Evidence for uncoupling of inflammation and joint remodeling in a mouse model of spondylarthritis

Rik J. U. Lories, Inge Derese, Cosimo De Bari, Frank P. Luyten

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162 Citations (Scopus)


OBJECTIVE: To study the relationship between inflammation and remodeling by inhibiting tumor necrosis factor alpha (TNFalpha) in male DBA/1 mice with spontaneous arthritis, a model of spondylarthritis (SpA). METHODS: TNFalpha was inhibited using etanercept, a soluble TNF receptor. The efficacy of the dose used (25 micro g/mouse) was confirmed in methylated bovine serum albumin (mBSA)-induced monarthritis, a model of inflammation-driven joint destruction. Male DBA/1 mice with spontaneous arthritis were caged together from the age of 10 weeks onward and were treated twice weekly with etanercept. The incidence and clinical severity of disease were recorded. Mice were killed at age 25 weeks, and histomorphologic analysis was performed. The presence of TNFalpha, NF-kappaB, and Smad signaling was studied using immunohistochemistry. Entheseal endochondral bone formation was modeled using micromass cultures of periosteal cells. RESULTS: Etanercept inhibited mouse TNFalpha in vitro and in vivo. Etanercept treatment of mBSA-induced arthritis had a significant effect on the severity of disease. Etanercept did not affect the incidence or severity of spontaneous arthritis. Pathologic analysis revealed no differences between etanercept-treated and phosphate buffered saline-treated mice. TNFalpha-positive cells were observed in the synovium, in vessel-associated cells, in fibrocartilage, and in new cartilage. Activation of Smad signaling was observed in earlier stages of disease than was active NF-kappaB signaling. TNFalpha inhibited chondrogenesis in the micromass model. CONCLUSION: Inhibition of TNF did not affect the severity and incidence of joint ankylosis in a mouse model of SpA. Therefore, the process of entheseal ankylosis may be independent of TNF. New tissue formation in SpA could be considered an additional and specific therapeutic target.
Original languageEnglish
Pages (from-to)489-497
Number of pages9
JournalArthritis & Rheumatism
Issue number2
Early online date30 Jan 2007
Publication statusPublished - 1 Feb 2007


  • animals
  • ankylosis
  • antibodies
  • antirheumatic agents
  • bone morphogenetic proteins
  • cells, cultured
  • disease models, animal
  • disease progression
  • immunoglobulin G
  • inflammation
  • joints
  • male
  • mice
  • mice, inbred DBA
  • NF-kappa B
  • osteogenesis
  • receptors, tumor necrosis factor
  • severity of illness index
  • smad proteins
  • spondylarthritis
  • tumor necrosis factor-alpha


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