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Focal adhesion kinase and mitogen-activated protein kinases are involved in chondrocyte activation by the 29-kDa amino-terminal fibronectin fragment.
J Biol Chem. 2002 Jan 11; 277(2):907-11.JB

Abstract

The 29-kDa amino-terminal fibronectin fragment (FN-f) has a potent chondrolytic effect and is thought to be involved in cartilage degradation in arthritis. However, little is known about signal transduction pathways that are activated by FN-f. Here we demonstrated that FN-f induced nitric oxide (NO) production from human articular chondrocytes. Expression of inducible nitric-oxide synthase (iNOS) mRNA and NO production were observed at 6 and 48 h after FN-f treatment, respectively. Interleukin-1beta (IL-1beta) mRNA up-regulation was stimulated by FN-f in human chondrocytes. To address the possibility that FN-f-induced NO release is mediated by IL-1beta production, the effect of IL-1 receptor antagonist (IL-1ra) was determined. IL-1ra partially inhibited FN-f-induced NO release although it almost completely inhibited IL-1beta-induced NO release. Tyrosine phosphorylation of focal adhesion kinase was induced transiently by FN-f treatment. Blocking antibodies to alpha(5) or beta(1) integrin and Arg-Gly-Asp-containing peptides did not inhibit FN-f-induced NO production. PP2, a Src family kinase inhibitor, or cytochalasin D, which selectively disrupts the network of actin filaments, inhibited both FAK phosphorylation and NO production induced by FN-f, but the phosphatidylinositol 3-kinase inhibitor wortmannin had no effect. Analysis of mitogen-activated protein kinases (MAPK) showed activation of extracellular signal-regulated kinase (ERK), c-Jun NH(2)-terminal kinase, and p38 MAPK. High concentrations of SB203580, which inhibit both JNK and p38 MAPK, and PD98059 a selective inhibitor of MEK1/2 that blocks ERK activation, inhibited FN-f induced NO production. These data suggest that focal adhesion kinase and MAPK mediate FN-f induced activation of human articular chondrocytes.

Authors+Show Affiliations

Division of Arthritis Research, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11677248

Citation

Gemba, Takefumi, et al. "Focal Adhesion Kinase and Mitogen-activated Protein Kinases Are Involved in Chondrocyte Activation By the 29-kDa Amino-terminal Fibronectin Fragment." The Journal of Biological Chemistry, vol. 277, no. 2, 2002, pp. 907-11.
Gemba T, Valbracht J, Alsalameh S, et al. Focal adhesion kinase and mitogen-activated protein kinases are involved in chondrocyte activation by the 29-kDa amino-terminal fibronectin fragment. J Biol Chem. 2002;277(2):907-11.
Gemba, T., Valbracht, J., Alsalameh, S., & Lotz, M. (2002). Focal adhesion kinase and mitogen-activated protein kinases are involved in chondrocyte activation by the 29-kDa amino-terminal fibronectin fragment. The Journal of Biological Chemistry, 277(2), 907-11.
Gemba T, et al. Focal Adhesion Kinase and Mitogen-activated Protein Kinases Are Involved in Chondrocyte Activation By the 29-kDa Amino-terminal Fibronectin Fragment. J Biol Chem. 2002 Jan 11;277(2):907-11. PubMed PMID: 11677248.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Focal adhesion kinase and mitogen-activated protein kinases are involved in chondrocyte activation by the 29-kDa amino-terminal fibronectin fragment. AU - Gemba,Takefumi, AU - Valbracht,Jean, AU - Alsalameh,Saifeddin, AU - Lotz,Martin, Y1 - 2001/10/24/ PY - 2001/10/26/pubmed PY - 2002/2/8/medline PY - 2001/10/26/entrez SP - 907 EP - 11 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 277 IS - 2 N2 - The 29-kDa amino-terminal fibronectin fragment (FN-f) has a potent chondrolytic effect and is thought to be involved in cartilage degradation in arthritis. However, little is known about signal transduction pathways that are activated by FN-f. Here we demonstrated that FN-f induced nitric oxide (NO) production from human articular chondrocytes. Expression of inducible nitric-oxide synthase (iNOS) mRNA and NO production were observed at 6 and 48 h after FN-f treatment, respectively. Interleukin-1beta (IL-1beta) mRNA up-regulation was stimulated by FN-f in human chondrocytes. To address the possibility that FN-f-induced NO release is mediated by IL-1beta production, the effect of IL-1 receptor antagonist (IL-1ra) was determined. IL-1ra partially inhibited FN-f-induced NO release although it almost completely inhibited IL-1beta-induced NO release. Tyrosine phosphorylation of focal adhesion kinase was induced transiently by FN-f treatment. Blocking antibodies to alpha(5) or beta(1) integrin and Arg-Gly-Asp-containing peptides did not inhibit FN-f-induced NO production. PP2, a Src family kinase inhibitor, or cytochalasin D, which selectively disrupts the network of actin filaments, inhibited both FAK phosphorylation and NO production induced by FN-f, but the phosphatidylinositol 3-kinase inhibitor wortmannin had no effect. Analysis of mitogen-activated protein kinases (MAPK) showed activation of extracellular signal-regulated kinase (ERK), c-Jun NH(2)-terminal kinase, and p38 MAPK. High concentrations of SB203580, which inhibit both JNK and p38 MAPK, and PD98059 a selective inhibitor of MEK1/2 that blocks ERK activation, inhibited FN-f induced NO production. These data suggest that focal adhesion kinase and MAPK mediate FN-f induced activation of human articular chondrocytes. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/11677248/Focal_adhesion_kinase_and_mitogen_activated_protein_kinases_are_involved_in_chondrocyte_activation_by_the_29_kDa_amino_terminal_fibronectin_fragment_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=11677248 DB - PRIME DP - Unbound Medicine ER -