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.

RANKL acts directly on RANK‐expressing prostate tumor cells and mediates migration and expression of tumor metastasis genes

“…The functional role of RANK on mammary epithelial cells [25] and tumors of epithelial origin [19,26,20] …”

The RANK/RANKL/osteoprotegerin system in rheumatoid arthritis: New insights from animal models

“…RANK, a heterotrimer containing 3 molecular intracellular domains (I, II, and III), belongs to the TNF receptor superfamily. It is expressed on the surface of hematopoietic osteoclast progenitors, mature osteoclasts, chondrocytes, mammary gland epithelial cells, trophoblast cells, dendritic cells (DCs), mature T cells, and hematopoietic precursors (4,20). Binding of RANK with its ligand RANKL results in osteoclastogenesis of monocyte/macrophage progenitor cells to osteoclasts and activation of mature osteoclasts (7,20).…”

“…It is expressed on the surface of hematopoietic osteoclast progenitors, mature osteoclasts, chondrocytes, mammary gland epithelial cells, trophoblast cells, dendritic cells (DCs), mature T cells, and hematopoietic precursors (4,20). Binding of RANK with its ligand RANKL results in osteoclastogenesis of monocyte/macrophage progenitor cells to osteoclasts and activation of mature osteoclasts (7,20). Of interest, synovial macrophages are able to differentiate in vitro into osteoclast-like cells in the presence of synovial fibroblast cells (5-7), which is comparable with the treatment of synovial macrophages with macrophage colony-stimulating factor (M-CSF) and RANKL to induce differentiation into osteoclast-like cells.…”

Progesterone signalling in breast cancer: a neglected hormone coming into the limelight

“…Amphiregulin is an essential paracrine mediator of the cell proliferation induced by ERα at puberty 53 and has also been linked to PR signalling in the rat mammary gland 54 ; WNT4 and receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL; also known as TNFSF11) have been established as important paracrine mediators of PR signalling 35,55,56 . Many other proteins have been implicated in mammary gland development by genetic experiments 43 but how they connect to hormonal control mechanisms remains to be established in most cases.…”

“…5b), a tumour necrosis factor-α (TNFα) family member that was first isolated as being important for dendritic cells, which was shown to be important for osteoclast function 70 . Subsequently, RANKL was implicated in mammary gland development 55 . Its abrogation in the mammary epithelium of mice resulted in a lactation defect, which was linked to prolactin receptor signalling via inhibitor of NF-κB kinase-α (IKKα) 71 .…”