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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bone Remodeling / drug effects
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Bone Remodeling / physiology
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cell Division / physiology
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Cell Survival / physiology
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Epithelial Cells / cytology
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Epithelial Cells / metabolism
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Epithelial Cells / transplantation
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Female
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Glycoproteins / genetics
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Glycoproteins / metabolism
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Gonadal Steroid Hormones / metabolism
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Gonadal Steroid Hormones / pharmacology
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Mammary Glands, Animal / cytology
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Mammary Glands, Animal / drug effects
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Mammary Glands, Animal / growth & development*
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Mammary Glands, Animal / metabolism*
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism*
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Mice
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Mice, Knockout
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Osteoporosis / etiology
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Osteoporosis / physiopathology
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Osteoprotegerin
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Phenotype
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Phosphorylation
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Pregnancy / metabolism
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins*
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RANK Ligand
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Receptor Activator of Nuclear Factor-kappa B
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Receptors, Cytoplasmic and Nuclear / genetics
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Receptors, Cytoplasmic and Nuclear / metabolism
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Receptors, Tumor Necrosis Factor
Substances
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Carrier Proteins
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Glycoproteins
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Gonadal Steroid Hormones
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Membrane Glycoproteins
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Osteoprotegerin
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Proto-Oncogene Proteins
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RANK Ligand
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Receptor Activator of Nuclear Factor-kappa B
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Receptors, Cytoplasmic and Nuclear
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Receptors, Tumor Necrosis Factor
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Tnfrsf11a protein, mouse
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Tnfrsf11b protein, mouse
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Tnfsf11 protein, mouse
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt