TNFα-mediated apoptosis in human osteoarthritic chondrocytes sensitized by PI3K-NF-κB inhibitor, not mTOR inhibitor

Li, Deling; Wu, Zhihong; Duan, Yuan‐Hui; Hao, Dongsheng; Zhang, Xinbo; Luo, Hui; Chen, Baosheng; Qiu, Guixing

doi:10.1007/s00296-011-1929-4

Cited by 9 publications

(3 citation statements)

References 31 publications

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“…NFκB signaling is the major signaling pathway activated by TNF-alpha in OA chondrocytes 37 , 38 . To understand whether the anti-inflammatory effect of BMMSC-EVs, could be mediated through the regulation of NFκB activity, we treated TNF-alpha-stimulated OA chondrocytes with BMMSC-EVs and analyzed the subcellular localization of the p65 subunit of NFκB.…”

Section: Resultsmentioning

confidence: 99%

Mesenchymal Stromal/stem Cell-derived Extracellular Vesicles Promote Human Cartilage Regeneration In Vitro

Vonk¹,

Dooremalen²,

Liv³

et al. 2018

Theranostics

290

211

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Osteoarthritis (OA) is a rheumatic disease leading to chronic pain and disability with no effective treatment available. Recently, allogeneic human mesenchymal stromal/stem cells (MSC) entered clinical trials as a novel therapy for OA. Increasing evidence suggests that therapeutic efficacy of MSC depends on paracrine signalling. Here we investigated the role of extracellular vesicles (EVs) secreted by human bone marrow derived MSC (BMMSC) in human OA cartilage repair.Methods: To test the effect of BMMSC-EVs on OA cartilage inflammation, TNF-alpha-stimulated OA chondrocyte monolayer cultures were treated with BMMSC-EVs and pro-inflammatory gene expression was measured by qRT-PCR after 48 h. To assess the impact of BMMSC-EVs on cartilage regeneration, BMMSC-EVs were added to the regeneration cultures of human OA chondrocytes, which were analyzed after 4 weeks for glycosaminoglycan content by 1,9-dimethylmethylene blue (DMMB) assay. Furthermore, paraffin sections of the regenerated tissue were stained for proteoglycans (safranin-O) and type II collagen (immunostaining).Results: We show that BMMSC-EVs inhibit the adverse effects of inflammatory mediators on cartilage homeostasis. When co-cultured with OA chondrocytes, BMMSC-EVs abrogated the TNF-alpha-mediated upregulation of COX2 and pro-inflammatory interleukins and inhibited TNF-alpha-induced collagenase activity. BMMSC-EVs also promoted cartilage regeneration in vitro. Addition of BMMSC-EVs to cultures of chondrocytes isolated from OA patients stimulated production of proteoglycans and type II collagen by these cells.Conclusion: Our data demonstrate that BMMSC-EVs can be important mediators of cartilage repair and hold great promise as a novel therapeutic for cartilage regeneration and osteoarthritis.

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Section: Resultsmentioning

confidence: 99%

Mesenchymal Stromal/stem Cell-derived Extracellular Vesicles Promote Human Cartilage Regeneration In Vitro

Vonk¹,

Dooremalen²,

Liv³

et al. 2018

Theranostics

290

211

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show abstract

“…Of note, AG490, a pan-JAK SMI significantly reduced leptininduced chondrocyte apoptosis in vitro as well as reducing STAT3 phosphorylation, reactive oxygen species, MMP-13 and B-cell lymphoma 2-associated X protein [146]. Interestingly, Li et al [147] showed that the PI3K/NF-κB pathway was activated by TNF-α in human chondrocytes. However, the effect of leptin did not involve mTOR, suggesting that newly developed small molecule mTOR inhibitors (reviewed in [36]) might not be useful for neutralizing activated PI3K/NF-κB in response to leptin-induced apoptosis.…”

Section: Signal Transduction Pathwaysmentioning

confidence: 99%

Pharmacologic Interventions for Preventing Chondrocyte Apoptosis in Rheumatoid Arthritis and Osteoarthritis

Malemud¹

2018

Drug Discovery - Concepts to Market

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Chronic inflammation drives the progression of rheumatoid arthritis (RA) and osteoarthritis (OA) to synovial joint failure. The inflammatory state in both musculoskeletal diseases is associated with significantly elevated levels of pro-inflammatory cytokines in joint synovial fluid, which is best exemplified by increases in interleukin-1β (IL-1β), IL-6, IL-17, tumor necrosis factor-α, among others, as well as increased activity of soluble mediators such as nitric oxide and certain growth factors including vascular endothelial growth factor and fibroblast growth factor. The multitude of these factors activate chondrocyte signal transduction pathways resulting in programmed cell death, otherwise known as apoptosis as well as compromising chondrocyte autophagy. Importantly, chondrocyte apoptosis causes a loss of articular cartilage vitality which dampens cartilage repair mechanisms because at present, the possibility that chondrocyte progenitor cells could replace those differentiated chondrocytes lost via apoptosis remains debatable. Certain pharmacologic interventions which have been proven to induce apoptosis in various cancer cell studies in vitro suggest the possibility that drugs could be developed to specifically suppress or completely inhibit chondrocyte apoptosis in RA and OA cartilage. This review supports that contention and indicates that apoptosis can be inhibited by identifying novel cellular targets which promote apoptosis and autophagy.

