Receptor activator of nuclear factor kappa B ligand (RANKL): another link between breast and bone

Mice rendered null for the genes encoding receptor activator of nuclear factor kappa B ligand (RANKL) or its receptor, RANK, are osteopetrotic because of failure of osteoclast development. The failure of lactation owing to the lack of development of lobulo-alveolar structures during pregnancy, despite earlier stages of mammary gland development being normal, is now added to each of these phenotypes. The breast phenotype in RANKL-/- (but not in RANK-/-) mice is rescued by treatment of pregnant mice with RANKL, indicating a key role for these tumour necrosis factor (TNF) ligand and receptor family members in a crucial terminal step in breast development and lactation. Both RANKL and RANK are synthesized by mammary epithelial cells, with both prolactin and parathyroid hormone-related protein (PTHrP) able to enhance production of mRNA for RANKL. These findings reveal a paracrine-autocrine system in lactation control, with novel signalling pathways that reflect intercellular communication processes in bone.