Salubrinal reduces expression and activity of MMP13 in chondrocytes

Objective: Stress to the endoplasmic reticulum (ER) and inflammatory cytokines induce expression and activity of matrix metalloproteinase 13 (MMP13). Since a synthetic agent, salubrinal, is known to alleviate ER stress and attenuate nuclear factor kappa B (NF kappa B) signaling, we addressed a question whether upregulation of MMP13 by ER stress and cytokines is suppressed by administration of salubrinal. Methods: Using C28/12 human chondrocytes, we applied ER stress with tunicamycin and inflammatory distress with tumor necrosis factor alpha (TNF alpha) and interleukin 1 beta (IL1 beta). RNA interference with siRNA specific to NF kappa B p65 (RelA) was employed to examine a potential involvement of NF kappa B signaling in salubrinal's action in regulation of MMP13. We also employed primary human chondrocytes and evaluated MMP13 activity. Results: The result showed that tunicamycin activated p38 mitogen-activated protein kinase (MAPK), while inflammatory cytokines activated p38 MAPK and NF kappa B. In both cases, salubrinal significantly reduced expression and activity of MMP13. Silencing NF kappa B reduced inflammatory cytokine-driven upregulation of MMP13 activity. Conclusions: The results demonstrate that salubrinal downregulates expression and activity MMP13 through p38 and NF kappa B signaling, suggesting its potential usage to treat degenerative diseases such as osteoarthritis. (C) 2013 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.