Receptor activator of nuclear factor kappa- ligand (RANKL), also known as tumor necrosis factor ligand superfamily member 11 (TNFSF11), TNF-related activation-induced cytokine (TRANCE), osteoprotegerin ligand (OPGL), and osteoclast differentiation factor (ODF), is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that in humans is encoded by the ''TNFSF11''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
RANKL is known as a type II
membrane protein
Membrane proteins are common proteins that are part of, or interact with, biological membranes. Membrane proteins fall into several broad categories depending on their location. Integral membrane proteins are a permanent part of a cell membrane ...
and is a member of the
tumor necrosis factor
Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
(TNF) superfamily.
RANKL has been identified to affect the
immune system
The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...
and control bone regeneration and remodeling. RANKL is an
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
regulator gene, a binding partner of
osteoprotegerin
Osteoprotegerin (OPG), also known as osteoclastogenesis inhibitory factor (OCIF) or tumour necrosis factor receptor superfamily member 11B (TNFRSF11B), is a cytokine receptor of the tumour necrosis factor (TNF) receptor superfamily encoded by the ...
(OPG), a
ligand
In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...
for the receptor
RANK
Rank is the relative position, value, worth, complexity, power, importance, authority, level, etc. of a person or object within a ranking, such as:
Level or position in a hierarchical organization
* Academic rank
* Diplomatic rank
* Hierarchy
* H ...
and controls cell proliferation by modifying protein levels of
Id4
ID4 is a protein coding gene. In humans, it encodes for the protein known as DNA-binding protein inhibitor ID-4.
This protein is known to be involved in the regulation of many cellular processes during both prenatal development and tumorigenesi ...
,
Id2
DNA-binding protein inhibitor ID-2 is a protein that in humans is encoded by the ''ID2'' gene.
Function
The protein encoded by this gene belongs to the inhibitor of DNA binding (ID) family, members of which are transcriptional regulators that ...
and
cyclin D1
Cyclin D1 is a protein that in humans is encoded by the ''CCND1'' gene.
Gene expression
The CCND1 gene encodes the cyclin D1 protein. The human CCND1 gene is located on the long arm of chromosome 11 (band 11q13). It is 13,388 base pairs lon ...
.
RANKL is expressed in several tissues and organs including: skeletal muscle, thymus, liver, colon, small intestine, adrenal gland, osteoblast, mammary gland epithelial cells, prostate and pancreas.
Variation in concentration levels of RANKL throughout several organs reconfirms the importance of RANKL in tissue growth (particularly bone growth) and immune functions within the body.
Tissue expression
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
The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of th ...
,
thymus
The thymus is a specialized primary lymphoid organ of the immune system. Within the thymus, thymus cell lymphocytes or ''T cells'' mature. T cells are critical to the adaptive immune system, where the body adapts to specific foreign invaders. ...
and
lymph nodes
A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that includ ...
. Low protein expression is found in
bone marrow
Bone marrow is a semi-solid tissue found within the spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It is composed of hematopoietic ce ...
, the
stomach
The stomach is a muscular, hollow organ in the gastrointestinal tract of humans and many other animals, including several invertebrates. The stomach has a dilated structure and functions as a vital organ in the digestive system. The stomach i ...
,
peripheral blood
Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the c ...
, the
spleen
The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes . , the
placenta
The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mater ...
,
leukocytes
White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
, the
heart
The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide t ...
, the
thyroid
The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans it is in the neck and consists of two connected lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the thyroid isthmus. The thy ...
, and
skeletal muscle
Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...
.
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
osteoblast
Osteoblasts (from the Greek language, Greek combining forms for "bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cell (biology), cells with a single Cell nucleus, nucleus that synthesize bone. However, in the p ...
s, serves to activate
osteoclast
An osteoclast () is a type of bone cell that breaks down bone tissue. This function is critical in the maintenance, repair, and remodeling of bones of the vertebral skeleton. The osteoclast disassembles and digests the composite of hydrated pro ...
s, which are critically involved in
bone resorption
Bone resorption is resorption of bone tissue, that is, the process by which osteoclasts break down the tissue in bones and release the minerals, resulting in a transfer of calcium from bone tissue to the blood.
The osteoclasts are multi-nucleated ...
. 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
An osteocyte, an oblate shaped type of bone cell with dendritic processes, is the most commonly found cell in mature bone. It can live as long as the organism itself. The adult human body has about 42 billion of them. Osteocytes do not divide and ...
is the major source of RANKL regulating bone remodeling.
RANKL derived from other cell types contributes to bone loss in conditions involving
inflammation
Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
such as
rheumatoid arthritis
Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involv ...
, and in
lytic lesions caused by
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
, such as in
multiple myeloma
Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, an ...
.
Gene and expression
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
An ectodomain is the domain of a membrane protein that extends into the extracellular space (the space outside a cell). Ectodomains are usually the parts of proteins that initiate contact with surfaces, which leads to signal transduction.A notable ...
.
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
An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...
.
Among the exons, Exon 1 encoded the intracellular and transmembrane protein domains and Exon 2-5 encoded the extracellular domains.
