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-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. CONCLUSIONS: These data suggest that NF-κB-associated signaling pathways are involved in the development of hemophilic arthropathy.
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-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. CONCLUSIONS: These data suggest that NF-κB-associated signaling pathways are involved in the development of hemophilic arthropathy.
Authors: Junjiang Sun; Baolai Hua; Eric W Livingston; Sarah Taves; Peter B Johansen; Maureane Hoffman; Mirella Ezban; Dougald M Monroe; Ted A Bateman; Paul E Monahan Journal: Blood Date: 2016-12-30 Impact factor: 22.113
Authors: Vikas Bhat; Merissa Olmer; Shweta Joshi; Donald L Durden; Thomas J Cramer; Richard Fw Barnes; Scott T Ball; Tudor H Hughes; Mauricio Silva; James V Luck; Randy E Moore; Laurent O Mosnier; Annette von Drygalski Journal: Am J Hematol Date: 2015-10-08 Impact factor: 10.047
Authors: Paul E Monahan; Junjiang Sun; Tong Gui; Genlin Hu; William B Hannah; David G Wichlan; Zhijian Wu; Joshua C Grieger; Chengwen Li; Thipparat Suwanmanee; Darrel W Stafford; Carmen J Booth; Jade J Samulski; Tal Kafri; Scott W J McPhee; R Jude Samulski Journal: Hum Gene Ther Date: 2015-01-21 Impact factor: 5.695