The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development

Cell. 2000 Sep 29;103(1):41-50. doi: 10.1016/s0092-8674(00)00103-3.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Remodeling / drug effects
  • Bone Remodeling / physiology
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Division / physiology
  • Cell Survival / physiology
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism
  • Epithelial Cells / transplantation
  • Female
  • Glycoproteins / genetics
  • Glycoproteins / metabolism
  • Gonadal Steroid Hormones / metabolism
  • Gonadal Steroid Hormones / pharmacology
  • Mammary Glands, Animal / cytology
  • Mammary Glands, Animal / drug effects
  • Mammary Glands, Animal / growth & development*
  • Mammary Glands, Animal / metabolism*
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Knockout
  • Osteoporosis / etiology
  • Osteoporosis / physiopathology
  • Osteoprotegerin
  • Phenotype
  • Phosphorylation
  • Pregnancy / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins*
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, Tumor Necrosis Factor

Substances

  • Carrier Proteins
  • Glycoproteins
  • Gonadal Steroid Hormones
  • Membrane Glycoproteins
  • Osteoprotegerin
  • Proto-Oncogene Proteins
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Tumor Necrosis Factor
  • Tnfrsf11a protein, mouse
  • Tnfrsf11b protein, mouse
  • Tnfsf11 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt