Endothelin-1 in osteoarthritic chondrocytes triggers nitric oxide production and upregulates collagenase production

Manacu, Christina Alexandra; Martel‐Pelletier, Johanne; Roy‐Beaudry, Marjolaine; Pelletier, Jean‐Pierre; Fernandes, Julio C.; Shipkolye, F; Mitrović, D; Moldovan, Florina

doi:10.1186/ar1489

Cited by 35 publications

(13 citation statements)

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“…We found that ET-1 did not act on IVD degeneration through induction of apoptosis. Others have reported similar results of ET-1 on articular chondrocytes without apoptosis [13].…”

Section: Discussionsupporting

confidence: 59%

“…ET-1 was firstly discovered in aortic endothelial cells, and has since been found to be produced by many cell types [12]. Interestingly, ET-1 is not only a potent vasoconstrictor, but is also associated with inflammation in degenerative diseases mainly via endothelin receptor type A. ET-1 causes excessive production of NO, which is generated following increases in inducible nitric oxide synthase (NOS) levels [13]–[15]. In addition, ET-1 promotes MMP-1 and MMP-13 synthesis and activation in osteoarthritis cartilage [16].…”

Section: Introductionmentioning

confidence: 99%

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Association of Endothelin-1 Expression and Cartilaginous Endplate Degeneration in Humans

et al. 2013

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BackgroundInflammatory cytokines are involved in intervertebral disc (IVD) degeneration. Endothelin-1 (ET-1), a 21-amino-acid cytokine implicated with cartilage degradation, is secreted by vascular endothelial cells and also by many other cell types. The expression of ET-1 in human IVD cartilage endplate (CEP) and its role in disc degeneration have not been explored.Methods and FindingsThe expression of ET-1 in degenerated CEP was analyzed by immunohistochemical staining and Western blotting; ET-1 was demonstrated in cartilaginous endplate cells (CECs) by immunofluorescent staining. The ET-1 mRNA expression and protein production by CECs stimulated by tumor necrosis factor alpha (TNF-α), a pro-inflammatory cytokine, were determined by real-time PCR analysis and Western blotting, respectively. The matrix metalloprotease-1 (MMP-1), MMP-13 and tissue inhibitor of metalloproteases-1 (TIMP-1) levels in the supernatant of cultured CECs treated with ET-1 were determined using enzyme-linked immunosorbent assays. Nitric oxide (NO) release and nitric oxide synthase (NOS) activity were measured using a spectrophotometric assay. The apoptosis of CECs by ET-1 was measured by an Annexin V-FITC detection assay. The production of ET-1 in degenerated cartilage endplate was significantly higher than normal CEP. The results showed that ET-1 was expressed by CECs and modulated by TNF-α in a dose-dependent manner. ET-1 increased production of MMP-1 and MMP-13, decreased TIMP-1 production, and induced NO and NOS release by cultured CECs. The direct stimulation of CECs by ET-1 did not promote cell apoptosis.ConclusionThe study results suggest that ET-1 played a pivotal role in human CEP degeneration, and may be a new target for development of therapies for this condition.

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“…We found that ET-1 did not act on IVD degeneration through induction of apoptosis. Others have reported similar results of ET-1 on articular chondrocytes without apoptosis [13].…”

Section: Discussionsupporting

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Association of Endothelin-1 Expression and Cartilaginous Endplate Degeneration in Humans

et al. 2013

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“…A previous report by Li and colleagues has shown that TGFB induces activation of AKT in precartilaginous stem cells, and inhibition of AKT activity suppresses TGFB-induced expression of SOX9 , AGN , and COL2 [ 50 ], indicating the crucial role of AKT signaling in chondrogenesis. In addition to the AKT signaling pathway, other pathways, such as the mitogen activated-protein kinase pathway [ 26 , 27 ] or the Ca 2+ /calmodulin-dependent protein kinase cascade [ 28 ], activated by ET1, may also be involved in the regulation of hMSC activities induced by ECs. However, investigation into how ECs regulate hMSCs through other signaling pathways is beyond the scope of this study.…”

Section: Discussionmentioning

confidence: 99%

“…ET1 binds to endothelin receptor type A or B on the cell surface to activate downstream signaling molecules of several pathways, including mitogen activated-protein kinase [ 26 , 27 ], Ca 2+ /calmodulin-dependent protein kinase [ 28 ], protein kinase C [ 29 , 30 ], and phosphatidylinositol 3-kinase/AKT [ 31 , 32 ]. It is known that these signaling molecules play a role in regulation of MSC behavior.…”

