Osteoprotegerin reverses osteoporosis by inhibiting endosteal osteoclasts and prevents vascular calcification by blocking a process resembling osteoclastogenesis

High systemic levels of osteoprotegerin (OPG) in OPG transgenic mice cause osteopetrosis with normal tooth eruption and bone elongation and inhibit th e development and activity of endosteal, but not periosteal, osteoclasts. W e demonstrate that both intravenous injection of recombinant OPG protein an d transgenic overexpression of OPG in OPG(-/-) mice effectively rescue the osteoporotic bone phenotype observed in OPG-deficient mice. However, intrav enous injection of recombinant OPG over a 4-wk period could not reverse the arterial calcification observed in OPG-/- mice. In contrast, transgenic OP G delivered from mid-gestation through adulthood does prevent the formation of arterial calcification in OPG(-/-) mice. Although OPG is normally expre ssed in arteries, OPG ligand (OPGL) and receptor activator of NF-kappa B (R ANK) are not: detected in the arterial walls of wild-type adult mice. Inter estingly, OPGL and RANK transcripts are detected in the calcified arteries of OPG(-/-) mice. Furthermore, RANK transcript expression coincides with th e presence of multinuclear osteoclast-like cells. These findings indicate t hat the OPG/OPGL/RANK signaling pathway may play an important role in both pathological and physiological calcification processes. Such findings may a lso explain the observed high clinical incidence of vascular calcification in the osteoporotic patient population.