| First Author | Sen D | Year | 2013 |
| Journal | J Thromb Haemost | Volume | 11 |
| Issue | 2 | Pages | 293-306 |
| PubMed ID | 23231432 | Mgi Jnum | J:195442 |
| Mgi Id | MGI:5484482 | Doi | 10.1111/jth.12101 |
| Citation | Sen D, et al. (2013) Nuclear factor (NF)-kappaB and its associated pathways are major molecular regulators of blood-induced joint damage in a murine model of hemophilia. J Thromb Haemost 11(2):293-306 |
| abstractText | BACKGROUND: 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-kappaB) 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-kappaB and many of these are part of the pathogenesis of various joint diseases, we reasoned that NF-kappaB-associated pathways may play a crucial role in blood-induced joint damage. To further understand its role, we screened NF-kappaB-associated pathways between 1 h to 90 days after injury. After a single articular bleed, distinct members of the NF-kappaB family (NF-kappaB1/NF-kappaB2/RelA/RelB) and their responsive pro-inflammatory cytokines (IL-1beta/IL-6/IFNgamma/TNFalpha) 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-kappaB-associated factors that contribute to hypoxia (HIF-1alpha, 3.3-6.5 fold), angiogenesis (VEGF-alpha, 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-kappaB 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. CONCLUSIONS: These data suggest that NF-kappaB-associated signaling pathways are involved in the development of hemophilic arthropathy. |
