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Inhibition of mitogen-activated protein kinase kinase induces apoptosis of human chondrocytes.
J Biol Chem. 2001 Apr 20; 276(16):13289-94.JB

Abstract

We previously have reported that the mitogen-activated protein kinase (MAPK) pathway is stimulated by adhesion of human chondrocytes to anti-beta(1)-integrin antibodies or collagen type II in vitro. These mechanisms most likely prevent chondrocyte dedifferentiation to fibroblast-like cells and chondrocyte death. To investigate whether this pathway plays an essential role for the differentiation, phenotype, and survival of chondrocytes, we blocked mitogen-activated protein kinase/extracellular signal-regulated kinase (Erk) (MEK), a kinase upstream of the kinase Erk by using U0126. Exposure of chondrocytes to U0126 caused activation of caspase-3 in a dose-dependent manner. Western blot analysis with an antibody specific for dually phosphorylated Erk shows that collagen type II induced phosphorylation of Erk1/2 was specifically blocked by U0126 in a dose-dependent manner. Immunohistochemical analysis showed that treated chondrocytes were caspase-3 positive. In treated chondrocytes, the cleavage of 116-kDa poly(ADP-ribose)polymerase resulted in the 85-kDa apoptosis-related cleavage fragment and was associated with caspase-3 activity. Analysis by electron microscopy showed typical morphological signs of apoptosis, such as crescent-shaped clumps of heterochromatin, and a degraded pericellular matrix. Thus, these results indicate that the MEK/Erk signal transduction pathway is involved in the maintenance of chondrocytes differentiation and survival. These data stimulate further investigations on the role of mitogen-activated protein kinase pathways in human chondrocytes.

Authors+Show Affiliations

Institute of Anatomy, Freie Universität Berlin, Königin-Luise-Strasse 15, D-14195 Berlin, Germany. mehshaki@zedat.fu-berlin.deNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

11278768

Citation

Shakibaei, M, et al. "Inhibition of Mitogen-activated Protein Kinase Kinase Induces Apoptosis of Human Chondrocytes." The Journal of Biological Chemistry, vol. 276, no. 16, 2001, pp. 13289-94.
Shakibaei M, Schulze-Tanzil G, de Souza P, et al. Inhibition of mitogen-activated protein kinase kinase induces apoptosis of human chondrocytes. J Biol Chem. 2001;276(16):13289-94.
Shakibaei, M., Schulze-Tanzil, G., de Souza, P., John, T., Rahmanzadeh, M., Rahmanzadeh, R., & Merker, H. J. (2001). Inhibition of mitogen-activated protein kinase kinase induces apoptosis of human chondrocytes. The Journal of Biological Chemistry, 276(16), 13289-94.
Shakibaei M, et al. Inhibition of Mitogen-activated Protein Kinase Kinase Induces Apoptosis of Human Chondrocytes. J Biol Chem. 2001 Apr 20;276(16):13289-94. PubMed PMID: 11278768.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of mitogen-activated protein kinase kinase induces apoptosis of human chondrocytes. AU - Shakibaei,M, AU - Schulze-Tanzil,G, AU - de Souza,P, AU - John,T, AU - Rahmanzadeh,M, AU - Rahmanzadeh,R, AU - Merker,H J, Y1 - 2001/01/16/ PY - 2001/3/30/pubmed PY - 2001/6/2/medline PY - 2001/3/30/entrez SP - 13289 EP - 94 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 276 IS - 16 N2 - We previously have reported that the mitogen-activated protein kinase (MAPK) pathway is stimulated by adhesion of human chondrocytes to anti-beta(1)-integrin antibodies or collagen type II in vitro. These mechanisms most likely prevent chondrocyte dedifferentiation to fibroblast-like cells and chondrocyte death. To investigate whether this pathway plays an essential role for the differentiation, phenotype, and survival of chondrocytes, we blocked mitogen-activated protein kinase/extracellular signal-regulated kinase (Erk) (MEK), a kinase upstream of the kinase Erk by using U0126. Exposure of chondrocytes to U0126 caused activation of caspase-3 in a dose-dependent manner. Western blot analysis with an antibody specific for dually phosphorylated Erk shows that collagen type II induced phosphorylation of Erk1/2 was specifically blocked by U0126 in a dose-dependent manner. Immunohistochemical analysis showed that treated chondrocytes were caspase-3 positive. In treated chondrocytes, the cleavage of 116-kDa poly(ADP-ribose)polymerase resulted in the 85-kDa apoptosis-related cleavage fragment and was associated with caspase-3 activity. Analysis by electron microscopy showed typical morphological signs of apoptosis, such as crescent-shaped clumps of heterochromatin, and a degraded pericellular matrix. Thus, these results indicate that the MEK/Erk signal transduction pathway is involved in the maintenance of chondrocytes differentiation and survival. These data stimulate further investigations on the role of mitogen-activated protein kinase pathways in human chondrocytes. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/11278768/Inhibition_of_mitogen_activated_protein_kinase_kinase_induces_apoptosis_of_human_chondrocytes_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=11278768 DB - PRIME DP - Unbound Medicine ER -