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Abstract
1 Department of Medical Biophysics and, Department of Laboratory Medicine and Pathobiology, Ontario Cancer Institute, University of Toronto, Ontario M5G 2M9, Canada
2 Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang, Kyungbuk 790-784, South Korea
3 The Amgen Institute, Ontario Cancer Institute and, Departments of Medical Biophysics and Immunology, University of Toronto, Ontario M5G 2C1, Canada
4 Department of Cell Biology, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA
5 Department of Pathology, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA
**Correspondence: Young-Yun Kong, (phone)+82-562-279-2287, (fax)+82-562-279-2199
**Correspondence: Josef M. Penninger, (416) 204-2241 (phone), (416) 204-2278 (fax)
SummaryOsteoprotegerin-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.
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