RETRACTED ARTICLE: GPR39 agonist TC-G 1008 ameliorates IL-1β-induced chondrocyte senescence

Abstract

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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“…Based on the existing reports, TP53, also known as p53, contributes to transcriptional regulation of the cell cycle, DNA repair, cell survival, and cell metabolism [35]. Inhibition of p53 exerts a substantial effect on promoting the senescence of IL-1β-induced chondrocytes [36].…”

“…Based on the existing reports, TP53, also known as p53, contributes to transcriptional regulation of the cell cycle, DNA repair, cell survival, and cell metabolism [ 35 ]. Inhibition of p53 exerts a substantial effect on promoting the senescence of IL-1 β -induced chondrocytes [ 36 ]. The potential role of TP53 in the regulation of inflammation has been described, whereby it significantly inhibits the production of proinflammatory factor IL-6 [ 37 ].…”

“…p53 can regulate cell differentiation and senescence. The inhibition of p53 expression potentially improves senescence and affects the destruction of IL-1 β -induced chondrocytes [ 36 ]. Compared to the inflammatory signaling pathway, the HIF-1 signaling pathway is slightly less in gout studies.…”

Activation of GPR39 With TC-G 1008 Attenuates Neuroinflammation Via SIRT1/PGC-1α/Nrf2 Pathway Post Neonatal Hypoxic-ischemic Injury in Rats

“…As a speci c agonist of GPR39, TC-G 1008 is widely used to explore the effect of GPR39 activation [25,43,44]. Previous studies have shown that treatment with TC-G 1008 (100 nM and 1 μM) enhanced keratinocyte proliferation through an ERK-dependent pathway [45].…”

“…Numerous studies have shown that activation of SIRT1 is a neuroprotective agent for ischemic stroke through several mechanisms [55][56][57][58]. TC-G 1008 treatment mitigated IL-1b-induced inhibition of SIRT1, and the effect of TC-G 1008 on p53 acetylation and chondrocyte senescence were abrogated when SIRT1 was silenced [44]. Previous studies have indicated that PGC-1α was a major regulator of ROS metabolism and mitochondria biogenesis which closely related to the pathology of ischemic diseases and neurodegenerative diseases [59].…”