Vol.18 No.4

Original Article

Tumor necrosis factor-α inhibits chondrogenic differentiation of synovial fibroblasts through p38 mitogen activating protein kinase pathways

Authors

Chiaki Okuma-Yoshioka1,2 , Hiroaki Seto1,2 , Yuho Kadono1 , Atsuhiko Hikita1 , Yasushi Oshima1 , Hisashi Kurosawa2 , Kozo Nakamura1 , Sakae Tanaka1

  • Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
  • Department of Orthopaedics, School of Medicine, Juntendo University, Tokyo, Japan
Received:

19 February 2008

Accepted:

10 March 2008

Published online:

25 April 2008

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Abstract

We previously reported that synovial fibroblastlike cells (SFs) can be differentiated into chondrocytes through activin receptor-like kinase (ALK) 3 activation. The aim of this study was to clarify the effect and signaling pathways of tumor necrosis factor (TNF)-α on the chondrogenic differentiation of SFs. Primary SFs from patients with rheumatoid arthritis (RA) were treated with recombinant human bone morphogenetic protein-2 or transduced with a constitutively active mutant of the ALK3 gene (ALK3CA) with or without TNF-α, and then cultured in pellets. Expression of chondrocyte-specific genes was analyzed by real-time polymerase chain reaction or by histological analysis. Inhibitors of mitogen-activating protein kinase (MAPK) pathways or adenovirus vectors carrying a dominant-negative mutant of the IjB kinase 2 gene (AxIKK2DN) were used to analyze the signaling pathways of TNF-α. Expression of chondrocyte-specific genes was induced in SFs either by rhBMP-2 treatment or by ALK3CA transduction, which was strongly suppressed by TNF-a treatment. TNF-a markedly increased the p38 MAPK pathways in SFs, and inhibition of p38 MAPK activation partially restored the inhibitory effect of TNF-α on the chondrogenic differentiation of SFs. Combination therapy BMP-2 and anti-TNF-α agents especially targeting p38 MAPK might be a good approach to stimulating neochondrogenesis in the damaged joints in RA.

Key words

Rheumatoid arthritis (RA) - Synovial fibroblast-like cell (SFs) - TNF-α - Chondrogenic differentiation - p38 MAPK