Human rheumatoid synovial fibroblasts promote osteoclastogenic activity by activating RANKL via TLR-2 and TLR-4 activation

Kyoung Woon Kim, Mi La Cho, Sang Heon Lee, Hye Joa Oh, Chang Min Kang, Ji Hyeon Ju, So Youn Min, Young Gyu Cho, Sung Hwan Park, Ho Youn Kim

Research output: Contribution to journalArticlepeer-review

121 Scopus citations


The interplay between the innate immune system and inflammatory bone destruction in the joints of individuals with rheumatoid arthritis (RA) remains unclear. This study was undertaken to explore the effect of toll-like receptor (TLR) signaling in fibroblast-like synoviocytes (FLS) on the expression of RANKL and induction of osteoclastogenic activity. The levels of RANKL mRNA and protein were measured using RT-PCR, real-time PCR, and immunostaining. Monocytes were cocultured with RA -FLS that had been stimulated with TLR ligands in fresh media and subsequently stained for tartrate-resistant acid phosphatase (TRAP) activity. Osteoclast molecule markers were measured using real-time PCR. Expression of TLR-2 and TLR-4 was higher in RA-FLS than in OA-FLS and normal skin fibroblasts. TLR-2 and TLR-4 ligands induced RANKL expression in RA-FLS. TLR stimulation of RA-FLS also induced the production of IL-1β and TNF-α to a lesser extent; however, it had no effect on IL-17 production. Inhibition of TLR induced IL-1β production, which partially reversed the upregulation of RANKL induced by TLR ligands. RA-FLS stimulated by TLR-2 and TLR-4 ligands and cocultured with human monocytes induced high levels of expression of TRAP, RANK, cathepsin K, calcitonin receptor, and matrix metalloproteinase-9, suggesting that RA-FLS promote osteoclast differentiation. Our results suggest that the TLR signaling pathway, through TLR-2 and TLR-4, induces RANKL expression in RA-FLS and the expression of RANKL promotes the differentiation of osteoclasts in RA synovium. Targeting specific TLRs may be a promising approach to prevent inflammatory bone destruction in the pathogenesis of RA.

Original languageEnglish (US)
Pages (from-to)54-64
Number of pages11
JournalImmunology Letters
Issue number1
StatePublished - May 15 2007


  • Autoimmune arthritis
  • FLS
  • Osteoclastogenesis
  • Toll-like receptor

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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