RANKL

The level of RANKL expression does not linearly correlate to the effect of this ligand. High protein expression of RANKL is commonly detected in the lungs, thymus and lymph nodes. Low protein expression is found in bone marrow, the stomach, peripheral blood, the spleen, the placenta, leukocytes, the heart, the thyroid, and skeletal muscle.[9] While bone marrow expresses low levels of RANKL, RANKL plays a critical role for adequate bone metabolism. This surface-bound molecule (also known as CD254), found on osteoblasts, serves to activate osteoclasts, which are critically involved in bone resorption. Osteoclastic activity is triggered via the osteoblasts' surface-bound RANKL activating the osteoclasts' surface-bound receptor activator of nuclear factor kappa-B (RANK). Recent studies suggest that in postnatal bones, the osteocyte is the major source of RANKL regulating bone remodeling.[10][11][12][13] RANKL derived from other cell types contributes to bone loss in conditions involving inflammation such as rheumatoid arthritis, and in lytic lesions caused by cancer, such as in multiple myeloma.

RANKL can be expressed in three different molecular forms consisting of either a: (1) trimeric transmembrane protein, (2) primary secreted form, and (3) truncated ectodomain.[14] RANKL is identified as a part of the TNF family; RANKL is specifically categorized under the TNFSF11, the TNF ligand superfamily member. RANKL is composed of 314 amino acids and was originally described to have a gene sequence containing 5 exons.[15][16] Among the exons, Exon 1 encoded the intracellular and transmembrane protein domains and Exon 2-5 encoded the extracellular domains.[15] RANKL’s extracellular domains are similar to other TNF family members in regards to the structural homology and are able to cleave from the cell surface.[15] While the function and significance of A kinase anchor protein 11(AKAP11) is presently unknown, AKAP11 is immediately upstream from RANKL for all species that has a RANKL gene.[16] The upstream of AKAP11 may suggest there is a complex regulator process that regulates the level of RANKL expression.

RANKL is a member of the tumor 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 may also bind to osteoprotegerin, a protein secreted mainly by cells of the osteoblast lineage which is a potent inhibitor of osteoclast formation by preventing binding of RANKL to RANK. RANKL also has a function in the immune system, where it is expressed by T helper cells and is thought to be involved in dendritic cell maturation. It is a dendritic cell survival factor and helps regulate T cell-dependent immune responses. T cell activation induces RANKL expression and can lead to an increase of osteoclastogenesis and bone loss. RANKL can also activate the antiapoptotic kinase AKT/PKB through a signaling complex involving SRC kinase and tumor necrosis factor receptor-associated factor 6 (TRAF6), indicating that RANKL may have a role in the regulation of apoptosis.[17] A further role for RANKL in immunity was found in sinusoidal macrophages in lymph nodes that alert the immune system to lymph-borne antigens.[18] In addition to directly signaling through RANK for macrophage differentiation, RANKL activates the adjacent lymphatic endothelial cells to create a niche environment for these specialized immune cells.[18]

Targeted disruption of the related gene in mice led to severe osteopetrosis and a lack of osteoclasts. Deficient mice, with an inactivation of RANKL or its receptor RANK, exhibited defects in early differentiation of T and B lymphocytes, and failed to form lobulo-alveolar mammary structures during pregnancy.[9][17] It was observed that during pregnancy, RANK-RANKL signaling played a critical role in regulating skeletal calcium release; in which contributed to the hormone response that stimulated proliferation in the mammary cells.[9] Ultimately, impaired lobuloalveolar mammary structures resulted in death of the fetus.[9] Those who suffer from osteoporosis often have a cardiovascular defect, such as heart failure. Some studies suggest, since RANK-RANKL pathway regulates calcium release and homeostasis, RANK-RANKL signal could invertedly affect the cardiovascular system; thus, an explanation for the positive correlation between osteoporosis and cardiovascular deficiencies.[9]

Primary tumors will commonly metastasize into the bone. Breast and prostate cancers typically have a greater chance of inducing secondary cancers within bone.[19] Stephen Paget's seed and soil theory suggests, the microenvironment in bone creates a sufficient ‘soil’ for secondary tumors to grow in. Some studies suggest the expression of RANKL allows sufficient micro environmental conditions to influence cancer cell migration (i.e. chronic lymphocytic leukemia (CLL) and multiple myeloma).[20] Among patients with multiple myeloma, RANKL activity was greatly increased. In fact RANKL surface expression and secreted RANKL expression was reported to be increased, 80% and 50% respectively.[20] Therefore, RANKL is considered to be a key signal regulator for cancer-induced bone loss.

According to the vicious cycle hypothesis, after secondary tumors cells have migrated to bone, the tumor cell will secrete cytokines and growth factors that can act on osteoblast lineage cells. Since osteoblasts control the regulation of RANKL, the stimulation via cytokines and growth factors will then stimulate osteoblasts to increase the expression of RANKL, often while simultaneously reducing bone formation. The additional RANKL-mediated osteoclast frequency and activity will in turn increase secretion of growth factors, or matrix derived factors, which can ultimately increase tumor growth and bone destruction activity.

RANKL, through its ability to stimulate osteoclast formation and activity, is a critical mediator of bone resorption and overall bone density. Overproduction of RANKL is implicated in a variety of degenerative bone diseases, such as rheumatoid arthritis and psoriatic arthritis. In addition to degenerative bone diseases, bone metastases can also induce pain and other abnormal health complexities that can significantly reduce a cancer patient’s quality of life. Some examples of these complications that are a consequence of bone metastasis are: hypercalcemia, pathological fractures and spinal cord compression.[21] Some findings also suggest that some cancer cells, particularly prostate cancer cells, can activate an increase in bone remodeling and ultimately increase overall bone production.[21] This increase in bone remodeling and bone production increases the overall growth of bone metastasizes. The overall control of bone remodeling is regulated by the binding of RANKL with its receptor or its decoy receptor, respectively, RANK and OPG.[21]

• Cluster of differentiation
• RANK
• Osteoprotegerin
• Osteoimmunology

• RANKL Signaling Pathway
• RANKL+Protein at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Overview of all the structural information available in the PDB for UniProt: O14788 (Tumor necrosis factor ligand superfamily member 11) at the PDBe-KB.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.