Skip header and navigation

Refine By

3 records – page 1 of 1.

Induction of increased cAMP levels in articular chondrocytes blocks matrix metalloproteinase-mediated cartilage degradation, but not aggrecanase-mediated cartilage degradation.

https://arctichealth.org/en/permalink/ahliterature77864
Source
Arthritis Rheum. 2007 May;56(5):1549-58
Publication Type
Article
Date
May-2007
Author
Karsdal Morten Asser
Sumer Eren Ufuk
Wulf Helle
Madsen Suzi H
Christiansen Claus
Fosang Amanda J
Sondergaard Bodil-Cecilie
Author Affiliation
Nordic Bioscience Diagnostics, Herlev, Denmark. mk@nordicbioscience.com
Source
Arthritis Rheum. 2007 May;56(5):1549-58
Date
May-2007
Language
English
Publication Type
Article
Keywords
1-Methyl-3-isobutylxanthine - pharmacology
Animals
Calcitonin - physiology
Cartilage, Articular - metabolism - pathology
Cattle
Cells, Cultured
Cyclic AMP - genetics - metabolism
Dose-Response Relationship, Drug
Endopeptidases - genetics - metabolism
Female
Forskolin - pharmacology
Glycosaminoglycans - metabolism
Matrix Metalloproteinases - genetics - metabolism
Oncostatin M - pharmacology
Osteoarthritis - metabolism - pathology
Phosphodiesterase Inhibitors - pharmacology
Tumor Necrosis Factor-alpha - pharmacology
Abstract
OBJECTIVE: Calcitonin has been suggested to have chondroprotective effects. One signaling pathway of calcitonin is via the second messenger cAMP. We undertook this study to investigate whether increased cAMP levels in chondrocytes would be chondroprotective. METHODS: Cartilage degradation was induced in bovine articular cartilage explants by 10 ng/ml oncostatin M (OSM) and 20 ng/ml tumor necrosis factor (TNF). In these cultures, cAMP levels were augmented by treatment with either forskolin (4, 16, or 64 microM) or 3-isobutyl-1-methyl xanthine (IBMX; 4, 16, or 64 microM). Cartilage degradation was assessed by 1) quantification of C-terminal crosslinking telopeptide of type II collagen fragments (CTX-II), 2) matrix metalloproteinase (MMP)-mediated aggrecan degradation by (342)FFGV- G2 assay, 3) aggrecanase-mediated degradation by (374)ARGS-G2 assay, 4) release of sulfated glycosaminoglycans (sGAG) into culture medium, 5) immunohistochemistry with a monoclonal antibody recognizing the CTX-II epitope, and 6) toluidine blue staining of proteoglycans. MMP expression and activity were assessed by gelatin zymography. RESULTS: OSM and TNF induced an 8,000% increase in CTX-II compared with control (P 80%). OSM and TNF stimulated MMP expression as visualized by zymography, and MMP expression was dose-dependently inhibited by forskolin and IBMX. The highest concentration of IBMX lowered cytokine-induced release of sGAG by 72%. CONCLUSION: Levels of cAMP in chondrocytes play a key role in controlling catabolic activity. Increased cAMP levels in chondrocytes inhibited MMP expression and activity and consequently strongly inhibited cartilage degradation. Specific cAMP modulators in chondrocytes may be potential treatments for cartilage degenerative diseases.
PubMed ID
17469134 View in PubMed
Less detail

Mechanisms of impaired beta-adrenoceptor-induced airway relaxation by interleukin-1beta in vivo in the rat.

