RANKL
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Location (UCSC) | Chr 13: 42.56 – 42.61 Mb | Chr 14: 78.51 – 78.55 Mb | |||||||
PubMed search | [3] | [4] |
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Receptor activator of nuclear factor kappa-Β 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 that in humans is encoded by the TNFSF11 gene.[5][6]
RANKL is known as a type II membrane protein and is a member of the tumor necrosis factor (TNF) superfamily.[7] RANKL has been identified to affect the immune system and control bone regeneration and remodeling. RANKL is an apoptosis regulator gene, a binding partner of osteoprotegerin (OPG), a ligand for the receptor RANK and controls cell proliferation by modifying protein levels of Id4, Id2 and cyclin D1.[8][9] 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.[9] 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
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
Function
RANKL is a member of the
Animal models
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]
Role in cancer
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 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]
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).[21][22] 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.[21] 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.[21]
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.[23] 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.[21] 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.[21]
Another clinical trial (NCT00321620) was established to determine the safety and effectiveness of using denosumab compared to zoledronic acid.[24] 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.[21] 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.[21] However, survival rates for both clinical groups were comparable.[21]
Breast cancer
Hormone receptor positive breast cancer patients have a significant increased risk of complications such as osteopenia and osteoporosis. About two out of every three breast cancer patients are hormone receptor positive.[25] 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.[21][26] Patients given denosumab had an increase in lumbar spine bone mineral density, a decrease in bone turnover markers, with no significant change in survival rates.[21]
NCT00321464 was another phase III RCT.[27] Similar to NCT00321620 (prostate), this trial measured the safety and efficacy of denosumab versus zoledronic acid. Both groups showed similar survival rates and adverse event frequency.[21]
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.[20][21] In a stage II clinical trial, denosumab decreased bone turnover markers by blocking the RANKL/RANK pathway.[21] 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).[28] 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.[21] In both breast and prostate cancers, patients in either denosumab or zoledronic acid groups both appeared to have comparable adverse events and survival rates.[21]
Medroxyprogesterone acetate
Women with menopause have often been given various types of postmenopausal hormone therapies to prevent osteoporosis and reduce menopausal symptoms.[29] Medroxyprogesterone acetate (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 due to an increase expression of RANKL.[29] 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.[30][31]
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000120659 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000022015 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 9312132.
- S2CID 4373990.
- S2CID 25285776.
- PMID 22969763.
- ^ PMID 16356770.
- PMID 32040934. Retrieved 8 March 2022.
- PMID 21909103.
- PMID 26393791.
- S2CID 21188945.
- S2CID 908214.
- ^ PMID 23698708.
- ^ PMID 19716455.
- ^ a b "Entrez Gene: TNFSF11 tumor necrosis factor (ligand) superfamily, member 11".
- ^ PMID 31201093.
- PMID 11417967.
- ^ PMID 23139212.
- ^ PMID 21285392.
- S2CID 10465712.
- ^ "AMG 162 in the Treatment of Bone Loss in Subjects Undergoing Androgen-Deprivation Therapy for Non-metastatic Prostate Cancer". Nct00089674. ClinicalTrials.gov. 20 September 2018.
- ^ "Study of Denosumab vs. Zoledronic Acid to Treat Bone Metastases in Men With Hormone-refractory Prostate Cancer". Nct00321620. ClinicalTrials.gov. August 2018.
- ^ "Hormone therapy for breast cancer". Cancer.org. Archived from the original on 2 December 2016. Retrieved 31 January 2014.
- ^ "AMG 162 in the Treatment of Bone Loss in Subjects Undergoing Aromatase Inhibitor Therapy for Non-metastatic Breast Cancer". Nct00089661. ClinicalTrials.gov. 20 September 2018.
- ^ "A Study Comparing Denosumab vs. Zoledronic Acid for the Treatment of Bone Metastases in Breast Cancer Subjects". Nct00321464. ClinicalTrials.gov. 20 September 2018.
- ^ "Study of Denosumab vs. Zoledronic Acid to Treat Bone Metastases in Subjects With Advanced Cancer or Multiple Myeloma". Nct00330759. ClinicalTrials.gov. August 2018.
- ^ PMID 23938070.
- PMID 20881962.
- S2CID 4322105.
Further reading
- Whyte M (2006). "The long and the short of bone therapy". N Engl J Med. 354 (8): 860–3.
- Buckley KA, Fraser WD (2003). "Receptor activator for nuclear factor kappaB ligand and osteoprotegerin: regulators of bone physiology and immune responses/potential therapeutic agents and biochemical markers". Ann. Clin. Biochem. 39 (Pt 6): 551–6. PMID 12564836.
- Jeffcoate W (2005). "Vascular calcification and osteolysis in diabetic neuropathy-is RANK-L the missing link?". Diabetologia. 47 (9): 1488–92. PMID 15322748.
- Collin-Osdoby P (2005). "Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin". Circ. Res. 95 (11): 1046–57. S2CID 263573984.
- Whyte MP, Mumm S (2005). "Heritable disorders of the RANKL/OPG/RANK signaling pathway". Journal of Musculoskeletal & Neuronal Interactions. 4 (3): 254–67. PMID 15615493.
- Clohisy DR, Mantyh PW (2005). "Bone cancer pain and the role of RANKL/OPG". Journal of Musculoskeletal & Neuronal Interactions. 4 (3): 293–300. PMID 15615497.
- Anandarajah AP, Schwarz EM (2006). "Anti-RANKL therapy for inflammatory bone disorders: Mechanisms and potential clinical applications". J. Cell. Biochem. 97 (2): 226–32. S2CID 33543150.
- Baud'huin M, Duplomb L, Ruiz Velasco C, Fortun Y, Heymann D, Padrines M (2007). "Key roles of the OPG-RANK-RANKL system in bone oncology". Expert Rev Anticancer Ther. 7 (2): 221–32. S2CID 12283459.
- Yogo K, Ishida-Kitagawa N, Takeya T (2007). "Negative autoregulation of RANKL and c-Src signaling in osteoclasts". J. Bone Miner. Metab. 25 (4): 205–10. S2CID 32120753.
- Boyce BF, Xing L (2007). "Biology of RANK, RANKL, and osteoprotegerin". PMID 17634140.
- McClung M (2007). "Role of RANKL inhibition in osteoporosis". Arthritis Research & Therapy. 9 (Suppl 1): S3. PMID 17634142.
External links
- 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.