The Ligand for Osteoprotegerin (OPGL) Directly Activates Mature Osteoclasts

Abstract

Osteoprotegerin (OPG) and OPG-ligand (OPGL) potently inhibit and stimulate, respectively, osteoclast differentiation (Simonet, W.S., D.L. Lacey, C.R. Dunstan, M. Kelley, M.-S. Chang, R. Luethy, H.Q. Nguyen, S. Wooden, L. Bennett, T. Boone, et al. 1997. Cell. 89:309–319; Lacey, D.L., E. Timms, H.-L. Tan, M.J. Kelley, C.R. Dunstan, T. Burgess, R. Elliott, A. Colombero, G. Elliott, S. Scully, et al. 1998. Cell. 93: 165–176), but their effects on mature osteoclasts are not well understood. Using primary cultures of rat osteoclasts on bone slices, we find that OPGL causes approximately sevenfold increase in total bone surface erosion. By scanning electron microscopy, OPGL-treated osteoclasts generate more clusters of lacunae on bone suggesting that multiple, spatially associated cycles of resorption have occurred. However, the size of individual resorption events are unchanged by OPGL treatment. Mechanistically, OPGL binds specifically to mature OCs and rapidly (within 30 min) induces actin ring formation; a marked cytoskeletal rearrangement that necessarily precedes bone resorption. Furthermore, we show that antibodies raised against the OPGL receptor, RANK, also induce actin ring formation. OPGL-treated mice exhibit increases in blood ionized Ca++ within 1 h after injections, consistent with immediate OC activation in vivo. Finally, we find that OPG blocks OPGL's effects on both actin ring formation and bone resorption. Together, these findings indicate that, in addition to their effects on OC precursors, OPGL and OPG have profound and direct effects on mature OCs and indicate that the OC receptor, RANK, mediates OPGL's effects.

The kiss of death: promises and failures of death receptors and ligands in cancer therapy

“…The receptor RANK (receptor activator of NF-B) is expressed on myeloid osteoclast precursors, mature osteoclasts and DCs, and the ligand, RANKL (TRANCE/OPGL/ODF), is found on T cells. [39][40][41] Like CD40, this receptor system lacks a death domain and has so far not been implicated in the induction of apoptosis. In contrast, it may deliver not only activation and differentiation but also survival signals to DCs, osteoclasts and their precursors.…”

Successful Treatment of an Adynamic Bone Disorder with Bone Morphogenetic Protein-7 in a Renal Ablation Model

“…Because PTH is not a particularly good stimulant of osteoblastic function (17-21), high levels of the hormone would be required to maintain remodeling rates. These elevations in bone remodeling become dystrophic because of PTH inhibition of osteoblast collagen production (17,19) and stimulation of RANKL (22,23).To test the hypothesis that CKD directly impairs bone remodeling in the absence of secondary hyperparathyroidism, we developed an ablative form of chronic kidney failure in the presence of normal Ca, Pi, and PTH levels. To maintain normal Ca and Pi levels to prevent PTH stimulation during kidney failure, we restricted dietary Pi and added calcitriol to (1) replace its deficiency; (2) stimulate Pi absorption; and (3)…”

Characterization of osteoclast precursors in human blood

“…OPGL, also known as TRANCE (TNF-related activation-induced cytokine) (Wong et al, 1997a), as RANKL (receptor activator of NF-kB ligand) (Anderson et al, 1997) and as ODF (osteoclast differentiation factor) , mediates the maturation of osteoclasts . OPG is a soluble receptor which inhibits OPGL-induced osteoclast formation and function in vivo and in vitro (Bucay et al, 1998;Fuller et al, 1998;Matsuzaki et al, 1998;Quinn et al, 1998;Burgess et al, 1999;. Overexpressing OPG transgenic mice (Simonet et al, 1997), as well as mice in which the OPGL gene is knocked out (Kong et al, 1999a), are osteopetrotic, whereas animals lacking OPG exhibit a high-turnover osteoporosis-like phenotype (Bucay et al, 1998).…”