Dataset Information

Low-dose ?-radiation inhibits IL-1?-induced dedifferentiation and inflammation of articular chondrocytes via blockage of catenin signaling.

ABSTRACT: Although low-dose radiation (LDR) regulates a wide range of biological processes, limited information is available on the effects of LDR on the chondrocyte phenotype. Here, we found that LDR, at doses of 0.5-2 centiGray (cGy), inhibited interleukin (IL)-1?-induced chondrocyte destruction without causing side effects, such as cell death and senescence. IL-1? treatment induced an increase in the expression of ?-, ?-, and ?-catenin proteins in chondrocytes via Akt signaling, thereby promoting dedifferentiation through catenin-dependent suppression of Sox-9 transcription factor expression and induction of inflammation through activation of the NF-?B pathway. Notably, LDR blocked cartilage disorders by inhibiting IL-1?-induced catenin signaling and subsequent catenin-dependent suppression of the Sox-9 pathway and activation of the NF-?B pathway, without directly altering catenin expression. LDR also inhibited chondrocyte destruction through the catenin pathway induced by epidermal growth factor, phorbol 12-myristate 13-acetate, and retinoic acid. Collectively, these results identify the molecular mechanisms by which LDR suppresses pathophysiological processes and establish LDR as a potentially valuable therapeutic tool for patients with cytokine- or soluble factors-mediated cartilage disorders.

SUBMITTER: Hong EH

PROVIDER: S-EPMC4321059 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Low-dose γ-radiation inhibits IL-1β-induced dedifferentiation and inflammation of articular chondrocytes via blockage of catenin signaling.

Hong Eun-Hee EH Song Jie-Young JY Song Jie-Young JY Lee Su-Jae SJ Park In-Chul IC Um Hong-Duck HD Park Jong Kuk JK Lee Kee-Ho KH Nam Seon Young SY Hwang Sang-Gu SG

IUBMB life 20140201 2

Although low-dose radiation (LDR) regulates a wide range of biological processes, limited information is available on the effects of LDR on the chondrocyte phenotype. Here, we found that LDR, at doses of 0.5-2 centiGray (cGy), inhibited interleukin (IL)-1β-induced chondrocyte destruction without causing side effects, such as cell death and senescence. IL-1β treatment induced an increase in the expression of α-, β-, and γ-catenin proteins in chondrocytes via Akt signaling, thereby promoting dedif ...[more]

PMID: 24604706

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Project description:Osteoarthritic (OA) chondrocytes are shown to express inducible nitric oxide synthase (iNOS) which produces high concentrations of nitric oxide (NO), particularly when stimulated with proinflammatory cytokines. NO is involved in OA cartilage degradation. On the other hand, c-Jun N-terminal Kinase (JNK) pathway mediates the activation and transcription of c-Jun, which is required for interleukin-1 (IL-1)-induction of matrix metalloproteinases-13 (MMP-13) in OA pathogenesis. Therefore, the selective inhibition of iNOS and c-Jun is a promising target for treatment and prevention of OA. The purpose of the study was to investigate the inhibitory effects of pentosan polysulfate (PPS) on IL-1?-induced iNOS, c-Jun and HIF-? isoforms upregulation in canine articular chondrocytes (CACs). Primary (P0) chondrocytes were isolated and cultured from femoral head cartilages of three (3) dogs. First passage (P1) chondrocytes were preincubated with 0, 1, 5, 15 and 40 ?g/mL of PPS for 4 hr before treatment with 10 ng/mL rhIL-1? for a further 8 hr. In addition, we evaluated the effects of single and multiple cytokine with or without LPS on iNOS protein induction. PPS significantly inhibited (P < 0.05) IL-1?-induced iNOS, c-Jun and HIF-1? mRNA upregulation in a dose-dependent pattern. iNOS mRNA was significantly inhibited at 15 and 40 ?g/mL whereas c-Jun and HIF-1? were significantly downregulated at 5, 15 and 40 ?g/mL of PPS compared to chondrocytes treated with only rhIL-1?. Intriguingly, CACs were recalcitrant to single IL-1?, TNF-? or LPS-induction of iNOS protein including to a combination of IL-1?+TNF-?, IL-1?+LPS except to TNF-?+LPS and IL-1?+TNF-?+LPS suggestive of a protective mechanism from iNOS detrimental effects on perpetuating OA. IL-1?+TNF-?+LPS-induced iNOS protein expression was significantly abrogated by PPS. We demonstrate for the first time that PPS is a novel inhibitor of IL-1?-induced iNOS, c-Jun, and HIF-1? mRNA upregulation and iNOS protein induction which may be beneficial for prevention and treatment OA.

Project description:Cannabidiol (CBD) is the most abundant non-psychoactive compound of Cannabis sativa extracts. Cannabinoids have been shown to exhibit anti-inflammatory, analgesic, antioxidant, neuroprotective, and anti-tumorigenic effects. In the present study, we investigated the effects of CBD on human articular chondrocytes. Cell viability was determined by Resazurin assays. Apoptosis was analyzed by annexin-V/7-actinomycin D (7-AAD) staining followed by flow cytometry. Caspase 3/7 activity was measured with caspase assays. Intracellular Ca2+ ([Ca2+ ]i ) was monitored by time-lapse fluorescence imaging. The perforated whole-cell patch-clamp technique was used for measuring the cell membrane potential. Erk1/2 phosphorylation was assessed by western blot analysis. The chondrocyte cell line C28/I2 and primary chondrocytes showed a reduced viability after treatment with concentrations of CBD greater than 4 µM. This apoptotic effect was accompanied by an increase of caspase 3/7 activity and an increase in the early apoptotic cell population. CBD elevated [Ca2+ ]i , which was accompanied by depolarization of the cell membrane potential. The increase of [Ca2+ ]i was abrogated, when Ca2+ was omitted from the bath solution, indicating an influx of extracellular Ca2+ . The cannabinoid receptor 1 (CB1) antagonist AM251 inhibited the Ca2+ influx triggered by CBD. Preincubation with AM251 reduced the toxic effects of CBD. By looking for mediators of the apoptotic CBD effect downstream of the CB1 receptor, enhanced Erk1/2 phosphorylation could be detected after CBD treatment. However, this Erk1/2 activation proved to be unaffected by CB1 receptor blockage. The present study demonstrates that CBD promotes apoptosis and [Ca2+ ]i elevation in human articular chondrocytes via a CB1-receptor-mediated mechanism. © 2019 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society J Orthop Res 37:2540-2549, 2019.

Dataset Information

Low-dose ?-radiation inhibits IL-1?-induced dedifferentiation and inflammation of articular chondrocytes via blockage of catenin signaling.

Publications

Low-dose γ-radiation inhibits IL-1β-induced dedifferentiation and inflammation of articular chondrocytes via blockage of catenin signaling.

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