Osteoprotegerin (OPG) acts as an endogenous decoy receptor in tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis of fibroblast-like synovial cells

Abstract

SUMMARYWe examined the role of osteoprotegerin (OPG) on tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in rheumatoid fibroblast-like synovial cells (FLS). OPG protein concentrations in synovial fluid from patients with rheumatoid arthritis (RA) correlated with those of interleukin (IL)-1 b or IL-6. A similar correlation was present between IL-1 b and IL-6 concentrations. Rheumatoid FLS in vitro expressed both death domain-containing receptors [death receptor 4 (DR4) and DR5] and decoy receptors [decoy receptor 1 (DcR1) and DcR2]. DR4 expression on FLS was weak compared with the expression of DR5, DcR1 and DcR2. Recombinant TRAIL (rTRAIL) rapidly induced apoptosis of FLS. DR5 as well as DR4 were functional with regard to TRAIL-mediated apoptosis induction in FLS; however, DR5 appeared be more efficient than DR4. In addition to soluble DR5 (sDR5) and sDR4, OPG administration significantly inhibited TRAIL-induced apoptogenic activity. OPG was identified in the culture supernatants of FLS, and its concentration increased significantly by the addition of IL-1 b in a time-dependent manner. Neither IL-6 nor tumour necrosis factor (TNF)-a increased the production of OPG from FLS. TRAIL-induced apoptogenic activity towards FLS was reduced when rTRAIL was added without exchanging the culture media, and this was particularly noticeable in the IL-1 b -stimulated FLS culture; however, the sensitivity of FLS to TRAIL-induced apoptosis itself was not changed by IL-1 b . Interestingly, neutralization of endogenous OPG by adding anti-OPG monoclonal antibody (MoAb) to FLS culture restored TRAIL-mediated apoptosis. Our data demonstrate that OPG is an endogenous decoy receptor for TRAIL-induced apoptosis of FLS. In addition, IL-1 b seems to promote the growth of rheumatoid synovial tissues through stimulation of OPG production, which interferes with TRAIL death signals in a competitive manner.

On the TRAIL to therapeutic intervention in liver disease

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Different expression levels of TNF receptors on the rheumatoid synovial macrophages derived from surgery and a synovectomy as detected by a new flow cytometric analysis

“…We previously reported apoptosis (Kawakami et al 1999Miyashita et al 2003Miyashita et al , 2004Tamai et al 2006), cell differentiation ), cell proliferation (Eguchi et al 1992;Migita et al 2000Migita et al , 2001, signal transduction (Yamasaki et al , 2002, sensitivity to drugs , and protein expression of the rheumatoid synovial cells Tanaka et al 2004) using the long-time cultured synovial cells derived from the knee joint replacement surgery. As the cell population and the expression of TNF receptors both dramatically changed in the synovial cells derived from both surgery and a synovectomy after long-term cultures (Fig.…”

Soluble TRAIL is present at high concentrations in seminal plasma and promotes spermatozoa survival

“…TRAILR3 and TRAILR4 are considered as membrane neutralizing or regulatory receptors. Although OPG has been initially identified as a member of the soluble tumor necrosis factor (TNF)-receptor family, inhibiting RANKLmediated osteoclastogenesis, several in vitro studies have shown its ability to also neutralize TRAIL (Emery et al 1998, Miyashita et al 2004). …”