytometry. The protein expression of SMAD2 was detected by Western blot. The fluorescence activity of each group was detected by dual luciferase reporter gene assay. Results: The expression of miR-15a in knee arthritis chondrocytes was significantly increased (p < .05) compared with that in normal chondrocytes. Moreover, overexpression of miR-15a and silencing of SMAD2 inhibited proliferation and promoted apoptosis in knee arthritis chondrocyte. MiR-15a targeted SMAD2. Overexpression of SMAD2 reversed the inhibitory effects on proliferation and promotion effects on apoptosis induced by miR-15a in knee arthritis chondrocytes. Conclusion: miR-15a can inhibit the proliferation and promote apoptosis of knee arthritis chondrocytes. The mechanism may be related to SMAD2, which will provide a new target for the treatment of knee arthritis.

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Crosstalk between Smad2/3 and specific isoforms of ERK in TGF‐β1‐induced TIMP‐3 expression in rat chondrocytes

Cited by 28 publications

References 38 publications

Melatonin promotes self-renewal of nestin-positive pancreatic stem cells through activation of the MT2/ERK/SMAD/nestin axis

Melatonin promotes self-renewal of nestin-positive pancreatic stem cells through activation of the MT2/ERK/SMAD/nestin axis

NMDA Receptor-mediated CaMKII/ERK Activation Contributes to Renal Fibrosis

Mechanism of miR-15a regulating the growth and apoptosis of human knee joint chondrocytes by targeting SMAD2

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