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.
While the function and significance of A kinase anchor protein 11(
AKAP11
A-kinase anchor protein 11 is an enzyme that in humans is encoded by the ''AKAP11'' gene.
Function
The A-kinase anchor proteins (AKAPs) are a group of structurally diverse proteins, which have the common function of binding to the regulatory s ...
) is presently unknown, AKAP11 is immediately upstream from RANKL for all species that has a RANKL gene.
The upstream of AKAP11 may suggest there is a complex regulator process that regulates the level of RANKL expression.
Function
RANKL is a member of the
tumor necrosis factor
Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
(TNF)
cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
family. It binds to RANK on cells of the myeloid lineage and functions as a key factor for
osteoclast
An osteoclast () is a type of bone cell that breaks down bone tissue. This function is critical in the maintenance, repair, and remodeling of bones of the vertebral skeleton. The osteoclast disassembles and digests the composite of hydrated pro ...
differentiation and activation. RANKL may also bind to
osteoprotegerin
Osteoprotegerin (OPG), also known as osteoclastogenesis inhibitory factor (OCIF) or tumour necrosis factor receptor superfamily member 11B (TNFRSF11B), is a cytokine receptor of the tumour necrosis factor (TNF) receptor superfamily encoded by the ...
, 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 cell
The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considere ...
s and is thought to be involved in
dendritic cell
Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. ...
maturation. It is a
dendritic cell
Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. ...
survival factor and helps regulate
T cell
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
-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
Tyrosine-protein kinase CSK also known as C-terminal Src kinase is an enzyme that, in humans, is encoded by the CSK gene. This enzyme phosphorylates tyrosine residues located in the C-terminal end of Src-family kinases (SFKs) including SRC, HC ...
and tumor necrosis factor receptor-associated factor 6 (
TRAF6
TRAF6 is a TRAF human protein.
Function
The protein encoded by this gene is a member of the TNF receptor associated factor (TRAF) protein family. TRAF proteins are associated with, and mediate signal transduction from members of the TNF recep ...
), indicating that RANKL may have a role in the regulation of
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
.
A further role for RANKL in immunity was found in sinusoidal
macrophage
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...
s in lymph nodes that alert the immune system to lymph-borne
antigen
In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...
s.
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.
[
]
Animal models
Targeted disruption of the related gene in mice led to severe osteopetrosis
Osteopetrosis, literally "stone bone", also known as marble bone disease or Albers-Schönberg disease, is an extremely rare Biological inheritance, inherited disease, disorder whereby the bones harden, becoming Density, denser, in contrast to mor ...
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.
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. Ultimately, impaired lobuloalveolar mammary structures resulted in death of the fetus. 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.
Role in cancer
Primary tumors A primary tumor is a tumor growing at the anatomical site where tumor progression began and proceeded to yield a cancerous mass. Most cancers develop at their primary site but then go on to metastasize or spread to other parts of the body. These fur ...
will commonly metastasize into the bone. Breast and prostate cancers typically have a greater chance of inducing secondary cancers within bone. Stephen Paget
Stephen Paget (17 July 1855 – 8 May 1926) was an English surgeon and pro-vivisection campaigner.[chronic lymphocytic leukemia
Chronic lymphocytic leukemia (CLL) is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell). Early on, there are typically no symptoms. Later, non-painful lymph node swelling, feeling tired, fever, nigh ...](_ ...<br></span></div>'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. <div class=)
(CLL) and multiple myeloma
Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, an ...
). 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. 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.
Clinical significance
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
Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involv ...
and psoriatic arthritis
Psoriatic arthritis is a long-term inflammatory arthritis that occurs in people affected by the autoimmune disease psoriasis. The classic feature of psoriatic arthritis is swelling of entire fingers and toes with a sausage-like appearance. Thi ...
. 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. 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. 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.
Denosumab
Denosumab is an FDA-approved fully human monoclonal antibody to RANKL and during pre-clinical trials was first used to treat postmenopausal patients suffering with osteoporosis (PMO). In denosumab's third stage of the FDA's clinical trial, it was shown to: (1) decrease bone turnover, (2) reduce fractures in the PMO population, and (3) increase bone mineral density. The anti-RANKL antibody, denosumab, is also approved for use in cancer settings, and in those indications, it is branded as Xgeva. In both prostate and breast cancer, denosumab has been shown to reduce cancer treatment–induced bone loss.
Prostate cancer
The HALT-prostate cancer trial (also known as NCT00089674) included 1468 non-metastatic prostate cancer patients who were currently receiving androgen deprivation therapy
Androgen deprivation therapy (ADT), also called androgen suppression therapy, is an antihormone therapy whose main use is in treating prostate cancer. Prostate cancer cells usually require androgen hormones, such as testosterone, to grow. ADT red ...
. Randomly selected patients were given either 60 mg of denosumab or calcium and vitamin D supplements. This was done to measure the effectiveness of preventing treatment-induced bone loss. The patients who received 60 mg of denosumab showed a +5.6% increased in bone mineral density and a 1.5% decrease in bone fracture rates.
