title: HLA-B27 alters the response to tumor necrosis factor α and promotes osteoclastogenesis in bone marrow monocytes from HLA-B27-transgenic rats.
abstract: OBJECTIVE
  To determine whether HLA-B27 expression alters the response of bone marrow monocytes from HLA-B27/human β2 -microglobulin-transgenic (B27-Tg) rats to tumor necrosis factor α (TNFα) and, if so, whether this affects the cells involved in bone homeostasis.
  
  
  METHODS
  Bone marrow monocytes were treated with RANKL or with TNFα to promote osteoclast formation. Osteoclasts were quantified by counting. Gene expression was measured using quantitative polymerase chain reaction analysis, and protein was detected by enzyme-linked immunosorbent assay, immunoblotting, or immunofluorescence. Effects of endogenously produced cytokines on osteoclast formation were determined with neutralizing antibodies.
  
  
  RESULTS
  TNFα treatment enhanced osteoclast formation 2.5-fold in HLA-B27-expressing cells as compared to wild-type or to HLA-B7/human β2 -microglobulin-expressing monocytes. TNFα induced ∼4-fold up-regulation of HLA-B27, which was associated with the accumulation of misfolded heavy chains, binding of the endoplasmic reticulum (ER) chaperone BiP, and activation of an ER stress response, which was not seen with HLA-B7. No differences were seen with RANKL-induced osteoclastogenesis. Enhanced interleukin-1α (IL-1α) production from ER-stressed bone marrow monocytes from B27-Tg rats was found to be necessary and sufficient for enhanced osteoclast formation. However, bone marrow monocytes from B27-Tg rats also produced more interferon-β (IFNβ), which attenuated the effect of IL-1α on osteoclast formation.
  
  
  CONCLUSIONS
  HLA-B27-induced ER stress alters the response of bone marrow monocytes from B27-Tg rats to TNFα, which is associated with enhanced production of IL-1α and IFNβ, cytokines that exhibit opposing effects on osteoclast formation. The altered response of cells expressing HLA-B27 to proinflammatory cytokines suggests that this class I major histocompatibility complex allele may contribute to the pathogenesis of spondyloarthritis and its unique phenotype through downstream effects involving alterations in bone homeostasis.
authors.affiliation: National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD 20892, USA.
authors.forename: Gerlinde
authors.initials: G
authors.lastname: Layh-Schmitt
authors.forename: Eva Y
authors.initials: EY
authors.lastname: Yang
authors.forename: Grace
authors.initials: G
authors.lastname: Kwon
authors.forename: Robert A
authors.initials: RA
authors.lastname: Colbert
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000378:metabolism; D001862:Bone Resorption / Q000188:drug therapy*; D059865:Endoplasmic Reticulum Stress; D005786:Gene Expression Regulation / Q000187:drug effects; D015796:HLA-B27 Antigen / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism; D053245:RANK Ligand / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D013167:Spondylitis, Ankylosing / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D015796:HLA-B27 Antigen; D053245:RANK Ligand; D014409:Tumor Necrosis Factor-alpha