Cellular activity and signaling induced by osteoprotegerin in osteoclasts: involvement of receptor activator of nuclear factor kappaB ligand and MAPK.
Osteoprotegerin (OPG) is a decoy receptor for receptor activator of nuclear factor kappaB ligand (RANKL), an inducer of osteoclastogenesis via its receptor RANK. We recently demonstrated that OPG also exerts a direct effect in osteoclasts by regulating protease expression. Herein, we showed that OPG-induced pro-matrix metalloproteinase-9 activity was abolished by ras/MAPK inhibitors in purified osteoclasts. OPG induced the phosphorylation of p38 and ERK1/2 in RAW264.7 cells. Only p38 activation was totally abolished by a blocking anti-RANKL antibody or an excess of RANKL. Surface plasmon resonance experiments revealed that RANK, RANKL and OPG are able to form a tertiary complex. These results suggested a potential formation of a tertiary complex RANK-RANKL-OPG on osteoclasts. Thus, OPG is not only a soluble decoy receptor for RANKL but must be also considered as a direct effector of osteoclast functions.
Theoleyre
S
S
EE 99-01, Pathophysiology of Bone Resorption Laboratory and Therapy of Primitive Bone Tumors, Medicine Faculty, 1 rue G. Veil, 44035 Nantes cedex 01, France.
Wittrant
Y
Y
Couillaud
S
S
Vusio
P
P
Berreur
M
M
Dunstan
C
C
Blanchard
F
F
Rédini
F
F
Heymann
D
D
D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002460:Cell Line; D002478:Cells, Cultured; D004789:Enzyme Activation; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D008024:Ligands; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D061965:Matrix Metalloproteinase Inhibitors; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008958:Models, Molecular; D010010:Osteoclasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D053244:Osteoprotegerin; D010766:Phosphorylation; D053245:RANK Ligand; D011817:Rabbits; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor; D015398:Signal Transduction / Q000502:physiology; D020349:Surface Plasmon Resonance; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases
D002352:Carrier Proteins; D006023:Glycoproteins; D008024:Ligands; D061965:Matrix Metalloproteinase Inhibitors; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9