Dataset Information

SOCS1 Regulates Apoptosis and Inflammation by Inhibiting IL-4 Signaling in IL-1?-Stimulated Human Osteoarthritic Chondrocytes.

ABSTRACT: Recently, Suppressor of Cytokine Signaling 1 (SOCS1) was identified as a potential therapeutic target for osteoarthritis (OA) treatment. However, the mechanisms and signaling pathways of SOCS1 in the regulation of OA development are unclear. The purpose of the current study was to investigate whether interleukin- (IL-) 4 was involved in regulatory mechanism of SOCS1 in human osteoarthritic chondrocytes. First, IL-1? was used to stimulate human osteoarthritic chondrocytes isolated from the articular cartilage of OA patients undergoing total knee replacement. The protein and mRNA expression levels of SOCS1 were upregulated in IL-1?-stimulated human osteoarthritic chondrocytes compared with control cells. The knockdown of SOCS1 increased cell viability and inhibited cell apoptosis. It was also found that IL-4 expression was increased by SOCS1 silencing. Additionally, knockdown of IL-4 reduced cell viability and increased cell apoptosis of osteoarthritic chondrocytes transfected with SOCS1 siRNA. Moreover, the decreased expression of inflammatory factors induced by SOCS1 was enhanced by IL-4 knockdown. In conclusion, IL-4 signaling plays a crucial role in the regulatory functions of SOCS1 in apoptosis and inflammation in human osteoarthritic chondrocytes. These findings provide a potential therapeutic target for the clinical treatment of OA.

SUBMITTER: He Q

PROVIDER: S-EPMC5360958 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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SOCS1 Regulates Apoptosis and Inflammation by Inhibiting IL-4 Signaling in IL-1<i>β</i>-Stimulated Human Osteoarthritic Chondrocytes.

He Qiang Q Sun Caihong C Lei Wei W Ma Jianbing J

BioMed research international 20170308

Recently, Suppressor of Cytokine Signaling 1 (SOCS1) was identified as a potential therapeutic target for osteoarthritis (OA) treatment. However, the mechanisms and signaling pathways of SOCS1 in the regulation of OA development are unclear. The purpose of the current study was to investigate whether interleukin- (IL-) 4 was involved in regulatory mechanism of SOCS1 in human osteoarthritic chondrocytes. First, IL-1<i>β</i> was used to stimulate human osteoarthritic chondrocytes isolated from the ...[more]

PMID: 28373981

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Project description:Shenmai injection (SMI) has been widely used as a therapy to treat a number of diseases. However, its anti-osteoarthritic properties have not yet been fully investigated. In the present study, the protective effect of SMI on knee articular cartilage of anterior cruciate ligament transected rabbits and interleukin-1β (IL-1β)-stimulated human chondrocytes was investigated. For the in vivo study, knee osteoarthritis (KOA) was induced in female New Zealand white rabbits by anterior cruciate ligament transection (ACLT) in the knee of right hind limb. Rabbits either underwent sham surgery or ACLT surgery. Out of the rabbits receiving ACLT surgery, half of the rabbits received one 0.3 ml Shenmai intra-articular injection in the knee per week for four weeks, following ACLT surgery. The other rabbits received the same volume of normal saline solution. The cartilage was subsequently collected for histological evaluation. For the in vitro study, cultured human chondrocytes were treated with 10 ng/ml IL-1β in the presence or absence of 5 and 2% (v/v) SMI for 24 h. Nitric oxide (NO) and prostaglandin E2 (PGE2) levels in cell culture supernatant were assessed using a Griess reaction and ELISA respectively. The mRNA expression of cyclooxgenase-2 (COX-2), inducible nitric oxide synthase (iNOS), matrix metalloproteinase (MMP)-1, MMP-13 and tissue inhibitors of metalloproteinase-1 (TIMP-1) in chondrocytes were detected by reverse transcription-quantitative polymerase chain reaction. The results of the current study revealed that treatment with SMI ameliorated cartilage degradation in the ACLT rabbit model, and decreased levels of NO and PGE2. Furthermore, treatment with SMI decreased levels of COX-2, iNOS, MMP-1 and MMP-13 mRNA expression and increased TIMP-1 mRNA expression in IL-1β-stimulated human chondrocytes. These results indicate that SMI suppresses inflammation and ameliorated cartilage degradation, making it a potential and promising therapeutic option to treat KOA.