Section: Introductionmentioning

confidence: 99%

Endothelial cells direct human mesenchymal stem cells for osteo- and chondro-lineage differentiation through endothelin-1 and AKT signaling

et al. 2015

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IntroductionHuman mesenchymal stem cells (hMSCs) reside in a perivascular niche of the body, suggesting that they interact closely with vascular endothelial cells (ECs) through cell-cell interaction or paracrine signaling to maintain cell functions. Endothelin-1 (ET1) is a paracrine factor mainly secreted by ECs. We thus hypothesize that ECs can regulate cellular activities of hMSCs and direct their stem cell fate.MethodsWe investigated whether co-cultured human aortic endothelial cells (HAECs) were able to regulate expression of potency- and lineage-related markers in bone marrow-derived hMSCs. We further explored the regulatory effects of ET1 on cell proliferation, expression of surface antigens and pluripotency-related markers, and multilineage differentiation in hMSCs. Activation of the AKT signaling pathway in hMSCs was also analyzed to identify its mechanistic role in the ET1-induced regulation.ResultsCo-cultured HAECs enhanced expression of mesenchymal lineage-related markers in hMSCs. Treatment of ET receptor antagonist downregulated the increased expression of CBFA1 in hMSCs cultured with HAEC-conditioned medium. hMSCs treated with ET1 showed cell proliferation and expression of surface antigens, CD73, CD90, and CD105, comparable with those without ET1 treatment. ET1-treated hMSCs also expressed upregulated mRNA transcript levels of OCT3/4, NANOG, CBFA1 and SOX9. When induced for lineage-specific differentiation, hMSCs pre-treated with ET1 showed enhanced osteogenesis and chondrogenesis. However, adipogenic differentiation of hMSCs was not affected by ET1 pretreatment. We further showed that the ET1-induced regulation was mediated by activation of AKT signaling.ConclusionOur results demonstrate that ET1 secreted by HAECs can direct bone marrow-derived hMSCs for osteo- and chondro-lineage differentiation through activation of the AKT signaling pathway, suggesting that ET1 plays a crucial role in regulation of hMSC activity. Our findings may help understand how hMSCs interact with ECs in a perivascular niche.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-015-0065-6) contains supplementary material, which is available to authorized users.

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“…Indeed, recent studies have revealed that endothelin-1 is produced in OA cartilage and synovial membrane, and that it upregulates MMP expression and synthesis, as well as increasing collagen type II degradation in human cartilage [60,61].…”

Section: Endothelin-1mentioning

confidence: 99%

Cytokines and Growth Factors in the Treatment of Osteoarthritis: What Could be the Best Disease Modifying Drugs

Martel‐Pelletier

Tardif²,

Laufer³

et al. 2005

CMCAIAA

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Osteoarthritis (OA) is by far the most prevalent arthritic disease affecting around 10% of the world's population and approximately 60% of 60-year-olds. It is also one of the most common arthritic diseases seen by general practitioners and rheumatologists. The increased frequency of OA with age, makes it a growing social health concern, as it is a disease associated with disability and pain. In the US today, the immediate cost of the disease is estimated at approximately 60 billion dollars a year. Despite the clinical success of non-steroidal anti-inflammatory drugs (NSAIDs) and of anti-cyclooxygenase (COX)-2 in treating symptoms, there is no cure for the disease to date. However, our knowledge of its etiopathogenesis has progressed significantly in the past few decades. Based on studies of human cells and animal models, targets for therapeutic intervention have been put forward and major efforts are underway to bring about new therapies that can reduce or stop the progression of the disease. This review should help the reader better understand the most recent advances regarding inflammatory and growth factors as new targets in reducing or stopping OA.

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Endothelin-1 in osteoarthritic chondrocytes triggers nitric oxide production and upregulates collagenase production

Cited by 35 publications

References 36 publications

Association of Endothelin-1 Expression and Cartilaginous Endplate Degeneration in Humans

Association of Endothelin-1 Expression and Cartilaginous Endplate Degeneration in Humans

Endothelial cells direct human mesenchymal stem cells for osteo- and chondro-lineage differentiation through endothelin-1 and AKT signaling

Cytokines and Growth Factors in the Treatment of Osteoarthritis: What Could be the Best Disease Modifying Drugs

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