The role of the RANKL/RANK/OPG system in the central nervous systems (CNS)
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INVITED REVIEW
The role of the RANKL/RANK/OPG system in the central nervous systems (CNS) Reiko Hanada1 Received: 10 July 2020 / Accepted: 11 August 2020 © The Japanese Society Bone and Mineral Research and Springer Japan KK, part of Springer Nature 2020
Abstract The receptor-activator of NF-κB ligand (RANKL) and its specific receptor RANK have essential roles in regulating bone metabolism and the immune system. Besides, the RANKL/RANK system plays important roles in multiple physiological and pathophysiological processes such as mammary gland development during pregnancy, cancer development, and bone metastasis. While it has long been known that RANKL and RANK are expressed in the central nervous system (CNS), the physiological roles of RANKL/RANK system in the CNS and the underlying molecular mechanisms have been elucidated recently. Over the last decade, several reports showed that the central RANKL/RANK system plays important roles in regulating body temperature, brain ischemia, autoimmune encephalopathy, feeding behavior, and energy metabolism. In this review, it is provided an updated information regarding the roles of RANKL/RANK system in the CNS. Keywords RANKL/RANK system · CNS · Thermogenesis · Brain ischemia · EAE · Feeding behavior
Introduction The receptor activator of NF-κB ligand (RANKL, also known as TNFSF11; tumor necrosis factor ligand superfamily member 11, OPGL; osteoprotegerin ligand, TRANCE; TNF-related activation-induced cytokine, and ODF; osteoclast differentiation factor, CD245) is a 317-amino acid protein that belongs to tumor necrosis factor (TNF) superfamily cytokines [1, 2]. Together with its specific receptor RANK (also known as TNFRSF11A, TRANCE-R, ODFR; osteoclast differentiation factor receptor, ODAR; osteoclast differentiation and activation receptor, and CD265) and its soluble decoy receptor osteoprotegerin (OPG, also known as OCIF; osteoclastogenesis inhibitory factor or TNFRSF11B; tumour necrosis factor receptor superfamily member 11B), both of which belongs to the TNFR superfamily, RANKL is essential for osteoclastogenesis and regulation of the immune system [3–8]. Genetic ablation of both RANKL and RANK revealed a crosstalk between the skeletal system and the immune system and showed that immune cells can function as regulators of bone metabolism, leading to * Reiko Hanada reiko‑hanada@oita‑u.ac.jp 1
Department of Neurophysiology, Faculty of Medicine, Oita University, Idaigaoka 1‑1, Yufu City, Oita 879‑5593, Japan
the establishment of the “osteoimmunology” field [9–14]. Furthermore, the RANKL/RANK system also plays important roles in the development of lactating mammary glands [15], bone metastasis [16], and the development of progestin driven mammary cancer [17, 18] While it has long been known that RANKL and RANK are expressed in the central nervous system (CNS) [4, 19], its physiological roles remained unknown for years. Over the last decade, several studies revealed the physiological roles of the RANKL/RANK/OPG system in the CNS. This review describes the novel f
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