The mechanism of inhibition of endothelin-1-induced stimulation of DNA synthesis in rat articular chondrocytes

Khatib, Abdel‐Majid; Ribault, Didier; Quintero, Maritza; Barbara, A.; Fiet, Jean; Mitrović, D

doi:10.1016/s0303-7207(97)00121-4

Cited by 12 publications

(8 citation statements)

References 26 publications

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“…ET-1 binds to the specific endothelin A or endothelin B receptors expressed on chondrocytes [4] and triggers a cascade of intracellular events, including phospholipase C activation [5], an increase in intracellular calcium [6,7], prostaglandin production [8] and nitric oxide (NO) release [9]. The effect of ET-1 on DNA and protein synthesis in chondrocytes is biphasic.…”

Section: Introductionmentioning

confidence: 99%

“…The effect of ET-1 on DNA and protein synthesis in chondrocytes is biphasic. The potent initial stimulatory effect of ET-1 decreases progressively with time and is followed by an inhibition [3,8]. The inhibitory effect seems to be mediated by NO and cGMP, both produced in response to ET-1 stimulation [8,9].…”

Section: Introductionmentioning

confidence: 99%

“…The potent initial stimulatory effect of ET-1 decreases progressively with time and is followed by an inhibition [3,8]. The inhibitory effect seems to be mediated by NO and cGMP, both produced in response to ET-1 stimulation [8,9]. Additionally, we have recently demonstrated that ET-1 is significantly increased locally in OA cartilage and synovial membrane when compared with normal tissues.…”

Section: Introductionmentioning

confidence: 99%

“…Another deleterious agent in joint cartilage is the NO radical [13,14], which downregulates DNA [8] and matrix synthesis [14] and upregulates matrix degradation via increased MMP synthesis [15]. Indeed, inhibition of NO production was shown to slow down the progression of OA.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2005

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The mechanism of endothelin-1 (ET-1)-induced nitric oxide (NO) production, MMP-1 production and MMP-13 production was investigated in human osteoarthritis chondrocytes. The cells were isolated from human articular cartilage obtained at surgery and were cultured in the absence or presence of ET-1 with or without inhibitors of protein kinase or LY83583 (an inhibitor of soluble guanylate cyclase and of cGMP). MMP-1, MMP-13 and NO levels were then measured by ELISA and Griess reaction, respectively. Additionally, inducible nitric oxide synthase (iNOS) and phosphorylated forms of p38 mitogen-activated protein kinase, p44/42, stress-activated protein kinase/Jun-N-terminal kinase and serine-threonine Akt kinase were determined by western blot. Results show that ET-1 greatly increased MMP-1 and MMP-13 production, iNOS expression and NO release. LY83583 decreased the production of both metalloproteases below basal levels, whereas the inhibitor of p38 kinase, SB202190, suppressed ET-1-stimulated production only. Similarly, the ET-1-induced NO production was partially suppressed by the p38 kinase inhibitor and was completely suppressed by the protein kinase A kinase inhibitor KT5720 and by LY83583, suggesting the involvement of these enzymes in relevant ET-1 signalling pathways. In human osteoarthritis chondrocytes, ET-1 controls the production of MMP-1 and MMP-13. ET-1 also induces NO release via iNOS induction. ET-1 and NO should thus become important target molecules for future therapies aimed at stopping cartilage destruction.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2005

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“…In addition, PgF 2 a and PgE 2 stimulate, and PgE 1 inhibits DNA synthesis in the same cell line (24). In our laboratory, PgE 2 , PgF 2 a, and TxB 2 induced concentrationdependent inhibition of [ 3 H]thymidine incorporation in rat AC monolayers (25). In synovial inflammation, articular cartilage and other tissues are frequently damaged.…”

Section: Discussionmentioning

confidence: 73%

Human synovium produces substances that inhibit DNA and stimulate proteoglycan and collagen synthesis by cultured human articular chondrocytes and synovial fibroblasts

Panasyuk¹,

Colantuoni²,

Khatib³

et al. 2003

Scandinavian Journal of Rheumatology

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The effects of synovial conditioned medium (SCM) on DNA, proteoglycan (PG), and protein-collagen synthesis and respective gene expressions, in human articular chondrocytes (AC) and DNA synthesis in synovial fibroblasts (SFb), were studied in monolayer culture. All SCM exhibited concentration-dependent inhibition of [3H]thymidine incorporation in both AC and SFb. In contrast, SCM from three OA patients stimulated [35S]SO4 and [3H]glycine incorporations and the expression (RT-PCR) of aggrecan- and type II collagen-specific mRNAs in AC. The production of agents that inhibit DNA synthesis was blocked by indomethacin and dexamethasone and stimulated by IL-1 beta and TNF-alpha. The inhibitory substances were not produced by heat-inactivated tissue nor cultured SFb or AC and were completely solubles in methanol. It is postulated that synovial tissue secretes lipids, most probably arachidonic acid metabolites. These may counteract growth of an inflammatory synovial pannus by inhibiting SFb proliferation and enhance repair of damaged tissues by stimulating the matrix synthesis.

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Endothelin 1 promotes osteoarthritic cartilage degradation via matrix metalloprotease 1 and matrix metalloprotease 13 induction

Roy‐Beaudry

Martel‐Pelletier

Pelletier

et al. 2003

Arthritis & Rheumatism

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Objective. Degradation of the collagenous extracellular matrix by metalloproteases (MMPs) plays an important role in the pathogenesis of osteoarthritis (OA). Recently, it was suggested that endothelin 1 (ET-1), a potent vasoconstrictor, may be involved in MMP regulation. This study investigated the role of ET-1 in OA cartilage degradation.Methods. We explored ET-1 expression and synthesis in normal and OA cartilage and synovial membrane by reverse transcription-polymerase chain reaction and immunohistochemistry. MMP-1 and MMP-13 gene expression and protein synthesis were investigated using Northern blotting and enzyme-linked immunosorbent assays. Additionally, ET-1-induced collagenase activity, type II collagen metabolites, and tissue inhibitor of metalloproteases 1 (TIMP-1) protein were evaluated.Results. We found expression and synthesis of ET-1, in situ, in both normal and OA cartilage and synovial membrane. We demonstrated that ET-1 induced gene expression and protein synthesis of both MMP-1 and MMP-13. These enzymes were produced in OA chondrocyte cultures, and the production increased in a dose-dependent manner in the presence of ET-1. In OA cartilage, ET-1 also induced type II collagenderived neoepitopes concomitantly with an increase in collagenase activity and a decrease in TIMP-1 protein.Conclusion. Our results provide strong evidence of the catabolic role of ET-1 in OA cartilage via MMP-1 and MMP-13 up-regulation. As well, ET-1 increased the net MMP/TIMP balance and secondarily increased collagen degradation. Hence, ET-1 becomes an attractive factor to target in the conception of new therapeutic approaches for OA and other diseases in which MMP-13 and MMP-1 actions are crucial in tissue alteration.

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The mechanism of inhibition of endothelin-1-induced stimulation of DNA synthesis in rat articular chondrocytes

Cited by 12 publications

References 26 publications

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

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

Human synovium produces substances that inhibit DNA and stimulate proteoglycan and collagen synthesis by cultured human articular chondrocytes and synovial fibroblasts

Endothelin 1 promotes osteoarthritic cartilage degradation via matrix metalloprotease 1 and matrix metalloprotease 13 induction

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