Nuclear factor (NF)-κB and its associated pathways are major molecular regulators of blood-induced joint damage in a murine model of hemophilia
Article first published online: 7 FEB 2013
© 2012 International Society on Thrombosis and Haemostasis
Journal of Thrombosis and Haemostasis
Volume 11, Issue 2, pages 293–306, February 2013
How to Cite
Nuclear factor (NF)-κB and its associated pathways are major molecular regulators of blood-induced joint damage in a murine model of hemophilia. J Thromb Haemost 2013; 11: 293–306., , , , , .
- Issue published online: 7 FEB 2013
- Article first published online: 7 FEB 2013
- Accepted manuscript online: 11 DEC 2012 10:28AM EST
- Manuscript Accepted: 26 NOV 2012
- Manuscript Received: 22 JUL 2012
- G.R.J. from the Department of Science of Technology
- Department of Biotechnology (DBT)
- Swarnajayanti Fellowship 2011
- nnovative Young Biotechnologist award 2010. Grant Numbers: BT/03/IYBA/2010, BT/PR14748/MED/12/491/2010, BT/01/COE/08/03
- mouse model;
The present study was designed to investigate the molecular signaling events from onset of bleeding through the development of arthropathy in a murine model of hemophilia A.
Methods and results
A sharp-injury model of hemarthrosis was used. A global gene expression array on joint-specific RNA isolated 3 h post-injury revealed nuclear factor-kappa B (NF-κB) as the major transcription factor triggering inflammation. As a number of genes encoding the cytokines, growth factors and hypoxia regulating factors are known to be activated by NF-κB and many of these are part of the pathogenesis of various joint diseases, we reasoned that NF-κB-associated pathways may play a crucial role in blood-induced joint damage. To further understand its role, we screened NF-κB-associated pathways between 1 h to 90 days after injury. After a single articular bleed, distinct members of the NF-κB family (NF-κB1/NF-κB2/RelA/RelB) and their responsive pro-inflammatory cytokines (IL−1β/IL−6/IFNγ/TNFα) were significantly up-regulated (> 2 fold, P < 0.05) in injured vs. control joints at the various time-points analyzed (1 h/3 h/7 h/24 h). After multiple bleeds (days 30/60/75/90), there was increased expression of NF-κB-associated factors that contribute to hypoxia (HIF-1α, 3.3−6.5 fold), angiogenesis (VEGF-α, 2.5−4.4 fold) and chondrocyte damage (matrix metalloproteinase−13, 2.8−3.8 fold) in the injured joints. Micro RNAs (miR) that are known to regulate NF-κB activation (miRs-9 and 155), inflammation (miRs-16, 155 and 182) and apoptosis (miRs-19a, 155 and 186) were also differentially expressed (−4 to +13-fold) after joint bleeding, indicating that the small RNAs could modulate the arthropathy phenotype.
These data suggest that NF-κB-associated signaling pathways are involved in the development of hemophilic arthropathy.