Activin A induces cell proliferation of fibroblast-like synoviocytes in rheumatoid arthritis

Arthritis Rheum. 2003 Sep;48(9):2442-9. doi: 10.1002/art.11249.


Objective: To investigate the expression of activin A and its receptors in rheumatoid arthritis (RA) synovial tissues, and to determine the effect of activin A on cultured fibroblast-like synoviocytes (FLS).

Methods: The localization of activin A and activin type II receptor (ARII) in synovial tissues of RA patients was analyzed by immunohistochemistry. The expression of activin A and activin receptors in human cultured FLS was examined by reverse transcriptase-polymerase chain reaction and Western blotting. Enzyme-linked immunosorbent assay was used to measure activin A in culture supernatants. The cell growth of FLS was determined by (3)H-thymidine incorporation and MTT assay.

Results: Immunohistochemical analysis confirmed the up-regulation of activin A in rheumatoid synovium as compared with osteoarthritis or normal joint tissues. CD68+ macrophage-lineage cells and vimentin-positive FLS were identified as activin-producing cells in rheumatoid synovium. Both cell types also expressed ARII. The expression of activin A and ARII on cultured FLS was confirmed at the protein and messenger RNA levels. Interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha, and transforming growth factor beta activated FLS to secrete activin A. Recombinant activin A accelerated the proliferation of FLS, while follistatin, an endogenous activin antagonist, partially inhibited FLS proliferation induced by IL-1 beta.

Conclusion: These results suggest that activin A acts as a growth factor of FLS in RA.

MeSH terms

  • Activin Receptors / metabolism
  • Activins / metabolism
  • Activins / pharmacology*
  • Adult
  • Aged
  • Arthritis, Rheumatoid / metabolism*
  • Arthritis, Rheumatoid / pathology
  • Cell Division / drug effects
  • Cells, Cultured
  • Fibroblasts / cytology*
  • Fibroblasts / drug effects*
  • Fibroblasts / metabolism
  • Growth Substances / metabolism
  • Growth Substances / pharmacology
  • Humans
  • Immunohistochemistry
  • Inhibin-beta Subunits / metabolism
  • Inhibin-beta Subunits / pharmacology*
  • Middle Aged
  • Synovial Membrane / cytology
  • Synovial Membrane / metabolism
  • Up-Regulation


  • Growth Substances
  • activin A
  • Activins
  • Inhibin-beta Subunits
  • Activin Receptors