Osteoprotegerin (OPG) is an essential secreted protein in bone turnover due to its role as a decoy receptor for the Receptor Activator of Nuclear Factor-kB ligand (RANKL) in the osteoclasts, thus inhibiting their differentiation. However, there are additional ligands of OPG that confer various biological functions. OPG can promote cell survival, cell proliferation and facilitates migration by binding TNF-related apoptosis inducing ligand (TRAIL), glycosaminoglycans or proteoglycans. A large number of in vitro, pre-clinical and clinical studies provide evidences of OPG involvement in vascular, bone, immune and tumor biology. This review describes an overview of the different OPG ligands regulating its biological functions.

Factor VIII-von Willebrand factor (FVIII·vWF) complex, a molecule involved in coagulation, can be physically associated with osteoprotegerin (OPG). OPG is an anti-osteoclastic protein and a soluble receptor for the proapoptotic protein TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), suggesting a potential role of FVIII·vWF complex in bone and cancer biology. We, thus, assessed the effects of FVIII·vWF complex on osteoclastogenesis and cell survival. We first evidenced that FVIII·vWF complex inhibited RANKL-induced osteoclastogenesis and enhanced the inhibitory effect of OPG. Interestingly, we revealed by surface plasmon resonance that FVIII·vWF complex bound to RANKL, whereas recombinant FVIII and vWF did not. By modeling, we showed that the OPG binding domain to the A1 domain of vWF was closely located and partially overlapped to its binding site to RANKL. Then, we demonstrated that FVIII·vWF complex cancelled the inhibitory activity of OPG on TRAIL-induced apoptosis and characterized interactions between these molecules. The present work evidenced a direct activity of FVIII·vWF complex on osteoclasts and on induced cell apoptosis, pointing out its potential involvement in physiological bone remodeling or in bone damages associated with severe hemophilia and cancer development.

We present a procedure that (i) automates the homology modeling of mammalian olfactory receptors (ORs) based on the six three-dimensional (3D) structures of G protein-coupled receptors (GPCRs) available so far and (ii) performs the docking of odorants on these models, using the concept of colony energy to score the complexes. ORs exhibit low-sequence similarities with other GPCR and current alignment methods often fail to provide a reliable alignment. Here, we use a fold recognition technique to obtain a robust initial alignment. We then apply our procedure to a human OR that we have previously functionally characterized. The analysis of the resulting in silico complexes, supported by receptor mutagenesis and functional assays in a heterologous expression system, suggests that antagonists dock in the upper part of the binding pocket whereas agonists dock in the narrow lower part. We propose that the potency of agonists in activating receptors depends on their ability to establish tight interactions with the floor of the binding pocket. We developed a web site that allows the user to upload a GPCR sequence, choose a ligand in a library and obtain the 3D structure of the free receptor and ligand–receptor complex (http://genome.jouy.inra.fr/GPCRautomodel).