The many roles of RANKL-RANK signaling in bone, breast and cancer

Receptor activator of nuclear factor-κB ligand (RANKL), its signaling receptor RANK, and its natural decoy receptor OPG are members of the tumor necrosis factor (TNF) and TNF receptor superfamily and are best known for their essential role in controlling osteoclastogenesis. RANKL in bone has also been shown to serve as a chemoattractant for cancer cells, thus explaining the tropism of certain cancers such as breast and prostate cancer to preferentially metastasize to bone. Surprisingly, studies of genetically engineered mice demonstrated that RANKL-RANK signaling is also required for proper formation of a lactating mammary gland and, intriguingly, the development of mammary cancer. RANK-deficient mice show a markedly delayed development of hormoneand oncogen-driven tumorigenesis and RANKL-RANK signaling is required for the proliferation and survival of cancerous mammary epithelial cells. Here we review the physiological functions of RANKL-RANK and how this system might be a key to understanding breast cancer. IBMS BoneKEy. 2011 May;8(5):237-256. 2011 International Bone & Mineral Society The Classical Role of the RANKL-RANKOPG Axis in Bone Remodeling The discovery of three tumor necrosis factor (TNF) and TNF receptor family members revolutionized the understanding of bone biology since these molecules were shown to regulate osteoclastogenesis in normal bone homeostasis and also during the development of bone pathologies such as osteoporosis and arthritis. These molecules were the receptor activator of NF-κB ligand (RANKL) (1-4), its cognate signaling receptor RANK (1), and its natural decoy receptor osteoprotegerin (OPG) (5-7). OPG (also called osteoclastogenesis inhibitory factor (OCIF), TNFRSF11B, TR1, or FDRC1) was the first molecule from this TNF receptor family to be discovered and was shown to inhibit osteoclastogenesis in vitro and in vivo (6;7). OPG lacks the typical transmembrane-spanning domain of TNF receptors, is secreted as a soluble glycoprotein (~55kDa) and forms disulfidelinked homodimers of ~110 kDa. OPG message is found in the brain, liver, lung, heart, kidney, skeletal muscle, skin, intestines, calvaria, stomach, testis, and placenta (5-9). Deletion of OPG from the mouse germline results in early-onset osteoporosis (10;11), demonstrating a critical requirement for OPG in the maintenance of postnatal bone mass. Furthermore, this finding suggested that OPG might neutralize a TNF-related factor that would by itself stimulate osteoclast development. Soon this factor was cloned and named OPG ligand (OPGL) or ODF (osteoclast differentiation factor) (3;4). Later it was realized that OPGL/ODF is identical to a molecule named RANKL and TRANCE (TNF-related activation-induced cytokine) which was first cloned due to its strong upregulation in T cells following antigen receptor stimulation (1;2;4). Throughout this review, we will use the now commonly accepted name for this protein, i.e., RANKL. RANKL is a type II transmembrane protein containing a membrane-anchoring domain, a connecting stalk, and a receptor-binding IBMS BoneKEy. 2011 May;8(5):237-256 http://www.bonekey-ibms.org/cgi/content/full/ibmske;8/5/237 doi: 10.1138/20110512