title: Osteoprotegerin reverses osteoporosis by inhibiting endosteal osteoclasts and prevents vascular calcification by blocking a process resembling osteoclastogenesis.
abstract: High systemic levels of osteoprotegerin (OPG) in OPG transgenic mice cause osteopetrosis with normal tooth eruption and bone elongation and inhibit the development and activity of endosteal, but not periosteal, osteoclasts. We demonstrate that both intravenous injection of recombinant OPG protein and transgenic overexpression of OPG in OPG(-/-) mice effectively rescue the osteoporotic bone phenotype observed in OPG-deficient mice. However, intravenous injection of recombinant OPG over a 4-wk period could not reverse the arterial calcification observed in OPG(-/-) mice. In contrast, transgenic OPG delivered from mid-gestation through adulthood does prevent the formation of arterial calcification in OPG(-/-) mice. Although OPG is normally expressed in arteries, OPG ligand (OPGL) and receptor activator of NF-kappaB (RANK) are not detected in the arterial walls of wild-type adult mice. Interestingly, OPGL and RANK transcripts are detected in the calcified arteries of OPG(-/-) mice. Furthermore, RANK transcript expression coincides with the presence of multinuclear osteoclast-like cells. These findings indicate that the OPG/OPGL/RANK signaling pathway may play an important role in both pathological and physiological calcification processes. Such findings may also explain the observed high clinical incidence of vascular calcification in the osteoporotic patient population.
authors.affiliation: Department of Biosystems Analysis, Amgen, Incorporated, Thousand Oaks, California 91320, USA.
authors.forename: H
authors.initials: H
authors.lastname: Min
authors.forename: S
authors.initials: S
authors.lastname: Morony
authors.forename: I
authors.initials: I
authors.lastname: Sarosi
authors.forename: C R
authors.initials: CR
authors.lastname: Dunstan
authors.forename: C
authors.initials: C
authors.lastname: Capparelli
authors.forename: S
authors.initials: S
authors.lastname: Scully
authors.forename: G
authors.initials: G
authors.lastname: Van
authors.forename: S
authors.initials: S
authors.lastname: Kaufman
authors.forename: P J
authors.initials: PJ
authors.lastname: Kostenuik
authors.forename: D L
authors.initials: DL
authors.lastname: Lacey
authors.forename: W J
authors.initials: WJ
authors.lastname: Boyle
authors.forename: W S
authors.initials: WS
authors.lastname: Simonet
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000473:pathology; D015153:Blotting, Western; D015519:Bone Density / Q000502:physiology*; D016466:CHO Cells; D002114:Calcinosis / Q000503:physiopathology*; D056657:Cathepsin K; D002403:Cathepsins / Q000378:metabolism; D006224:Cricetinae; D005269:Femur / Q000033:anatomy & histology / Q000000981:diagnostic imaging / Q000378:metabolism; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism* / Q000648:ultrastructure; D010022:Osteopetrosis / Q000235:genetics / Q000378:metabolism*; D010024:Osteoporosis / Q000235:genetics / Q000378:metabolism*; D053244:Osteoprotegerin; D011859:Radiography; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D000071681:Tartrate-Resistant Acid Phosphatase
chemical_list: D006023:Glycoproteins; D007527:Isoenzymes; D016328:NF-kappa B; D053244:Osteoprotegerin; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; C506030:TNFRSF11B protein, human; C506031:Tnfrsf11b protein, mouse; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K; C534132:Ctsk protein, mouse