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

Arthritis Rheum. 2012 Jul;64(7):2201-10. doi: 10.1002/art.34403.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • Tumor Necrosis Factor-alpha
  • Dual Specificity Phosphatase 1
  • Dusp1 protein, mouse