Participation of trans glutaminase in the activation of latent transforming growth factor beta 1 in aging articular cartilage

Objective. Transglutaminase (TGase) catalyzes the calcium-dependent crossli nking of polypeptide chains, resulting in posttranslational protein modific ations that affect both intracellular and extracellular processes. We previ ously demonstrated a dramatic elevation of TGase activity levels in aging a rticular chondrocytes and postulated a role for TGase in the pathologic pro cesses common in aging joints. In several cell systems, TGase participates in the activation of latent transforming growth factor beta (LTGF beta). Si nce TGF beta is a key factor in age-related cartilage diseases, the purpose of the present study was to determine whether TGase from aging articular c hondrocytes participates in LTGF beta activation. Methods. We measured the ability of old and young porcine articular chondro cytes to activate 10 ng/ml of LTGF beta 1 in the presence and absence of TG ase inhibitors. The activity of plasmin, another key participant in LTGF be ta activation, was also measured. Results. Old chondrocytes activated 11 +/- 1.8% (mean +/- SD) of exogenous LTGF beta 1 at 6 hours, while young chondrocytes activated 4.2 +/- 0.5% of exogenous LTGF beta 1. The addition of 3 different TGase inhibitors suppres sed active TGF beta 1 in the cell layer to levels that were 35-69% of contr ol values in old chondrocytes and had no effect on young chondrocytes. The ability to suppress TGF beta activation correlated with the ability of each of the TGase inhibitors to inhibit TGase activity. The activity of plasmin , which enzymatically activates LTGF beta 1, did not differ between young a nd old chondrocytes and was unaffected by TGase inhibition. Conclusion. We report here a novel pathologic function for TGase in aging a rticular cartilage. This work supports a role for elevated TGase activity i n age-related arthritis based in part on its participation in the activatio n of the critical growth factor TGF beta in articular cartilage.