Abstract
A receptor that mediates osteoprotegerin ligand (OPGL)-induced osteoclast differentiation and activation has been identified via genomic analysis of a primary osteoclast precursor cell cDNA library and is identical to the tumor necrosis factor receptor (TNFR) family member RANK. The RANK mRNA was highly expressed by isolated bone marrow-derived osteoclast progenitors and by mature osteoclasts in vivo. Recombinant OPGL binds specifically to RANK expressed by transfected cell lines and purified osteoclast progenitors. Transgenic mice expressing a soluble RANK-Fc fusion protein have severe osteopetrosis because of a reduction in osteoclasts, similar to OPG transgenic mice. Recombinant RANK-Fc binds with high affinity to OPGL in vitro and blocks osteoclast differentiation and activation in vitro and in vivo. Furthermore, polyclonal Ab against the RANK extracellular domain promotes osteoclastogenesis in bone marrow cultures suggesting that RANK activation mediates the effects of OPGL on the osteoclast pathway. These data indicate that OPGL-induced osteoclastogenesis is directly mediated through RANK on osteoclast precursor cells.
MeSH terms
-
Animals
-
Bone Development
-
Calcium-Calmodulin-Dependent Protein Kinases / metabolism
-
Carrier Proteins*
-
Cell Differentiation / drug effects
-
Cell Line
-
Cloning, Molecular
-
Gene Expression Regulation, Developmental*
-
Glycoproteins / pharmacology*
-
Glycoproteins / physiology
-
Humans
-
Immunoglobulin G
-
JNK Mitogen-Activated Protein Kinases
-
Male
-
Membrane Glycoproteins*
-
Mice
-
Mice, Inbred Strains
-
Mice, Transgenic
-
Mitogen-Activated Protein Kinases*
-
Osteoclasts / cytology*
-
Osteoclasts / drug effects
-
Osteogenesis
-
Osteoprotegerin
-
RANK Ligand
-
Receptor Activator of Nuclear Factor-kappa B
-
Receptors, Cytoplasmic and Nuclear*
-
Receptors, Tumor Necrosis Factor / genetics
-
Receptors, Tumor Necrosis Factor / physiology*
-
Recombinant Fusion Proteins / metabolism
-
Recombinant Proteins / metabolism
-
Signal Transduction
-
Transcription, Genetic
-
Transfection
Substances
-
Carrier Proteins
-
Glycoproteins
-
Immunoglobulin G
-
Membrane Glycoproteins
-
Osteoprotegerin
-
RANK Ligand
-
Receptor Activator of Nuclear Factor-kappa B
-
Receptors, Cytoplasmic and Nuclear
-
Receptors, Tumor Necrosis Factor
-
Recombinant Fusion Proteins
-
Recombinant Proteins
-
TNFRSF11A protein, human
-
TNFRSF11B protein, human
-
TNFSF11 protein, human
-
Tnfrsf11a protein, mouse
-
Tnfrsf11b protein, mouse
-
Tnfsf11 protein, mouse
-
Calcium-Calmodulin-Dependent Protein Kinases
-
JNK Mitogen-Activated Protein Kinases
-
Mitogen-Activated Protein Kinases