title: Tumor necrosis factor alpha-mediated joint destruction is inhibited by targeting osteoclasts with osteoprotegerin.
abstract: OBJECTIVE
  To study the effects of osteoclast-targeted therapies, such as osteoprotegerin (OPG) and pamidronate, on joint inflammation and bone destruction using a tumor necrosis factor alpha (TNF alpha)-transgenic mouse model.
  
  
  METHODS
  Mice were placed into 5 groups that received either OPG, pamidronate, a combination of both agents, infliximab as a positive control, or phosphate buffered saline as a negative control. Treatment was initiated at the onset of arthritis, continued over 6 weeks, and thereafter, the clinical, radiologic, and histologic outcomes were assessed.
  
  
  RESULTS
  A significant improvement in clinical symptoms, as assessed by the reduction of paw swelling, was only found in the infliximab group, whereas all other treatment groups failed to show significant improvement. However, when assessing structural damage with radiographic analysis, a significant retardation of joint damage was evident in animals treated with OPG (55% reduction of erosions), pamidronate (50% reduction of erosions) the combination therapy of OPG and pamidronate (64% reduction of erosions), and with infliximab (66% reduction of erosions). Confirming these data, quantitative histologic analysis revealed a significant reduction in the size of bone erosions in all treatment groups (OPG 56%, pamidronate 53%, OPG and pamidronate 81%, and infliximab 46%) compared with the control group. Furthermore, a significant reduction of osteoclast numbers was seen in animals treated with OPG alone or in combination with pamidronate as well as in animals treated with infliximab.
  
  
  CONCLUSIONS
  These data suggest that OPG alone or in combination with bisphosphonates is an effective therapeutic tool for the prevention of TNF alpha-mediated destruction of bone by reducing the number of bone-resorbing cells in the inflammatory tissue.
authors.affiliation: University of Vienna, Vienna, Austria.
authors.forename: Kurt
authors.initials: K
authors.lastname: Redlich
authors.forename: Silvia
authors.initials: S
authors.lastname: Hayer
authors.forename: Andrea
authors.initials: A
authors.lastname: Maier
authors.forename: Colin R
authors.initials: CR
authors.lastname: Dunstan
authors.forename: Makiyeh
authors.initials: M
authors.lastname: Tohidast-Akrad
authors.forename: Susanne
authors.initials: S
authors.lastname: Lang
authors.forename: Birgit
authors.initials: B
authors.lastname: Türk
authors.forename: Peter
authors.initials: P
authors.lastname: Pietschmann
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Woloszczuk
authors.forename: Silva
authors.initials: S
authors.lastname: Haralambous
authors.forename: George
authors.initials: G
authors.lastname: Kollias
authors.forename: Günter
authors.initials: G
authors.lastname: Steiner
authors.forename: Josef S
authors.initials: JS
authors.lastname: Smolen
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001168:Arthritis / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000209:etiology* / Q000473:pathology; D001175:Arthrography; D002021:Buffers; D002452:Cell Count; D004164:Diphosphonates / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D006023:Glycoproteins / Q000627:therapeutic use*; D006801:Humans; D000069285:Infliximab; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D010010:Osteoclasts / Q000187:drug effects* / Q000473:pathology; D053244:Osteoprotegerin; D000077268:Pamidronate; D010710:Phosphates; D018160:Receptors, Cytoplasmic and Nuclear / Q000627:therapeutic use*; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D012965:Sodium Chloride / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology*
chemical_list: D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D002021:Buffers; D004164:Diphosphonates; D006023:Glycoproteins; D053244:Osteoprotegerin; D010710:Phosphates; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C506030:TNFRSF11B protein, human; C506031:Tnfrsf11b protein, mouse; D014409:Tumor Necrosis Factor-alpha; D012965:Sodium Chloride; D000069285:Infliximab; D000077268:Pamidronate