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 Feb;11(2):293-306. doi: 10.1111/jth.12101.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytokines / metabolism
  • Disease Models, Animal
  • Factor VIII / genetics
  • Factor VIII / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Genotype
  • Hemarthrosis / blood
  • Hemarthrosis / etiology*
  • Hemarthrosis / genetics
  • Hemarthrosis / immunology
  • Hemarthrosis / pathology
  • Hemophilia A / blood
  • Hemophilia A / complications*
  • Hemophilia A / genetics
  • Inflammation / blood
  • Inflammation / immunology
  • Inflammation Mediators / metabolism
  • Knee Joint / metabolism*
  • Knee Joint / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • MicroRNAs / metabolism
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Phenotype
  • Reproducibility of Results
  • Signal Transduction*
  • Synovial Fluid / immunology
  • Synovial Fluid / metabolism
  • Time Factors


  • Cytokines
  • Inflammation Mediators
  • MicroRNAs
  • NF-kappa B
  • Factor VIII