Faculty Collaboration Database

Regulation of transglutaminase activity in articular chondrocytes through thrombin receptor-mediated factor XIII synthesis. Thromb Haemost 2004 Mar;91(3):558-68

Date

02/26/2004

Pubmed ID

14983233

DOI

10.1160/TH03-07-0462

Scopus ID

2-s2.0-1642346951 (requires institutional sign-in at Scopus site)   11 Citations

Abstract

Transglutaminases are a family of enzymes that catalyze the formation of epsilon-(gamma-glutamyl)lysine isopeptide bonds in proteins, an activity that has been implicated in the pathogenesis of cartilage matrix mineralization in degenerative arthritis. Type II transglutaminase and thrombin-activatable factor XIII have been identified in articular cartilage. Thrombin, a coagulation protease, is found in pathological synovial fluids, and is known to stimulate transglutaminase activity in non-articular tissues. We investigated the effects of thrombin on transglutaminase activity in porcine articular chondrocytes. Direct addition of thrombin to chondrocyte lysates resulted in increased transglutaminase activity due to proteolytic conversion of factor XIII to XIIIa. Thrombin-treated chondrocyte cultures (0.001 to 2.0 U/ml) also showed increased transglutaminase activity. Thrombin treatment of chondrocyte cultures increased transglutaminase activity as early as 15 minutes after addition, an effect that we attributed to factor XIII activation. Additional stimulatory effects of thrombin were observed in cultured chondrocytes at 4 and 24 hours. A thrombin receptor agonist peptide (TRAP) which activates the PAR1 thrombin receptor mimicked these later effects. Thrombin treatment of chondrocyte cultures increased factor XIII mRNA and protein levels, without affecting levels of type II transglutaminase. Thus, thrombin stimulates transglutaminase activity in articular cartilage by directly cleaving factor XIII and by receptor-mediated up-regulation of factor XIII synthesis. Such increases in potential transglutaminase activity may facilitate pathological matrix calcification in degenerative arthritis.

Author List

Rosenthal AK, Mosesson MW, Gohr CM, Masuda I, Heinkel D, Seibenlist KR

Author

Ann K. Rosenthal MD Associate Dean, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Arthritis
Cartilage
Chondrocytes
Coloring Agents
Dose-Response Relationship, Drug
Ethylmaleimide
Factor XIII
Factor XIIIa
Hirudins
Lyases
Proteoglycans
RNA, Messenger
Receptors, Thrombin
Reverse Transcriptase Polymerase Chain Reaction
Swine
Tetrazolium Salts
Thiazoles
Thrombin
Time Factors
Transglutaminases