title: RANK-Independent Osteoclast Formation and Bone Erosion in Inflammatory Arthritis.
abstract: Proinflammatory molecules promote osteoclast-mediated bone erosion by up-regulating local RANKL production. However, recent evidence suggests that combinations of cytokines, such as tumor necrosis factor (TNF) plus interleukin-6 (IL-6), induce RANKL-independent osteoclastogenesis. The purpose of this study was to better understand TNF/IL-6-induced osteoclast formation and to determine whether RANK is absolutely required for osteoclastogenesis and bone erosion in murine inflammatory arthritis.
  
  
  
  Myeloid precursors from wild-type (WT) mice or mice with either germline or conditional deletion of Rank, Nfatc1, Dap12, or Fcrg were treated with either RANKL or TNF plus IL-6. Osteoprotegerin, anti-IL-6 receptor (anti-IL-6R), and hydroxyurea were used to block RANKL, the IL-6R, and cell proliferation, respectively. Clinical scoring, histologic assessment, micro-computed tomography, and quantitative polymerase chain reaction (qPCR) were used to evaluate K/BxN serum-transfer arthritis in WT and RANK-deleted mice. Loss of Rank was verified by qPCR and by osteoclast cultures.
  
  
  
  TNF/IL-6 generated osteoclasts in vitro that resorbed mineralized tissue through a pathway dependent on IL-6R, NFATc1, DNAX-activation protein 12, and cell proliferation, but independent of RANKL or RANK. Bone erosion and osteoclast formation were reduced, but not absent, in arthritic mice with inducible deficiency of RANK. TNF/IL-6, but not RANKL, induced osteoclast formation in bone marrow and synovial cultures from animals deficient in Rank. Multiple IL-6 family members (IL-6, leukemia inhibitory factor, oncostatin M) were up-regulated in the synovium of arthritic mice.
  
  
  
  The persistence of bone erosion and synovial osteoclasts in Rank-deficient mice, and the ability of TNF/IL-6 to induce osteoclastogenesis, suggest that more than one cytokine pathway exists to generate these bone-resorbing cells in inflamed joints.
authors: Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors: William
authors: W
authors: O'Brien
authors: Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors: Brian M
authors: BM
authors: Fissel
authors: University of Massachusetts Medical School, Worcester.
authors: Yukiko
authors: Y
authors: Maeda
authors: Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors: Jing
authors: J
authors: Yan
authors: Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors: Xianpeng
authors: X
authors: Ge
authors: University of Massachusetts Medical School, Worcester.
authors: Ellen M
authors: EM
authors: Gravallese
authors: Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors: Antonios O
authors: AO
authors: Aliprantis
authors: Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors: Julia F
authors: JF
authors: Charles
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics* / Q000276:immunology; D001862:Bone Resorption / Q000235:genetics* / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006918:Hydroxyurea / Q000494:pharmacology; D066298:In Vitro Techniques; D015850:Interleukin-6 / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000235:genetics*; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics* / Q000276:immunology; D053244:Osteoprotegerin / Q000494:pharmacology; D053245:RANK Ligand / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics*; D017452:Receptors, IgG / Q000235:genetics; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D055114:X-Ray Microtomography
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D017452:Receptors, IgG; D019947:Receptors, Interleukin-6; C505687:Tnfrsf11a protein, mouse; D014409:Tumor Necrosis Factor-alpha; C484963:Tyrobp protein, mouse; D006918:Hydroxyurea