https://arctichealth.org/en/permalink/ahliterature11157
Source
J Clin Invest. 1996 Oct 15;98(8):1780-7
Publication Type
Article
Date
Oct-15-1996
Author
H. Koto
J C Mak
E B Haddad
W B Xu
M. Salmon
P J Barnes
K F Chung
Author Affiliation
Thoracic Medicine, National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, London, United Kingdom.
Source
J Clin Invest. 1996 Oct 15;98(8):1780-7
Date
Oct-15-1996
Language
English
Publication Type
Article
Keywords
Animals
Autoradiography
Bronchi - drug effects - physiology
Cyclic AMP - metabolism
Forskolin - pharmacology
GTP-Binding Proteins - analysis
Interleukin-1 - pharmacology
Isoproterenol - pharmacology
Muscle Relaxation - drug effects
RNA, Messenger - analysis
Rats
Rats, Inbred BN
Receptors, Adrenergic, beta - analysis - genetics - physiology
Research Support, Non-U.S. Gov't
Trachea - drug effects - physiology
Abstract
We studied the in vivo mechanism of beta-adrenergic receptor (beta-AR) hyporesponsiveness induced by intratracheal instillation of interleukin-1beta (IL-1beta, 500 U) in Brown-Norway rats. Tracheal and bronchial smooth muscle responses were measured under isometric conditions ex vivo. Contractile responses to electrical field stimulation and to carbachol were not altered, but maximal relaxation induced by isoproterenol (10(-6)-10(-5) M) was significantly reduced 24 h after IL-1beta treatment in tracheal tissues and to a lesser extent, in the main bronchi. Radioligand binding using [125I]iodocyanopindolol revealed a 32+/-7% reduction in beta-ARs in lung tissues from IL-1beta-treated rats, without any significant changes in beta2-AR mRNA level measured by Northern blot analysis. Autoradiographic studies also showed significant reduction in beta2-AR in the airways. Isoproterenol-stimulated cyclic AMP accumulation was reduced by IL-1beta at 24 h in trachea and lung tissues. Pertussis toxin reversed this hyporesponsiveness to isoproterenol but not to forskolin in lung tissues. Western blot analysis revealed an IL-1beta-induced increase in Gi(alpha) protein expression. Thus, IL-1beta induces an attenuation of beta-AR-induced airway relaxation through mechanisms involving a reduction in beta-ARs, an increase in Gi(alpha) subunit, and a defect in adenylyl cyclase activity.
PubMed ID
8878428 View in PubMed
Less detail

Sphingosine modulation of cAMP levels and beating rate in rat heart.

https://arctichealth.org/en/permalink/ahliterature9760
Source
Fundam Clin Pharmacol. 2002 Dec;16(6):495-502
Publication Type
Article
Date
Dec-2002
Author
V Edda Benediktsdóttir
Anna M Jónsdóttir
Bergthóra H Skúladóttir
Alain Grynberg
Jón Skarphéoinsson
Jóhannes Helgason
Sigmundur Gudbjarnason
Author Affiliation
Science Institute, University of Iceland Vatnsmýrarvegur 16, IS-101, Reykjavik Iceland. eb@raunvis.hi.is
Source
Fundam Clin Pharmacol. 2002 Dec;16(6):495-502
Date
Dec-2002
Language
English
Publication Type
Article
Keywords
Adrenergic beta-Agonists - pharmacology
Animals
Animals, Newborn
Cells, Cultured
Comparative Study
Cyclic AMP - metabolism
Dose-Response Relationship, Drug
Forskolin - pharmacology
Heart Rate - drug effects
Isoproterenol - pharmacology
Myocytes, Cardiac - drug effects - physiology
Rats
Rats, Wistar
Receptors, Adrenergic, beta - drug effects - physiology
Research Support, Non-U.S. Gov't
Signal Transduction
Sphingosine - pharmacology - physiology
Time Factors
Abstract
Sphingolipids, especially as elements of the sphingomyelin signal transduction cycle, are thought to play a significant role as second messengers and modulators of events in heart muscle cells. A possible modulatory role of sphingosine in signal transduction in the beta-adrenergic pathway in the heart was examined. Neonatal rat cardiomyocytes were incubated with sphingosine and/or other agents after which cAMP levels and contraction rates were measured. Heart rate in anaesthetized rats was also measured before and after sphingosine injection in the jugular vein. Sphingosine caused a decrease in basal cAMP levels and diminished isoproterenol-induced increase in cAMP levels. These changes were dose- and time-dependent and showed a significant negative effect on signal transmission in the beta-adrenergic pathway in cardiomyocytes. Increase in cAMP intracellular levels by forskolin, which activates adenylcyclase, was not inhibited by sphingosine. A phosphodiesterase inhibitor was used in all experiments in which cAMP was measured excluding effects on cAMP breakdown. It was also demonstrated that sphingosine caused reduction in the beating rate of cultured cardiomyocytes and a dose-dependent reduction in heart rate of anaesthetized rats. The sphingosine-induced inhibition of bradycardic response of anaesthetized rats reached a maximum about 5-10 min after the onset of sphingosine administration and returned to normal within 60 min. Sphingosine may modulate the signal transmission of the beta-adrenoceptor pathway upstream of adenylcyclase in rat cardiomyocytes. This may contribute to the sphingosine-induced decrease in heart rate of rats in vivo.
PubMed ID
12685508 View in PubMed
Less detail