title: Dual-specificity phosphatase 1-null mice exhibit spontaneous osteolytic disease and enhanced inflammatory osteolysis in experimental arthritis.
abstract: OBJECTIVE
  Bone formation and destruction are usually tightly linked; however, in disorders such as rheumatoid arthritis, periodontal disease, and osteoporosis, elevated osteoclast activity leads to bone destruction. Osteoclast formation and activation are controlled by many signaling pathways, including p38 MAPK. Dual-specificity phosphatase 1 (DUSP-1) is a factor involved in the negative regulation of p38 MAPK. The purpose of this study was to examine the effect of Dusp1 deficiency on bone destruction.
  
  
  METHODS
  Penetrance, onset, and severity of collagen-induced arthritis were recorded in DUSP-1+/+ and DUSP-1-/- mice. Bone destruction was assessed by histologic and micro-computed tomographic examination of the joints. The in vitro formation and activation of osteoclasts from DUSP-1+/+ and DUSP-1-/- precursors were assessed in the absence or presence of tumor necrosis factor (TNF).
  
  
  RESULTS
  The formation and activation of osteoclasts in vitro in the presence of TNF were enhanced by Dusp1 gene disruption. DUSP-1-/- mice exhibited higher penetrance, earlier onset, and increased severity of experimental arthritis, accompanied by greater numbers of osteoclasts in inflamed joints and more extensive loss of bone. A DUSP-1-/- mouse colony of mixed genetic background also demonstrated striking spontaneous osteolytic destruction of distal phalanges.
  
  
  CONCLUSIONS
  DUSP-1 is a critical regulator of osteoclast activity and limits bone destruction in an experimental model of rheumatoid arthritis. Defects in the expression or activity of DUSP1 in humans may correlate with a propensity to develop osteolytic lesions in arthritis.
authors.affiliation: University of Oxford, Oxford, UK.
authors.forename: Youridies
authors.initials: Y
authors.lastname: Vattakuzhi
authors.forename: Sonya M
authors.initials: SM
authors.lastname: Abraham
authors.forename: Andrew
authors.initials: A
authors.lastname: Freidin
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Clark
authors.forename: Nicole J
authors.initials: NJ
authors.lastname: Horwood
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics* / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007596:Joints / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010014:Osteolysis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D012720:Severity of Illness Index; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D014409:Tumor Necrosis Factor-alpha; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse