RANK Ligand

About RANK Ligand:

RANKL aka RANK Ligand is receptor activator of nuclear factor kappa-Β ligand and also known as tumour necrosis factor ligand superfamily member 11 (TNFSF11), osteoclast differentiation factor (ODF), TNF-related activation-induced cytokine (TRANCE) and osteoprotegerin ligand (OPGL). It is a protein that is encoded by the TNFSF11 gene in humans.
RANKL is known as a type II membrane protein. It is a member of the tumour necrosis factor (TNF) superfamily. RANKL has been identified to control bone regeneration and modelling and also the immune system. RANKL is a binding partner of osteoprotegerin (OPG), a ligand for the receptor RANK, an apoptosis regulator gene and controls cell proliferation by modifying protein levels of ld4, ld2 and cyclin D1. RANKL is expressed in several organs and tissues such as skeletal muscle, liver, colon, adrenal gland, small intestine, thymus, osteoblast, mammary gland epithelial cells, pancreas and prostate. Variations in concentration levels of RANKL across several organs confirms the importance of RANKL in tissue growth and immune functions.

Function
RANKL is a part of the tumour necrosis factor (TNF) cytokine family. It binds to RANK on cells of the myeloid lineage and functions as a key factor for osteoclast differentiation and activation. RANKL can also bind to osteoprotegerin, a protein secreted mainly by cells of the osteoblast lineage and it is a potent inhibitor of osteoclast formation by preventing the binding of RANKL to RANK. RANKL also has functions in the immune system where it is expressed by T helper cells. It is thought to be involved in dendritic cell maturation. The protein is shown to be a dendritic cell survival factor and is involved in the regulation of T cell-dependent immune response. T cell activation was reported to induce expression of the gene and lead to an increase of osteoclastogenesis and bone loss. It was also shown to activate antiapoptotic kinase AKT/PKB through a signalling complex that involved SRC kinase and tumour necrosis factor receptor-associated factor 6 (TRAF6). This indicates that the protein may also have a role in the regulation of cell apoptosis.

Role in Cancer
Primary tumours commonly metastasize into the bone. Breast and prostate cancers have a greater chance of inducing secondary cancers within the bone. Stephen Paget’s seed and soil theory suggests that the microenvironment in bone creates a “soil2 for secondary tumours to grow in. Other studies suggest that the expression of RANKL allows sufficient micro environmental conditions to influence cancer cell migration (such as chronic lymphocytic leukaemia (CLL) and multiple myeloma). In patients with multiple myeloma, RANKL activity is greatly increased. RANKL surface expression and secreted RANKL expression was reported to be increased by 80% and 50% respectively. Therefore, RANKL is considered to be a key signal regulator for bone loss induced by cancer.