Protective effect of vildagliptin on TNF‐α‐induced chondrocyte senescence

Bi, Jianping; Cai, Wusheng; Ma, Teng; Deng, Aiwei; Ma, Ping; Han, Ye Eon; Lou, Chunbiao; Wu, Leilei

doi:10.1002/iub.2049

Cited by 33 publications

(26 citation statements)

References 30 publications

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“…The cell surface expression of DPP4 makes it a promising candidate for targeted treatment of senescent cells through antibody-dependent cell-mediated cytotoxicity [ 8 ]. Treatment of senescence-related chronic disease, as shown by recent studies with DPP4 inhibitors that ameliorated atherosclerosis in type 2 DM patients [ 30 , 31 ], prevented vascular aging [ 32 ] and protected chondrocytes from TNF- α -induced senescence [ 33 ]. We noticed increased SIRT1 in association with DPP4 reduction upon CBX4 activation of WI-38 cells.…”

Section: Discussionmentioning

confidence: 99%

CBX4 Regulates Replicative Senescence of WI-38 Fibroblasts

Chen

Zhang

et al. 2022

Oxidative Medicine and Cellular Longevity

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Cellular senescence is characterized by cell cycle arrest and senescence-associated secretory phenotypes. Cellular senescence can be caused by various stress stimuli such as DNA damage, oxidative stress, and telomere attrition and is related to several chronic diseases, including atherosclerosis, Alzheimer’s disease, and osteoarthritis. Chromobox homolog 4 (CBX4) has been shown to alleviate cellular senescence in human mesenchymal stem cells and is considered a possible target for senomorphic treatment. Here, we explored whether CBX4 expression is associated with replicative senescence in WI-38 fibroblasts, a classic human senescence model system. We also examined whether and how regulation of CBX4 modifies the senescence phenotype and functions as an antisenescence target in WI-38. During the serial culture of the WI-38 primary fibroblast cell line to a senescent state, we found increased expression of senescence markers, including senescence β-galactosidase (SA-βgal) activity, protein expression of p16, p21, and DPP4, and decreased proliferation marker EdU; moreover, CBX4 protein expression declined. With knockdown of CBX4, SA-βgal activity and p16 protein expression increased, and EdU decreased. With the activation of CBX4, SA-βgal activity, p16, and DPP4 protein decreased. In addition, CBX4 knockdown increased, while CBX4 activation decreased, gene expression of both CDKN2A (encoding the p16 protein) and DPP4. Genes related to DNA damage and cell cycle pathways were regulated by CBX4. These results demonstrate that CBX4 can regulate replicative senescence in a manner consistent with a senomorphic agent.

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Section: Discussionmentioning

confidence: 99%

CBX4 Regulates Replicative Senescence of WI-38 Fibroblasts

Chen

Zhang

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…After stimulation, the cell cycle of chondrocytes was analyzed using flow cytometry. Briefly, after fixation with ethanol, cells were permeabilized with 0.1% Triton X-100 and stained with propidium iodide [18]. The patterns of cell cycles were counted via flow cytometry.…”

Section: Flow Cytometrymentioning

confidence: 99%

RETRACTED ARTICLE: GPR39 agonist TC-G 1008 ameliorates IL-1β-induced chondrocyte senescence

Wang

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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Aging-related osteoarthritis (OA) is the most common type of arthritis. Chondrocyte senescence has been linked with the pathogenesis of OA. Here, we examined the expression of GPR39 in chondrocytes and its modulatory effect on IL-1b-induced cellular senescence. We show that GPR39 is moderately expressed in human chondrocytes and its expression is repressed by the pro-inflammatory cytokine IL-1b. The GPR39 agonist TC-G 1008 mitigates IL-1b-induced chondrocyte senescence. Mechanistically, we show that TC-G 1008 mitigates IL-1b-induced cell cycle arrest at G1 phase by suppressing the expression of p53, p21, PAI-1, and K382 acetylation of p53. Moreover, we show that TC-G 1008 treatment restores IL-1b-induced inhibition of SIRT1 and the silencing of SIRT1 abolishes the function of TC-G 1008 on p53 acetylation and senescence, suggesting that the function of GPR39 signaling is mediated by SIRT1 in chondrocytes. Altogether, our findings implicate that the activation of GPR39 signaling ameliorates IL-1b-induced chondrocyte senescence and the GPR39 agonist TC-G 1008 could have the potential to modulate aging-associated OA.

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“…However, gliptins can bind to DPP4 in a region in close proximity with the SLIG aminoacids sequence and may thus hamper the direct interaction between sDPP4 and PAR2 in endothelial cells. 52 Interestingly, it was reported that linagliptin treatment ameliorates the progression of premature aging phenotype in klotho KO (knockout) mice-a model of premature aging. 53 Besides, obese mice treated with DPP4 inhibitors exhibited greater survival and life span.…”

Section: Discussionmentioning

confidence: 99%

DPP4 Promotes Human Endothelial Cell Senescence and Dysfunction via the PAR2–COX-2–TP Axis and NLRP3 Inflammasome Activation

et al. 2022

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Background: Abnormal accumulation of senescent cells in the vessel wall leads to a compromised vascular function contributing to vascular aging. Soluble DPP4 (dipeptidyl peptidase 4; sDPP4) secretion from visceral adipose tissue is enhanced in obesity, now considered a progeric condition. sDPP4 triggers vascular deleterious effects, albeit its contribution to vascular aging is unknown. We aimed to explore sDPP4 involvement in vascular aging, unraveling the molecular pathway by which sDPP4 acts on the endothelium. Methods: Human endothelial cell senescence was assessed by senescence-associated β-galactosidase assay, visualization of DNA damage, and expression of prosenescent markers, whereas vascular function was evaluated by myography over human dissected microvessels. In visceral adipose tissue biopsies from a cohort of obese patients, we explored several age-related parameters in vitro and ex vivo. Results: By a common mechanism, sDPP4 triggers endothelial cell senescence and endothelial dysfunction in isolated human resistance arteries. sDPP4 activates the metabotropic receptor PAR2 (protease-activated receptor 2), COX-2 (cyclooxygenase 2) activity, and the production of TXA 2 (thromboxane A2) acting over TP (thromboxane receptor) receptors (PAR2–COX-2–TP axis), leading to NLRP3 (nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing 3) inflammasome activation. Obese patients exhibited impaired microarterial functionality in comparison to control nonobese counterparts. Importantly, endothelial dysfunction in obese patients positively correlated with greater expression of DPP4, prosenescent, and proinflammatory markers in visceral adipose tissue nearby the resistance arteries. Moreover, when DPP4 activity or sDPP4-induced prosenescent mechanism was blocked, endothelial dysfunction was restored back to levels of healthy subjects. Conclusions: These results reveal sDPP4 as a relevant mediator in early vascular aging and highlight its capacity activating main proinflammatory mediators in the endothelium that might be pharmacologically tackled.

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Protective effect of vildagliptin on TNF‐α‐induced chondrocyte senescence

Cited by 33 publications

References 30 publications

CBX4 Regulates Replicative Senescence of WI-38 Fibroblasts

CBX4 Regulates Replicative Senescence of WI-38 Fibroblasts

RETRACTED ARTICLE: GPR39 agonist TC-G 1008 ameliorates IL-1β-induced chondrocyte senescence

DPP4 Promotes Human Endothelial Cell Senescence and Dysfunction via the PAR2–COX-2–TP Axis and NLRP3 Inflammasome Activation

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