RANKL Employs Distinct Binding Modes to Engage RANK and the Osteoprotegerin Decoy Receptor

Abstract

SUMMARY Osteoprotegerin (OPG) and receptor activator of nuclear factor kappa B (RANK) are members of the TNFR superfamily that regulate osteoclast formation and function by competing for RANK ligand (RANKL). RANKL promotes osteoclast development through RANK activation, while OPG inhibits this process by sequestering RANKL. For comparison, we solved crystal structures of RANKL with RANK, and RANKL with OPG. Complementary biochemical and functional studies reveal that the monomeric cytokine-binding region of OPG binds RANKL with ~500 fold higher affinity than RANK, and inhibits RANKL-stimulated osteoclastogenesis ~150 times more effectively, in part because the binding cleft of RANKL makes unique contacts with OPG. Several side chains as well as the C-D and D-E loops of RANKL occupy different orientations when bound to OPG versus RANK. High affinity OPG binding requires a 90s-loop Phe residue that is mutated in juvenile Paget’s disease. These results suggest cytokine plasticity may help to fine tune specific TNF-family cytokine/receptor pair selectivity.

Inflammatory osteolysis: a conspiracy against bone

“…RANK activation by RANKL depends upon cytokine-mediated trimerization of the receptor in a TNF receptor-associated factor 6-dependent (TRAF6-dependent) manner (14)(15)(16). RANKL/ RANK signaling induces MAP kinases and NF-κB, eventuating in the activation and expression of NFATc1, the key osteoclasto genic transcription factor (17)(18)(19)(20).…”

“…RANKL/ RANK signaling induces MAP kinases and NF-κB, eventuating in the activation and expression of NFATc1, the key osteoclasto genic transcription factor (17)(18)(19)(20). Elevation of RANKL abundance, which is typically the crucial event regulating bone resorption, is negatively regulated by osteoprotegerin (OPG) (21)(22)(23), a decoy receptor with a higher affinity for the osteoclastogenic cytokine than that of RANK; thus, RANKL binding to OPG effectively limits osteoclastogenesis (9,15). In fact, loss-of-function OPG mutations prompt a severe generalized osteolytic disorder known as juvenile Paget's disease (24).…”

Screening for Multiple Autoantibodies in Plasma of Patients with Breast Cancer

“…It is a secreted protein with no cytoplasmic domain or transmembrane (56,57) and it is a negative regulator of bone turnover (58). It is expressed in other tissues such as the skin, heart, stomach, lung, kidney, liver, intestines, and breast (59,60).…”

Regulation of bone and cartilage by adenosine signaling

“…These components form osteoid, which eventually undergoes mineralization [4][5][6][7]. Importantly, osteoblasts control osteoclast differentiation through expression of both surface and soluble receptor activator of NFkB Ligand (RANKL), a critical osteoclast differentiation factor, and through production of osteoprotegerin (OPG), a soluble receptor of RANKL which prevents the interaction of RANKL with its receptor [8][9][10]. Indeed, the RANKL/OPG ratio is a major determinant of bone mass [11].…”