1LB5
36-398: 8792 21934 ENSG00000141655 ENSMUSG00000026321 Q9Y6Q6 O35305 NM_001270949 NM_001270950 NM_001270951 NM_001278268 NM_003839 NM_009399 NP_001257878 NP_001257879 NP_001257880 NP_001265197 NP_003830 NP_033425 Receptor activator of nuclear factor κ B ( RANK ), also known as TRANCE receptor or TNFRSF11A , is a member of
72-543: A biosimilar to Prolia; and Wyost (denosumab-bbdz), a biosimilar to Xgeva. In December 2009, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency issued a positive opinion for denosumab for the treatment of postmenopausal osteoporosis in women and for the treatment of bone loss in men with hormone ablation therapy for prostate cancer . Denosumab, as Prolia,
108-517: A TMD entirely (e.g. DcR3 ). In addition, most TNF receptors require specific adaptor protein such as TRADD , TRAF , RIP and FADD for downstream signalling. TNF receptors are primarily involved in apoptosis and inflammation , but they can also take part in other signal transduction pathways, such as proliferation , survival, and differentiation . TNF receptors are expressed in a wide variety of tissues in mammals, especially in leukocytes . The term death receptor refers to those members of
144-648: A length of 100 Angstroms which makes it the longest member of the TNFR family to date. The binding of RANKL to RANK trimerizes the receptor and activates a signaling pathway. The RANK-RANKL complex forms a heterohexameric complex. Only two of the four RANK CRDs are in direct contact with the RANKL. The majority of the complex's residues are hydrophilic. Unlike other members of the TNFSF, each surface interaction in RANK-RANKL
180-470: A loss of fever response to increased levels of RANKL. It has also been shown to be a critical mediator of fever response to lipopolysaccharide-induced fever and pro-inflammatory cytokines IL-1B and TNFa. This key role of the RANK-RANKL system may link the osteoporosis and hot flashes seen as symptoms of hormonal changes in post-menopausal women. RANK is constitutively expressed in mammary epithelial tissues. Calcium transferred from mother to fetus and neonate
216-591: A vicious cycle of bone destruction that is seen in metastatic bone tumors. Most therapies that target the RANK/RANKL/OPG axis aim to either down-regulate expression of RANKL or upregulate the expression of the decoy receptor OPG. For example, denosumab is a fully human monoclonal antibody that is directed against RANKL. In phase I and II trials, denosumab led to a decrease in bone resorption in multiple myeloma, prostate cancer and breast cancer patients. Another study looked into developing small mimetics based on
252-618: Is Samsung Bioepis NL B.V. Xbryk is a biosimilar medicinal product that is highly similar to the reference product Xgeva (denosumab), which was authorized in the EU in July 2011. Health Canada approved Jubbonti, a biosimilar to Prolia, in February 2024; and approved Wyost, a biosimilar to Xgeva, in March 2024. also known as RANKL . This protein was shown to be a dentritic cell survival factor and
288-495: Is Sandoz GmbH. In March 2024, the CHMP adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Wyost, intended for the prevention of bone complications in adults with advanced cancer involving bone and for the treatment of adults and skeletally mature adolescents with giant cell tumour of bone. The applicant for this medicinal product is Sandoz GmbH. Denosumab, as Wyost,a biosimilar,
324-668: Is a member of the tumor necrosis factor receptor (TNFR) superfamily. RANK is activated by RANKL (the RANK-Ligand), which exists as cell surface molecules on osteoblasts. Activation of RANK by RANKL promotes the maturation of pre-osteoclasts into osteoclasts. Denosumab inhibits this maturation of osteoclasts by binding to and inhibiting RANKL. Denosumab mimics the natural action of osteoprotegerin , an endogenous RANKL inhibitor, that presents with decreasing concentrations (and perhaps decreased effectiveness ) in people with osteoporosis. This protects bone from degradation, and helps to counter
360-454: Is a target for therapy in many diseases including estrogen deficiency-associated osteoporosis, rheumatoid arthritis, Paget's disease, periodontal disease, and bone tumors and malignancies. RANK has also been shown to be a key in the thermoregulation signaling in females, which seems to be regulated by ovarian sex hormones. RANK is expressed in key regions of the brain associated with thermoregulation. Inactivation of RANK in these regions causes
396-448: Is active in the body for only six months. Similarly to bisphosphonates , denosumab appears to be implicated in increasing the risk of osteonecrosis of the jaw (ONJ) following extraction of teeth or oral surgical procedures but, unlike bisphosphonate, the risk declines to zero approximately 6 months after injection. Invasive dental procedures should be avoided during this time. The most common side effects are joint and muscle pain in
SECTION 10
#1732797990643432-574: Is common in children. Vertebral compression fractures have also occurred in some people after discontinuing treatment. In August 2009, a meeting was held between Amgen and the Advisory Committee for Reproductive Health Drugs (ACRHD) of the U.S. Food and Drug Administration (FDA) to review the potential uses of denosumab. In October 2009, the FDA delayed approval of denosumab, stating that it needed more information. In June 2010, denosumab
