Mechanism of Inhibition of Endothelin-1–stimulated Proteoglycan and Collagen Synthesis in Rat Articular Chondrocytes

Khatib, Abdel‐Majid; Siegfried, Géraldine; Messai, Habib; Moldovan, Florina; Mitrović, D

doi:10.1006/cyto.2001.1001

Cited by 17 publications

(15 citation statements)

References 23 publications

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“…12,33,37,38 This assumption is based on the known inhibitory effects of cGMP on collagen synthesis and the TGFb1 pathway, and its vasculoprotective effects on arterial SMC. [14][15][16][17]20,[45][46][47] However, the anti-apoptotic and pro-proliferative effects of sildenafil that we found in the corporal smooth muscle do not agree with the fact that cGMP inhibits vascular SMC proliferation. 48,49 Since the effects of BCNR on the corporal histology and pharmacokinetics are the same as those seen in the aged rat, we assume that cGMP effects on corporal SMC may be modulated by some specific features in the corporal SMC themselves or the tissue milieu, that are not operative in the vascular SMC.…”

Section: Discussioncontrasting

confidence: 90%

“…This confirmed our previous observation that CVOD is induced by BCNR, and showed that UCNR induced a moderate CVOD. 14 Continuous oral treatment with sildenafil normalized the drop rate and response to papaverine (top and bottom) in both the UCNR and BCNR animals.…”

Section: Resultsmentioning

confidence: 99%

“…[11][12][13] It is likely that this occurs through the maintenance of high levels of cGMP, since this compound reduces collagen synthesis and the activation of the pro-fibrotic TGFb1 pathway and protects SMC from apoptosis, while stimulating the spontaneous induction of inducible nitric oxide synthase (iNOS, also known as NOS2). [14][15][16][17][18][19][20][21][22][23] The expression of iNOS in certain non-immunological tissues is assumed to be a defense mechanism against fibrosis. [24][25][26][27][28][29] The nitric oxide produced by iNOS, besides inhibiting collagen synthesis and the TGFb1 pathway, also quenches reactive oxygen species, and in some cases, the differentiation of fibroblasts to myofibroblasts, the cells that produce collagen in many fibrotic conditions.…”

Section: Introductionmentioning

confidence: 99%

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Long-term continuous sildenafil treatment ameliorates corporal veno-occlusive dysfunction (CVOD) induced by cavernosal nerve resection in rats

et al. 2007

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It was recently reported in the rat that vardenafil given in a continuous long-term manner was successful in preventing smooth muscle fibrosis in the penile corpora cavernosa and corporal venoocclusive dysfunction (CVOD) that occur following bilateral cavernosal nerve resection (BCNR), a model for human erectile dysfunction after radical prostatectomy. To expand on this finding and to determine whether this effect was common to other PDE5 inhibitors, and occurred in part by stimulation of the spontaneous induction of inducible nitric oxide synthase (iNOS, also known as NOS2), male Fischer 344 rats (N ¼ 10/group) were subjected to either BCNR or unilateral cavernosal nerve resection (UCNR) and treated with sildenafil (20 mg kg À1 day À1 ) in the drinking water daily for 45 days. Additional BCNR groups received L-NIL (6.7 mg kg À1 day À1 ) as inhibitor of iNOS activity, with or without concurrent sildenafil administration. It was determined that sildenafil, like vardenafil, (1) prevented the 30% decrease in the smooth muscle cell/collagen ratio, and the 3-4-fold increase in apoptosis and reduction in cell proliferation, and partially counteracted the increase in collagen, seen with both UCNR and BCNR; and (2) normalized the CVOD, measured by dynamic infusion cavernosometry, induced by both BCNR and UCNR. The long-term inhibition of iNOS activity exacerbated corporal fibrosis and CVOD in the BCNR rats, but sildenafil functional effects were not affected by L-NIL. These data suggest that the salutary effects of continuous long-term PDE5 inhibitors on erectile function post-cavernosal nerve resection involve their ability to prevent the alterations in corporal histology induced by cavernosal nerve damage, in a process apparently independent from endogenous iNOS induction.

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Section: Discussioncontrasting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Long-term continuous sildenafil treatment ameliorates corporal veno-occlusive dysfunction (CVOD) induced by cavernosal nerve resection in rats

et al. 2007

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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 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%

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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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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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Mechanism of Inhibition of Endothelin-1–stimulated Proteoglycan and Collagen Synthesis in Rat Articular Chondrocytes

Cited by 17 publications

References 23 publications

Long-term continuous sildenafil treatment ameliorates corporal veno-occlusive dysfunction (CVOD) induced by cavernosal nerve resection in rats

Long-term continuous sildenafil treatment ameliorates corporal veno-occlusive dysfunction (CVOD) induced by cavernosal nerve resection in rats

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

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