title: Nuclear factor (NF)-κB and its associated pathways are major molecular regulators of blood-induced joint damage in a murine model of hemophilia.
abstract: 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.
  
  
  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.affiliation: Department of Hematology, Christian Medical College, Vellore, Tamil Nadu, India.
authors.forename: D
authors.initials: D
authors.lastname: Sen
authors.forename: A
authors.initials: A
authors.lastname: Chapla
authors.forename: N
authors.initials: N
authors.lastname: Walter
authors.forename: V
authors.initials: V
authors.lastname: Daniel
authors.forename: A
authors.initials: A
authors.lastname: Srivastava
authors.forename: G R
authors.initials: GR
authors.lastname: Jayandharan
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005169:Factor VIII / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005838:Genotype; D006395:Hemarthrosis / Q000097:blood / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D006467:Hemophilia A / Q000097:blood / Q000150:complications* / Q000235:genetics; D007249:Inflammation / Q000097:blood / Q000276:immunology; D018836:Inflammation Mediators / Q000378:metabolism; D007719:Knee Joint / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D015203:Reproducibility of Results; D015398:Signal Transduction; D013582:Synovial Fluid / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D035683:MicroRNAs; D016328:NF-kappa B; D005169:Factor VIII