Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand

A receptor that mediates osteoprotegerin ligand (OPGL)-induced osteoclast d ifferentiation and activation has been identified via genomic analysis of a primary osteoclast precursor cell cDNA library and is identical to the tum or necrosis factor receptor (TNFR) family member RANK. The RANK mRNA was hi ghly expressed by isolated bone marrow derived osteoclast progenitors and b y mature osteoclasts in vivo. Recombinant OPGL binds specifically to RANK e xpressed by transfected cell lines and purified osteoclast progenitors. Tra nsgenic mice expressing a soluble RANK-Fc fusion protein have severe osteop etrosis because of a reduction in osteoclasts, similar to OPG transgenic mi ce. Recombinant RANK-Fc binds with high affinity to OPGL in vitro and block s osteoclast differentiation and activation in,vitro and in vivo. Furthermo re, polyclonal Ab against the RANK extracellular domain promotes osteoclast ogenesis in bone marrow cultures suggesting that RANK activation mediates t he effects of OPGL on the osteoclast pathway. These data indicate that OPGL -induced osteoclastogenesis is directly mediated through RANK on osteoclast precursor cells.