468-702: Is continuous. TRAF6 has been shown to be imperative to the RANK-related osteoclastogenesis pathway. RANKL binds to RANK, which then binds to TRAF6. TRAF6 stimulates the activation of the c-jun N-terminal kinase (JNK) and nuclear factor kappa-b (NF-κB) pathways which trigger differentiation and activation of osteoclasts. This system is balanced by the relative expression of OPG to RANKL, which are highly regulated by many factors including hormones, immune signals, and growth factors. An overexpression of RANKL can cause an overproduction and activation of osteoclasts, which break down bone. The balance between RANKL and OPG
504-630: Is mediated by RANKL, but over-expression of RANK alone is sufficient to activate the NF-κB pathway. RANKL (receptor activator for nuclear factor κ B ligand) is found on the surface of stromal cells , osteoblasts , and T cells . Mutations affecting RANK have been associated with infantile malignant osteopetrosis in humans, mice and cats. RANK is a 616 amino acid type I transmembrane protein . Its extracellular domain consists of 184 amino acids, its transmembrane domain has 21 amino acids, and its cytoplasmic domain consists of 383 amino acids. Like other members of
540-493: Is provided by the degradation of the female bone by increased osteoclastic activity, which is regulated by the RANK/RANKL axis. RANKL also works through RANK to provide proliferative and survival signals to promote the final stages of lactating mammary gland development. Dysfunctional RANK or RANKL causes the arrest of differentiation and expansion of the alveolar bunds into mature lobulo-alveolar mammary structures, disabling
576-422: Is the process by which the body continuously removes old bone tissue and replaces it with new bone. It is driven by various types of cells, most notably osteoblasts (which secrete new bone) and osteoclasts (which break down bone); osteocytes are also present in bone. Precursors to osteoclasts, called pre-osteoclasts, express surface receptors called RANK (receptor activator of nuclear factor-kappa B ). RANK
612-436: Is unresectable or where resection would result in significant morbidity. In January 2024, the FDA added a black box warning to Prolia because of the risk of severe hypocalcemia in those with advanced kidney disease. An FDA review found that Prolia had resulted in "hospitalization, life-threatening events, and death" in that population. In March 2024, the FDA approved applications from Sandoz for Jubbonti (denosumab-bbdz),
648-440: The tumor necrosis factor receptor (TNFR) molecular sub-family. RANK is the receptor for RANK-Ligand ( RANKL ) and part of the RANK/RANKL/OPG signaling pathway that regulates osteoclast differentiation and activation. It is associated with bone remodeling and repair, immune cell function, lymph node development, thermal regulation, and mammary gland development. Osteoprotegerin (OPG) is a decoy receptor for RANKL, and regulates
684-576: The TNF receptor superfamily that contain a death domain , such as TNFR1, Fas receptor , DR4 and DR5 . They were named after the fact that they seemed to play an important role in apoptosis (programmed cell death), although they are now known to play other roles as well. In the strict sense, the term TNF receptor is often used to refer to the archetypal members of the superfamily, namely TNFR1 and TNFR2 , which recognize TNF-alpha. There are 27 family members, numerically classified as TNFRSF#, where # denotes
720-425: The TNFR family, it has four extracellular cysteine -rich pseudo-repeat domains (CRDs). It shares 40% amino acid identity with CD40 . RANK is encoded on human chromosome 18q22.1. It shows 85% homology between mouse and human homologues. There are two monomers of RANK related by noncrystallographic 2-fold symmetry perpendicular to the long axis of the molecules in the asymmetric unit. RANK contains four CRDs spanning
756-455: The ability to bind tumor necrosis factors (TNFs) via an extracellular cysteine -rich domain. With the exception of nerve growth factor (NGF), all TNFs are homologous to the archetypal TNF-alpha . In their active form, the majority of TNF receptors form trimeric complexes in the plasma membrane. Accordingly, most TNF receptors contain transmembrane domains (TMDs), although some can be cleaved into soluble forms (e.g. TNFR1 ), and some lack
SECTION 20
#1732797990643792-469: The arms or legs. Denosumab is an inhibitor of RANKL (receptor activator of nuclear factor kappa-Β ligand) , which works by decreasing the development of osteoclasts , which are cells that break down bone . It was developed by the biotechnology company Amgen . Denosumab is used for those with osteoporosis at high risk for fractures , bone loss due to certain medications, and in those with bone metastases . A 2012 meta-analysis found that denosumab
828-435: The arms or legs. There is an increased risk of infections such as cellulitis , hypocalcemia (low blood calcium), hypersensitivity allergy reactions, osteonecrosis of the jaw , and atypical femur fractures . Another trial showed significantly increased rates of eczema and hospitalization due to infections of the skin. It has been proposed that the increase in infections under denosumab treatment might be connected to
