title: Proteasome inhibition aggravates tumor necrosis factor-mediated bone resorption in a mouse model of inflammatory arthritis.
abstract: OBJECTIVE
  The proteasome inhibitor bortezomib has potent anti-myeloma and bone-protective activity. Recently, bortezomib was shown to directly inhibit osteoclastogenesis. The aim of this study was to analyze the influence and therapeutic effect of bortezomib in a mouse model of inflammatory arthritis.
  
  
  METHODS
  Heterozygous human tumor necrosis factor α (hTNFα)-transgenic mice and their wild-type (WT) littermates were intravenously injected with 0.75 mg/kg of bortezomib or phosphate buffered saline twice weekly. The mice were assessed for clinical signs of arthritis. After 6 weeks of treatment, mice were analyzed for synovial inflammation, cartilage damage, bone erosions, and systemic bone changes. Osteoclast precursors from WT and hTNF-transgenic mice were isolated from bone marrow, treated with bortezomib, and analyzed for osteoclast differentiation, bone resorption, and expression of osteoclast-specific genes as well as apoptosis and ubiquitination.
  
  
  RESULTS
  Bortezomib-treated hTNF-transgenic mice showed moderately increased inflammatory activity and dramatically enhanced bone erosions associated with a significant increase in the number of synovial osteoclasts. Interestingly, bortezomib did not alter systemic bone turnover in either hTNF-transgenic mice or WT mice. In vitro, treatment with therapeutically relevant concentrations of bortezomib resulted in increased differentiation of monocytes into osteoclasts and more resorption pits. Molecularly, bortezomib increased the expression of TNF receptor-associated factor 6, c-Fos, and nuclear factor of activated T cells c1 in osteoclast precursors.
  
  
  CONCLUSIONS
  In TNF-mediated bone destruction, bortezomib treatment increased synovial osteoclastogenesis and bone destruction. Hence, proteasome inhibition may have a direct bone-resorptive effect via stimulation of osteoclastogenesis during chronic arthritis.
authors.affiliation: University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Polzer
authors.forename: Kirsten
authors.initials: K
authors.lastname: Neubert
authors.forename: Silke
authors.initials: S
authors.lastname: Meister
authors.forename: Benjamin
authors.initials: B
authors.lastname: Frey
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baum
authors.forename: Jörg H
authors.initials: JH
authors.lastname: Distler
authors.forename: Eva
authors.initials: E
authors.lastname: Gückel
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.forename: Reinhard E
authors.initials: RE
authors.lastname: Voll
authors.forename: Jochen
authors.initials: J
authors.lastname: Zwerina
mesh_terms: D000818:Animals; D001168:Arthritis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D001862:Bone Resorption / Q000188:drug therapy* / Q000276:immunology; D001842:Bone and Bones / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002358:Cartilage, Articular / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D002908:Chronic Disease; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D053244:Osteoprotegerin / Q000276:immunology / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000276:immunology* / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology*; D053245:RANK Ligand / Q000276:immunology / Q000378:metabolism; D013583:Synovial Membrane / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology*
chemical_list: D001897:Boronic Acids; D053244:Osteoprotegerin; D061988:Proteasome Inhibitors; D011719:Pyrazines; D053245:RANK Ligand; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex