Modulatory effects of inflammation and therapy on GDF-5 expression in rheumatoid arthritis synovium

Scand J Rheumatol. Nov-Dec 2008;37(6):401-9. doi: 10.1080/03009740802120010.

Abstract

Objective: Growth differentiation factor-5 (GDF-5), a member of the transforming growth factor (TGF)-beta family, is involved in joint development during embryogenesis and has the potential to regenerate cartilage in adult animals. As progression of chronic joint diseases is influenced by cytokines of the synovial tissue, we examined the expression and effects of GDF-5 in this tissue.

Methods: Microarray experiments were investigated for differential expression of GDF-5 in synovial tissues, synovial fibroblasts, and peripheral blood cells. GDF-5 expression was validated by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR), immunohistochemistry, double immunofluorescence, and in situ hybridization in synovial tissue of normal donors (ND) and patients with osteoarthritis (OA) and rheumatoid arthritis (RA). Effects of inflammation and therapy were investigated in RA and OA fibroblasts after stimulation with interleukin (IL)-1beta, tumour necrosis factor (TNF)-alpha, methotrexate (MTX), and prednisolone. The influence of GDF-5 on macrophages was studied by chemotaxis assay.

Results: Microarray analysis and immunostaining revealed expression predominantly in synovial fibroblasts. Compared to patients without immunomodulating drugs, expression of GDF-5 was decreased significantly in patients receiving glucocorticoids and/or disease-modifying antirheumatic drugs (DMARDs) (p = 0.007), but did not differ between the total group of ND, OA, and RA. Stimulation with prednisolone and TNFalpha reduced GDF-5 expression in OA and RA fibroblasts, whereas MTX and IL-1beta revealed minor or no relevant change. GDF-5 also reduced cell migration of macrophages (p<0.001).

Conclusion: GDF-5 is expressed in synovial fibroblasts and may counteract macrophage infiltration. Its modulation by inflammation and therapy suggests that glucocorticoids play a conflicting role by suppressing not only inflammation but also putative mechanisms of repair.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antirheumatic Agents / pharmacology
  • Antirheumatic Agents / therapeutic use*
  • Arthritis, Rheumatoid / drug therapy
  • Arthritis, Rheumatoid / metabolism*
  • Case-Control Studies
  • Cell Migration Assays, Macrophage
  • Cytokines / pharmacology
  • Down-Regulation
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Gene Expression
  • Glucocorticoids / pharmacology
  • Glucocorticoids / therapeutic use*
  • Growth Differentiation Factor 5 / metabolism*
  • Humans
  • Immunohistochemistry
  • Immunosuppression
  • In Situ Hybridization
  • Methotrexate / pharmacology
  • Methotrexate / therapeutic use
  • Middle Aged
  • Oligonucleotide Array Sequence Analysis
  • Prednisolone / pharmacology
  • Prednisolone / therapeutic use
  • Reverse Transcriptase Polymerase Chain Reaction
  • Synovial Membrane / drug effects
  • Synovial Membrane / metabolism*
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Antirheumatic Agents
  • Cytokines
  • Glucocorticoids
  • Growth Differentiation Factor 5
  • Tumor Necrosis Factor-alpha
  • Prednisolone
  • Methotrexate