Project description:ObjectiveTo explore the effect of miR-1307-5p which specifically inhibits transforming growth factor beta-induced gene (TGFBI) on the biologic behavior of osteoarthritis (OA) chondrocytes.MethodsWe detected miR-1307-5p and TGFBI expression in the cartilage tissue specimens of OA patients and mice, respectively. RNA22 was applied to predict the target gene of miR-1307-5p, and we further verified the relationship by performing a dual luciferase reporter experiment. Enzyme-linked immunosorbent assay was used to measure the expression of matrix metalloproteinase inhibitor-1 (TIMP-1), interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in the culture medium of mouse chondrocytes. Quantitative reverse transcription-polymerase chain reaction and western blot were used to measure the expression of Bax and Bcl-2. MTT method was applied to detect the proliferation activity of chondrocytes, while flow cytometry was implemented to detect the apoptosis of chondrocytes.ResultsThe expression of miR-1307-5p in cartilage tissue specimens of OA patients was up-regulated, while TGFBI expression was down-regulated. Compared with normal mice cartilage tissue specimens, the expression of miR-1307-5p in cartilage tissue specimens of OA mouse was increased, while TGFBI expression was decreased (both P<0.05). The results of the dual luciferase reporter experiment showed that TGFBI was a target gene of miR-1307-5p. In cell experiments, compared with the normal group, TIMP-1 and Bcl-2 expression, and cell proliferation activities in all model groups were decreased. IL-1β, IL-6, TNF-α, Bax expression, and cell apoptosis rates were increased (all P<0.05). Compared with the blank group, TIMP-1 and Bcl-2 expression, and cell proliferation activities in the miR-1307-5p inhibitor group and the TGFBI group were increased, while IL-1β, IL-6, TNF-α, and Bax expression, and cell apoptosis rates were decreased (all P<0.05). The changes in all indicators in the miR-1307-5p mimic group were opposite to those of the miR-1307-5p inhibitor group (all P<0.05). There were no significant differences concerning all indicators between the blank group and the NC group, and between the blank group and the miR-1307-5p mimic + TGFBI group (all P>0.05).ConclusionThe suppression of miR-1307-5p expression can increase TGFBI expression, promoting the proliferation of chondrocytes in OA mice, while inhibiting their apoptosis.

Project description:A switch from autophagy to apoptosis is implicated in chondrocytes during the osteoarthritis (OA) progression with currently unknown mechanism(s). In this study we utilized a flow fluid shear stress (FFSS) model in cultured chondrocytes and a unilateral anterior crossbite (UAC) animal model. We found that both FFSS and UAC actively induced endoplasmic reticulum stress (ERS) in the temporomandibular joints (TMJ) chondrocytes, as demonstrated by dramatic increases in expression of HSPA5, p-EIF2AK3, p-ERN1 and ATF6. Interestingly, both FFSS and UAC activated not only pro-death p-EIF2AK3-mediated ERS-apoptosis programs but also pro-survival p-ERN1-mediated autophagic flux in chondrocytes. Data from FFSS demonstrated that MTORC1, a downstream of p-ERN1, suppressed autophagy but promoted p-EIF2AK3 mediated ERS-apoptosis. Data from UAC model demonstrated that at early stage both the p-ERN1 and p-EIF2AK3 were activated and MTORC1 was inhibited in TMJ chondrocytes. At late stage, MTORC1-p-EIF2AK3-mediated ERS apoptosis were predominant, while p-ERN1 and autophagic flux were inhibited. Inhibition of MTORC1 by TMJ local injection of rapamycin in rats or inducible ablation of MTORC1 expression selectively in chondrocytes in mice promoted chondrocyte autophagy and suppressed apoptosis, and reduced TMJ cartilage loss induced by UAC. In contrast, MTORC1 activation by TMJ local administration of MHY1485 or genetic deletion of Tsc1, an upstream MTORC1 suppressor, resulted in opposite effects. Collectively, our results establish that aberrant mechanical loading causes cartilage degeneration by activating, at least in part, the MTORC1 signaling which modulates the autophagy and apoptosis programs in TMJ chondrocytes. Thus, inhibition of MTORC1 provides a novel therapeutic strategy for prevention and treatment of OA.Abbreviations : ACTB: actin beta; ATF6: activating transcription factor 6; BECN1: beclin 1; BFL: bafilomycin A1; CASP12: caspase 12; CASP3: caspase 3; DAPI: 4',6-diamidino-2-phenylindole; DDIT3: DNA-damage inducible transcript 3; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; ER: endoplasmic reticulum; ERS: endoplasmic reticulum stress; ERN1/IRE1: endoplasmic reticulum to nucleus signaling 1; FFSS: flow fluid shear stress; HSPA5/GRP78/BiP: heat shock protein 5; LAMP2: lysosome-associated membrane protein 2; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin complex 1; OA: osteoarthritis; PRKAA1/2/AMPK1/2: protein kinase, AMP-activated, alpha 1/2 catalytic subunit; RPS6: ribosomal protein S6; Rapa: rapamycin; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; TG: thapsigargin; TMJ: temporomandibular joints; TSC1/2: tuberous sclerosis complex 1/2; UAC: unilateral anterior crossbite; UPR: unfolded protein response; XBP1: x-box binding protein 1.

Dataset Information

SOCS1 Regulates Apoptosis and Inflammation by Inhibiting IL-4 Signaling in IL-1?-Stimulated Human Osteoarthritic Chondrocytes.

Publications

SOCS1 Regulates Apoptosis and Inflammation by Inhibiting IL-4 Signaling in IL-1<i>β</i>-Stimulated Human Osteoarthritic Chondrocytes.

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