Another clinical trial (NCT00321620) was established to determine the safety and effectiveness of using denosumab compared to zoledronic acid
Zoledronic acid, also known as zoledronate and sold under the brand name Zometa by Novartis among others, is a medication used to treat a number of bone diseases. These include osteoporosis, high blood calcium due to cancer, bone breakdown due ...
. In this trial, they used 1901 bone metastatic prostate patients whom were also suffering with other complication of bone diseases. Again, patients were randomized and some were given either 120 mg of denosumab or 4 mg of zoledronic acid. Patients who were given 120 mg of denosumab (in comparison to those who were given 4 mg of zoledronic acid) showed a greater increase in hypocalcemia, a greater resistance to bone turnover markers uNTx, a delay response in both pathological fractures and spinal cord compression. However, survival rates for both clinical groups were comparable.
Breast cancer
Hormone receptor positive breast cancer patients have a significant increased risk of complications such as osteopenia
Osteopenia, known as "low bone mass" or "low bone density", is a condition in which bone mineral density is low. Because their bones are weaker, people with osteopenia may have a higher risk of fractures, and some people may go on to develop osteop ...
and osteoporosis
Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone ...
. About two out of every three breast cancer patients are hormone receptor positive. In the past several years, denosumab has been used in clinical trials, primarily because a large population is affected by bone complication among those who have breast cancer.
252 patients enlisted in the HALT-BC clinical trial (also known as NCT00089661). In addition to receiving vitamin D and calcium supplements, half of the patients were randomly given 60 mg of denosumab while the other half were given a placebo. Patients given denosumab had an increase in lumbar spine
The lumbar vertebrae are, in human anatomy, the five vertebrae between the rib cage and the pelvis. They are the largest segments of the vertebral column and are characterized by the absence of the foramen transversarium within the transverse p ...
bone mineral density, a decrease in bone turnover markers, with no significant change in survival rates.
NCT00321464 was another phase III RCT. Similar to NCT00321620 (prostate), this trial measured the safety and efficacy of denosumab versus zoledronic acid
Zoledronic acid, also known as zoledronate and sold under the brand name Zometa by Novartis among others, is a medication used to treat a number of bone diseases. These include osteoporosis, high blood calcium due to cancer, bone breakdown due ...
. Both groups showed similar survival rates and adverse event frequency.
Multiple myeloma
Patients whom are diagnosed with multiple myeloma have approximately 80-100% chance of developing bone complications due to an increase in activity and/or formation of osteoclasts and a decrease activity of osteoblasts. In a stage II clinical trial, denosumab decreased bone turnover markers by blocking the RANKL/RANK pathway. Once this trial was completed, 1176 patients with either multiple myeloma or progressed cancers were entered into the stage III clinical trial (known as NCT00330759). The main objective of the NCT00330759 trial was to compare effects of patients who were given 120 mg of denosumab relative to patients give 4 mg of zoledronic acid. As a result of this trial, during a month period, patients who received denosumab had a decrease in pathological fractures and spinal cord compression; however, as time progressed it appear that denosumab had significantly delayed bone complications. In both breast and prostate cancers, patients in either denosumab or zoledronic acid groups both appeared to have comparable adverse events and survival rates.
Medroxyprogesterone acetate
Women with menopause have often been given various types of postmenopausal hormone therapies to prevent osteoporosis and reduce menopausal symptoms. Medroxyprogesterone acetate
Medroxyprogesterone acetate (MPA), also known as depot medroxyprogesterone acetate (DMPA) in injectable form and sold under the brand name Depo-Provera among others, is a hormonal medication of the progestin type. It is used as a method of bi ...
(MPA) is a synthetic progestin and was commonly used as a contraceptive or used as a hormone therapy for endometriosis or osteoporosis. Recent studies suggest, using MPA increases patient risks of developing breast cancer
Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a re ...
due to an increase expression of RANKL. MPA causes a substantial induction of RANKL in mammary-gland epithelial cells while deletion of RANKL decreases the incidence MPA-induced breast cancer. Hence inhibition of RANKL has potential for the prevention and treatment of breast cancer.
See also
* Cluster of differentiation
The cluster of differentiation (also known as cluster of designation or classification determinant and often abbreviated as CD) is a protocol used for the identification and investigation of cell surface molecules providing targets for immunophen ...
* RANK
Rank is the relative position, value, worth, complexity, power, importance, authority, level, etc. of a person or object within a ranking, such as:
Level or position in a hierarchical organization
* Academic rank
* Diplomatic rank
* Hierarchy
* H ...
* Osteoprotegerin
Osteoprotegerin (OPG), also known as osteoclastogenesis inhibitory factor (OCIF) or tumour necrosis factor receptor superfamily member 11B (TNFRSF11B), is a cytokine receptor of the tumour necrosis factor (TNF) receptor superfamily encoded by the ...
* Osteoimmunology
References
Further reading
link
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External links
RANKL Signaling Pathway
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{{Use dmy dates, date=April 2017
Cytokines
Clusters of differentiation