Investigating the Interaction between Osteoprotegerin and Rankl or Trail: Evidence for a Pivotal Role for Osteoprotegerin in Regulating Two Distinct Pathways
نویسندگان
چکیده
Osteoprotegerin (OPG) binds the ligand for receptor activator of nuclear factor kappa B (RANKL) to prevent association with its receptor RANK and inhibit osteoclast-mediated bone resorption. OPG has been reported, recently, to inhibit TNF-related apoptosisinduced ligand (TRAIL)-induced tumor cell apoptosis. This raises the possibility that OPG may play a unique role in regulating these two signalling pathways. However, there are little data on the interactions between OPG, RANKL and TRAIL and the relative affinity of OPG for these two ligands is unknown. In the present study we examined the ability of OPG to bind native human TRAIL and RANKL under physiological conditions. Native TRAIL was expressed in E. coli, purified to homogeneity and shown to induce human myeloma cell apoptosis. OPG inhibited native TRAIL from binding the TRAIL-R1 at 37C in vitro. Similarly, OPG prevented RANKL from binding to RANK. TRAIL also prevented OPGmediated inhibition of RANKL from binding RANK. The affinity of OPG for native TRAIL and RANKL at 37C was determined by plasmon surface resonance analysis. OPG had a binding affinity for TRAIL of 45 nM, whereas, the affinity of OPG for RANKL was 23 nM. These data suggest that OPG can bind both RANKL and TRAIL and that the affinity of OPG for these two ligands is of a similar order of magnitude. Furthermore, OPG prevented TRAIL-mediated reductions in cell viability, whereas TRAIL inhibited OPG–mediated inhibition of osteoclastogenesis in vitro. This highlights the pivotal role of OPG in regulating the biology of both RANKL and TRAIL.
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