title: The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development.
abstract: Osteoprotegerin-ligand (OPGL) is a key osteoclast differentiation/activation factor essential for bone remodeling. We report that mice lacking OPGL or its receptor RANK fail to form lobulo-alveolar mammary structures during pregnancy, resulting in death of newborns. Transplantation and OPGL-rescue experiments in opgl-/- and rank-/- pregnant females showed that OPGL acts directly on RANK-expressing mammary epithelial cells. The effects of OPGL are autonomous to epithelial cells. The mammary gland defect in female opgl-/- mice is characterized by enhanced apoptosis and failures in proliferation and PKB activation in lobulo-alveolar buds that can be reversed by recombinant OPGL treatment. These data provide a novel paradigm in mammary gland development and an evolutionary rationale for hormonal regulation and gender bias of osteoporosis in females.
authors.affiliation: Department of Medical Biophysics, Ontario Cancer Institute, University of Toronto, Canada.
authors.forename: J E
authors.initials: JE
authors.lastname: Fata
authors.forename: Y Y
authors.initials: YY
authors.lastname: Kong
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: T
authors.initials: T
authors.lastname: Sasaki
authors.forename: J
authors.initials: J
authors.lastname: Irie-Sasaki
authors.forename: R A
authors.initials: RA
authors.lastname: Moorehead
authors.forename: R
authors.initials: R
authors.lastname: Elliott
authors.forename: S
authors.initials: S
authors.lastname: Scully
authors.forename: E B
authors.initials: EB
authors.lastname: Voura
authors.forename: D L
authors.initials: DL
authors.lastname: Lacey
authors.forename: W J
authors.initials: WJ
authors.lastname: Boyle
authors.forename: R
authors.initials: R
authors.lastname: Khokha
authors.forename: J M
authors.initials: JM
authors.lastname: Penninger
mesh_terms: D000818:Animals; D016723:Bone Remodeling / Q000187:drug effects / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism / Q000637:transplantation; D005260:Female; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D012739:Gonadal Steroid Hormones / Q000378:metabolism / Q000494:pharmacology; D008321:Mammary Glands, Animal / Q000166:cytology / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010024:Osteoporosis / Q000209:etiology / Q000503:physiopathology; D053244:Osteoprotegerin; D010641:Phenotype; D010766:Phosphorylation; D011247:Pregnancy / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor
chemical_list: D002352:Carrier Proteins; D006023:Glycoproteins; D012739:Gonadal Steroid Hormones; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D011518:Proto-Oncogene Proteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505687:Tnfrsf11a protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt