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Osteoporosis
Published in Jason Liebowitz, Philip Seo, David Hellmann, Michael Zeide, Clinical Innovation in Rheumatology, 2023
Mazen Nasrallah, Marcy B. Bolster
Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor k-B ligand (RANKL), which binds to its receptor RANK on the surface of osteoclasts. By antagonizing the binding of RANKL to RANK, denosumab inhibits the activation and maturation of osteoclasts, and it likely reduces osteoclast survival.5 Denosumab was approved by the FDA in 2010 for the treatment of postmenopausal women at high risk of osteoporotic fractures, as well as those who are intolerant of or have failed other therapies, and it represented a milestone in bone health therapy by being the first approved monoclonal antibody therapy in osteoporosis.6 Denosumab is also approved for other indications, including men with high risk of fracture7 and glucocorticoid-induced osteoporosis.8
Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Developed by the biotechnology company Amgen, denosumab is a fully human monoclonal antibody used for the treatment of multiple myeloma, bone metastases, and giant cell tumor of the bone. In other therapeutic areas it is used for osteoporosis and treatment-induced bone loss. Denosumab is designed to inhibit RANKL (the RANK ligand), a protein that acts as the primary signal for bone loss. In many bone loss conditions, RANKL overwhelms the body’s natural defense mechanisms for bone destruction. By binding to RANKL, this antibody can reduce bone loss and improve outcome for a number of bone-related diseases.
Biochemistry of Exercise Training: Effects on Bone
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
Panagiota Klentrou, Rozalia Kouvelioti
The RANKL/RANK pathway is known for its roles in osteoclast maturation, bone modelling, and bone remodelling. Receptor activator of NF-kB (RANK), RANKL, and OPG are the main components of this signalling system. Interestingly, taking part in bone haemostasis is not the only effect of this pathway (13).
RANK pathway in cancer: underlying resistance and therapeutic approaches
Published in Journal of Chemotherapy, 2023
It acts as a ligand for the nuclear factor-kB receptor activator, causing the recruitment of TNF TRAF adaptor proteins and the activation of downstream pathways. OPG is a decoy receptor that controls this signaling cascade by interacting with the RANK/RANKL receptor. Other networks, which are active in diverse ways depending on the conditions, also regulate RANK/RANKL signaling. When osteoclasts mature into osteoclasts, RANK/RANKL signaling is activated. Postmenopausal osteoporosis and cancer-induced bone loss and disrupt this signaling system. The tumor microenvironment has many RANK/RANKL-expressing cells. The RANKL/RANK pathway is typically overexpressed in breast, prostate, endometrial, cervix, stomach, esophagus, bladder, thyroid, and other organ cancers. Patients with these cancers have a poor prognosis as well. Researchers discovered that RANK signaling is essential for the formation of Treg cells and the production of cytokines in both the innate and adaptive immune systems. Chemoresistance is established in vitro by RANK production, which activates several signal transduction pathways. When RANKL is suppressed, anti-CTLA-4 monoclonal antibodies are more successful in treating solid tumors and experimental metastases in mice. As a result, RANK inhibitors are increasingly being utilized with immunotherapy to sensitize cancers that have previously resisted such treatment [75]. More investigation into the immunomodulatory effects of RANK/RANKL suppression in conjunction with other treatment methods is required.
Receptor Activator of Nuclear Factor (Nf)-kb Ligand Promotes T Helper 17 Cell Differentiation through Fas
Published in Immunological Investigations, 2022
Zilin Cui, Rui Feng, Zirong Liu, Yehong Gong, Yamin Zhang
Receptor activator of nuclear factor (NF)-kB ligand (RankL) was first reported as a new member of the tumor necrosis factor (TNF) superfamily which is mainly expressed in tissues and cells such as osteoblasts, dendritic cells, stromal cells, and T cells. Its ligand is a receptor activator of NF-kB (Rank), expressed in mature dendritic cells, macrophages, osteoclasts, and T cells (Anderson et al. 1997; Bishop et al. 2009; Ji et al. 2009). In recent years, the Rank-RankL signaling pathway has attracted extensive attention in the immune system, especially the differentiation and functional regulation of immune cells. It has been shown that Rank-RankL signaling was closely related to Th17 differentiation and function. In a mouse rheumatoid arthritis model, IL-27 could inhibit the expression of RankL, thereby inhibiting the differentiation of CD4 + T cells into Th17 cells and reducing bone destruction (Kamiya et al. 2011). Another study reported that mesenchymal stem cells phagocytosed apoptotic cells and promoted the secretion of IL-17 of CD4 + T through enhancing the expression of RankL during differentiation into osteoblasts (Tso et al. 2010).
Targeting the RANK/RANKL pathway in autoimmune disease and malignancy: future perspectives
Published in Expert Review of Clinical Immunology, 2021
Receptor activator of nuclear factor-kappa B (RANK) is a member of the tumor necrosis factor alpha (TNFα) superfamily of cytokines; its only known ligand is RANKL, and their interaction triggers recruitment of TNF receptor-associated factor adaptor proteins and leads to the activation of an elevated number of downstream signaling pathways [1]. RANK/RANKL signaling is controlled by a decoy receptor, osteoprotegerin (OPG), that engages with RANK to bind RANKL; it therefore blocks its activation and allows for tight regulation of RANK signaling. RANK pathway is critical for the differentiation of bone-resorbing osteoclasts and is altered in disease processes such as osteoporosis [2]. Importantly, it also plays an important role in the immune responses, both adaptive and innate, and increases the release of specific cytokines [3]. Indeed, RANK and RANKL positive cells are commonly retrieved in pro-inflammatory environment, including both cancer and autoimmune diseases.