Dual-specificity phosphatase 1-null mice exhibit spontaneous osteolytic disease and enhanced inflammatory osteolysis in experimental arthritis

Youridies Vattakuzhi, Sonya M Abraham, Andrew Freidin, Andrew R Clark, Nicole J Horwood

Research output: Contribution to journalArticle

24 Citations (Scopus)

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.

CONCLUSION: 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.

Original languageEnglish
Pages (from-to)2201-2210
Number of pages10
JournalArthritis and Rheumatism
Volume64
Issue number7
Early online date24 Jan 2012
DOIs
Publication statusPublished - Jul 2012

Keywords

  • Animals
  • Arthritis, Experimental/genetics
  • Arthritis, Rheumatoid/genetics
  • Dual Specificity Phosphatase 1/genetics
  • Inflammation/genetics
  • Joints/drug effects
  • Mice
  • Mice, Knockout
  • Osteoclasts/drug effects
  • Osteolysis/genetics
  • Severity of Illness Index
  • Tumor Necrosis Factor-alpha/pharmacology

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