The ligand for osteoprotegerin (OPGL) directly activates mature osteoclasts.
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.
Burgess
T L
TL
Department of Mammalian Cell Molecular Biology, Amgen Inc., Thousand Oaks, California 91320-1789, USA. tburgess@amgen.com
Qian
Y
Y
Kaufman
S
S
Ring
B D
BD
Van
G
G
Capparelli
C
C
Kelley
M
M
Hsu
H
H
Boyle
W J
WJ
Dunstan
C R
CR
Hu
S
S
Lacey
D L
DL
D000199:Actins / Q000378:metabolism; D000818:Animals; D001862:Bone Resorption / Q000378:metabolism*; D001842:Bone and Bones / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism / Q000494:pharmacology*; D002417:Cattle; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006934:Hypercalcemia / Q000139:chemically induced / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D008855:Microscopy, Electron, Scanning; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects* / Q000648:ultrastructure; D010024:Osteoporosis / Q000378:metabolism; D053244:Osteoprotegerin; D053245:RANK Ligand; D051381:Rats; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism
D000199:Actins; D002352:Carrier Proteins; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505687:Tnfrsf11a protein, mouse; C506031:Tnfrsf11b protein, mouse; C506032:Tnfrsf11b protein, rat; C505689:Tnfsf11 protein, mouse