864-443: The member number, sometimes followed a letter. Denosumab Denosumab , sold under the brand names Prolia and Xgeva among others, is a human monoclonal antibody used for the treatment of osteoporosis , treatment-induced bone loss, metastases to bone, and giant cell tumor of bone . Denosumab is contraindicated in people with low blood calcium levels . The most common side effects are joint and muscle pain in
900-472: The production of milk. RANK and RANKL have been reported to be expressed in some breast cancer and prostate cancer cell lines. RANKL expression in infiltrating T cells within mammary carcinomas activate RANK-expressing neoplastic mammary epithelial cells which stimulate metastasis. The expression of RANKL in these cells and the expression of RANK in bone cells may be the biological presentation of Paget's seed and soil idea. The affinity for RANK of RANKL may be
936-430: The progression of the disease. It is contraindicated in people with hypocalcemia ; sufficient calcium and vitamin D levels must be reached before starting on denosumab therapy. Data regarding interactions with other drugs are missing. It is unlikely that denosumab exhibits any clinically relevant interactions. Denosumab works by lowering the hormonal message that leads to excessive osteoclast-driven bone removal and
972-460: The reason these cancers tend to metastasize to bone. Once the tumor is seeded in the bone, the tumor cells stimulate bone resorption by secreting factors such as RANKL or prompting the surrounding stroma to express growth factors. These growth factors then upregulate production of RANKL which leads to osteoclastogenesis and bone destruction. The destruction of bone releases more growth factors and RANKL which induces more osteoclastogenesis, triggering
1008-424: The role of RANKL in the immune system . RANKL is expressed by T helper cells , and is thought to be involved in dendritic cell maturation. Use of Prolia can increase the risk of severe hypocalcemia among those with advanced kidney disease, especially those on dialysis. Discontinuation of denosumab is associated with a rebound increase in bone turnover. In rare cases this has led to severe hypercalcemia, but
1044-486: The stimulation of the RANK signaling pathway by competing for RANKL. The cytoplasmic domain of RANK binds TRAFs 1, 2, 3, 5, and 6 which transmit signals to downstream targets such as NF-κB and JNK . RANK is constitutively expressed in skeletal muscle, thymus, liver, colon, small intestine, adrenal gland, osteoclast , mammary gland epithelial cells, prostate, vascular cell, and pancreas. Most commonly, activation of NF-κB
1080-521: The structure of OPG that bind to RANK as well as RANKL and cause defective coupling between the two. RANK has been shown to interact with: This article incorporates text from the United States National Library of Medicine , which is in the public domain . Tumor necrosis factor receptor The tumor necrosis factor receptor superfamily ( TNFRSF ) is a protein superfamily of cytokine receptors characterized by
1116-439: The treatment of osteoporosis in women who have been through menopause, treatment of bone loss linked to hormone ablation in men at increased risk of fractures, or treatment of bone loss associated with long-term treatment with systemic glucocorticoid. The applicant for this medicinal product is Samsung Bioepis NL B.V. Obodence is a biosimilar medicinal product that is highly similar to the reference product Prolia (denosumab), which
RANK - Misplaced Pages Continue
1152-506: Was approved by the FDA for use in postmenopausal women with risk of osteoporosis under the brand name Prolia, and in November 2010 as Xgeva for the prevention of skeleton-related events in people with bone metastases from solid tumors . Denosumab is the first RANKL inhibitor to be approved by the FDA. In June 2013, the FDA approved denosumab for treatment of adults and skeletally mature adolescents with giant cell tumor of bone that
1188-620: Was approved for medical use in the European Union in May 2010, and as Xgeva in July 2011. In March 2024, the CHMP adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Jubbonti, intended for the treatment of osteoporosis in women who have been through menopause and in men at increased risk of fractures whose bone loss is linked to hormone ablation or long-term treatment with systemic glucocorticoid. The applicant for this medicinal product
1224-430: Was approved for medical use in the European Union in May 2024 for all indications of denosumab treated by Xgeva.. Denosumab, as Jubbonti, a biosimilar, was approved for medical use in the European Union in May 2024 for all indications of denosumab treated by Prolia. In November 2024, the CHMP adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Obodence, intended for
1260-419: Was authorized in the EU in May 2010. In November 2024, the CHMP adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Xbryk, intended for the prevention of bone complications in adults with advanced cancer involving bone and for the treatment of adults and skeletally mature adolescents with giant cell tumor of bone. The applicant for this medicinal product
1296-400: Was better than placebo, zoledronic acid , and pamidronate , in reducing the risk of fractures in those with cancer. In those with postmenopausal osteoporosis denosumab decreases the risk of fractures but increases the risk of infection. A 2013 review concluded that it is a reasonable treatment for postmenopausal osteoporosis. A 2017 review did not find benefit in males. Bone remodeling
#642357