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“…Additionally, some of the agents that their combined using with TRAIL has been acceptable outcomes but in limited cell lines have been listed below. kurarinone (Seo et al, ; Zhou, Cao, Wang, & Wu, ), monensin (Yoon et al, ), paxiline (Kang et al, ), diclofenac/hyaluronic acid (Dic/HA) (Fecker et al, ), nickel2+ (Schmidt et al, ), SHetA2 (Lin et al, ), BAY 11–7085 (Shen et al, ), compound c (Jang et al, ), FAK inhibitor PH11 (Dao et al, ), caffeic acid phenethyl ester (CAPE) (Li, Wu, et al, ), fasudil (Wang et al, ), cathepsin S inhibitor ZFL (Seo et al, ), 4‐(4‐Chloro‐2‐methylphenoxy)‐N‐hydroxybutanamide (CMH) (Bijangi‐Vishehsaraei, Huang, Safa, Saadatzadeh, & Murphy, ), actinomycin (Haimerl, Erhardt, Sass, & Tiegs, ), H1 (derivative of tetrandrine) (Lin, Wang, et al, ), genistein (Siegelin, Siegelin, Habel, & Gaiser, ), icaritin (Han, Xu, et al, ), ABT‐737 and VX–680 (Choi et al, ), 6‐shogaol (Han, Woo, et al, ), cathepsin E (Yasukochi, Kawakubo, Nakamura, & Yamamoto, ), ozarelix (Festuccia et al, ), transglutaminase 2 inhibitor (TGM2I) (Li, Xu, Bai, Chen, & Lin, ), amurensin G (Kim, Kim, Lee, et al, ), volasertib (Jeon et al, ), temozolomide (TMZ) (Zhitao, Long, Jia, Yunchao, & Anhua, ), chalcone‐24 (Xu et al, ), gingerol (Lee, Kim, Jung, Lee, & Park, ), triptolide (Chen et al, ), AKT inhibitor API‐1 (Li, Ren, et al, ), smac mimetic compounds (SMC) (Cheung et al, ), dicoumarol (Park, Min, Choi, & Kwon, ), partenolide (Trang et al, ), Pyrrolo‐1, 5‐benzoxazepine (PBOX) (Nathwani et al, ), embelin (Siegelin, Gaiser, & Siegelin, ), myricetin (Siegelin, Gaiser, Habel, & Siegelin, ), quercetin (Jung, Heo, Lee, Kwon, & Kim, ), silibinin (Son et al, ), epigallocatechin gallate (EGCG) (Abou El Naga et al, ), icariside II (Du et al, ), anisomycin (Seo et al, ), dioscin (Kim, Kim, Park, et al, ), celecoxib (Chen et al, ), micro RNA 126 (MiR‐126) (Zhang, Zhou, Zhu, & Yuan, ), gambognic acid (Ye et al, ), survivin inhibitor YM155 (Woo, Min, Seo, &...…”

Section: Intracellular Anti‐apoptotic Proteins As Targeted Therapymentioning

confidence: 99%

Down‐regulation of intracellular anti‐apoptotic proteins, particularly c‐FLIP by therapeutic agents; the novel view to overcome resistance to TRAIL

Hassanzadeh

Hagh

Alivand

et al. 2018

Journal Cellular Physiology

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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL or Apo2L) is a member of the tumor necrosis factor (TNF) superfamily that induces apoptosis in different types of cancer cells via activation of caspase cascade. TRAIL interacts with its cognate receptors that placed on cancer cells surface, including TRAIL-R1 (death receptor 4, DR4), TRAIL-R2 (death receptor 5, DR5), TRAIL-R3 (decoy receptor 1, DcR1), TRAIL-R4 (decoy receptor 2, DcR2), and osteoprotegerin (OPG). Despite high apoptosis-inducing ability of TRAIL, various cancerous cells gain resistance to TRAIL gradually, and consequently TRAIL potential for apoptosis stimulation in these cells diminishes intensely. According to diverse ranges of examinations, intracellular anti-apoptotic proteins, such as cellular-FLICE inhibitory protein (c-FLIP), apoptosis inhibitors (IAPs), myeloid cell leukemia sequence 1 (MCL-1), BCL-2, BCL-XL, and survivin play key role in cancer cells resistance to TRAIL. These proteins attenuate cancer cells sensitivity to TRAIL via various functions, importantly through caspase cascade suppression. The c-FLIP avoids from caspase 8 activation by FADD via binding to caspase 8 cleavage of FADD. Moreover, it activates signaling pathways that involved in cancer cells survival and proliferation. Intriguingly, it appears that the down-regulation of intracellular anti-apoptotic proteins, particularly c-FLIP is effectiveness goal for TRAIL-resistant cancers therapy, because their up-regulation in association with poor prognosis has been observed in various types of TRAIL-resistant cancers. In this review, we tried to collect and examine investigations that researchers have been able to sensitize cancer cells to TRAIL through targeting of c-FLIP alone or with other intracellular anti-apoptotic proteins directly or indirectly. It seems that co-treatment of resistant cells by TRAIL with other therapeutic agents with the aim of intracellular anti-apoptotic proteins inhibition is hopeful and attractive approach to overcome various TRAIL-resistant cancers.

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TNFα-mediated apoptosis in human osteoarthritic chondrocytes sensitized by PI3K-NF-κB inhibitor, not mTOR inhibitor

Cited by 9 publications

References 31 publications

Mesenchymal Stromal/stem Cell-derived Extracellular Vesicles Promote Human Cartilage Regeneration In Vitro

Mesenchymal Stromal/stem Cell-derived Extracellular Vesicles Promote Human Cartilage Regeneration In Vitro

Pharmacologic Interventions for Preventing Chondrocyte Apoptosis in Rheumatoid Arthritis and Osteoarthritis

Down‐regulation of intracellular anti‐apoptotic proteins, particularly c‐FLIP by therapeutic agents; the novel view to overcome resistance to TRAIL

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