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Predominant activation of MAP kinases and pro-destructive/pro-inflammatory features by TNF α in early-passage synovial fibroblasts via TNF receptor-1: failure of p38 inhibition to suppress matrix metalloproteinase-1 in rheumatoid arthritis
  1. Elke Kunisch1,
  2. Muktheshwar Gandesiri1,
  3. Reneé Fuhrmann2,
  4. Andreas Roth2,
  5. Rando Winter2,
  6. Raimund W Kinne1
  1. 1Experimental Rheumatology Unit, Department of Orthopaedics, Friedrich Schiller University Jena, Germany
  2. 2Clinic of Orthopaedics, Friedrich Schiller University Jena, Germany
  1. Correspondence to:
    Dr R W Kinne
    Experimental Rheumatology Unit, Department of Orthopaedics, Friedrich Schiller University Jena, Klosterlausnitzer Str. 81, D-07607 Eisenberg, Germany; raimund.w.kinne{at}


Objective: To examine the relative importance of tumour necrosis factor-receptor 1 (TNF-R1) and TNF-R2 and their signalling pathways for pro-inflammatory and pro-destructive features of early-passage synovial fibroblasts (SFB) from rheumatoid arthritis (RA) and osteoarthritis (OA).

Methods: Cells were stimulated with tumour necrosis factor (TNF)α or agonistic anti-TNF-R1/TNF-R2 monoclonal antibodies. Phosphorylation of p38, ERK and JNK kinases was assessed by western blot; proliferation by bromodesoxyuridine incorporation; interleukin (IL)6, IL8, prostaglandin E2 (PGE2) and matrix metalloproteinase (MMP)-1 secretion by ELISA; and MMP-3 secretion by western blot. Functional assays were performed with or without inhibition of p38 (SB203580), ERK (U0126) or JNK (SP600125).

Results: In RA- and OA-SFB, TNFα-induced phosphorylation of p38, ERK or JNK was exclusively mediated by TNF-R1. Reduction of proliferation and induction of IL6, IL8 and MMP-1 were solely mediated by TNF-R1, whereas PGE2 and MMP-3 secretion was mediated by both TNF-Rs. In general, inhibition of ERK or JNK did not significantly alter the TNFα influence on these effector molecules. In contrast, inhibition of p38 reversed TNFα effects on proliferation and IL6/PGE2 secretion (but not on IL8 and MMP-3 secretion). The above effects were comparable in RA- and OA-SFB, except that TNFα-induced MMP-1 secretion was reversed by p38 inhibition only in OA-SFB.

Conclusion: In early-passage RA/OA-SFB, activation of MAPK cascades and pro-inflammatory/pro-destructive features by TNFα is predominantly mediated by TNF-R1 and, for proliferation and IL6/PGE2 secretion, exclusively regulated by p38. Strikingly, RA-SFB are insensitive to p38 inhibition of MMP-1 secretion. This indicates a resistance of RA-SFB to the inhibition of pro-destructive functions and suggests underlying structural/functional alterations of the p38 pathway, which may contribute to the pathogenesis or therapeutic sensitivity of RA, or both.

  • ARA, American Rheumatism Association
  • BrdU, bromodesoxyuridine
  • FCS, fetal calf serum
  • IL, interleukin
  • DMEM, Dulbecco’s modified Eagle’s medium
  • mAbs, monoclonal antibodies
  • MAPK, mitogen-activated protein kinases
  • MMP, matrix metalloproteinase
  • OA, osteoarthritis
  • PBS, phosphate-buffered saline
  • PGE2, prostaglandin E2
  • RA, rheumatoid arthritis
  • SFB, synovial fibroblasts
  • TNF, tumour necrosis factor
  • TNF-receptor
  • synovial fibroblast
  • p38 MAP kinase
  • interleukin
  • matrix metalloproteinase

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  • Published Online First 11 January 2007

  • Elke Kunisch and Muktheshwar Gandesiri contributed equally to this work.

  • The study was supported by the German Federal Ministry of Education and Research (BMBF; grants FKZ 01ZZ9602, 01ZZ0105, and 010405 to RW Kinne, Interdisciplinary Centre for Clinical Research (IZKF) Jena, including a grant for junior researchers to E Kunisch; grants FKZ 0312704B and 0313652B to RW Kinne, Jena Centre for Bioinformatics; grant 01GS0413, NGFN-2 to RW Kinne), the German Research Foundation (DFG; grants KI 439/7-1 and KI 439/6-1 to RW Kinne), and a grant for the advancement of female scientists to E Kunisch (LUBOM Thuringia).

  • Competing interests: None.