title: LGR4 is a receptor for RANKL and negatively regulates osteoclast differentiation and bone resorption.
abstract: Tumor necrosis factor (TNF) superfamily member 11 (TNFSF11, also known as RANKL) regulates multiple physiological or pathological functions, including osteoclast differentiation and osteoporosis. TNFRSF11A (also called RANK) is considered to be the sole receptor for RANKL. Herein we report that leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4, also called GPR48) is another receptor for RANKL. LGR4 competes with RANK to bind RANKL and suppresses canonical RANK signaling during osteoclast differentiation. RANKL binding to LGR4 activates the Gαq and GSK3-β signaling pathway, an action that suppresses the expression and activity of nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 1 (NFATC1) during osteoclastogenesis. Both whole-body (Lgr4(-/-)) and monocyte conditional knockout mice of Lgr4 (Lgr4 CKO) exhibit osteoclast hyperactivation (including elevation of osteoclast number, surface area, and size) and increased bone erosion. The soluble LGR4 extracellular domain (ECD) binds RANKL and inhibits osteoclast differentiation in vivo. Moreover, LGR4-ECD therapeutically abrogated RANKL-induced bone loss in three mouse models of osteoporosis. Therefore, LGR4 acts as a second RANKL receptor that negatively regulates osteoclast differentiation and bone resorption.
authors.affiliation: East China Normal University and Shanghai Changzheng Hospital Joint Research Center for Orthopedic Oncology, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
authors.forename: Jian
authors.identifier: 0000-0003-3583-0154
authors.initials: J
authors.lastname: Luo
authors.affiliation: East China Normal University and Shanghai Changzheng Hospital Joint Research Center for Orthopedic Oncology, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
authors.forename: Zhengfeng
authors.identifier: 0000-0003-2011-9466
authors.initials: Z
authors.lastname: Yang
authors.affiliation: East China Normal University and Shanghai Changzheng Hospital Joint Research Center for Orthopedic Oncology, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ma
authors.affiliation: East China Normal University and Shanghai Changzheng Hospital Joint Research Center for Orthopedic Oncology, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
authors.forename: Zhiying
authors.initials: Z
authors.lastname: Yue
authors.affiliation: East China Normal University and Shanghai Changzheng Hospital Joint Research Center for Orthopedic Oncology, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Lin
authors.affiliation: East China Normal University and Shanghai Changzheng Hospital Joint Research Center for Orthopedic Oncology, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
authors.forename: Guojun
authors.initials: G
authors.lastname: Qu
authors.affiliation: East China Normal University and Shanghai Changzheng Hospital Joint Research Center for Orthopedic Oncology, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
authors.forename: Jinping
authors.initials: J
authors.lastname: Huang
authors.affiliation: Shanghai Center for Bioinformation Technology, Shanghai Academy of Science and Technology, Shanghai, China.
authors.forename: Wentao
authors.initials: W
authors.lastname: Dai
authors.affiliation: East China Normal University and Shanghai Changzheng Hospital Joint Research Center for Orthopedic Oncology, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
authors.forename: Chenghai
authors.initials: C
authors.lastname: Li
authors.affiliation: East China Normal University and Shanghai Changzheng Hospital Joint Research Center for Orthopedic Oncology, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
authors.forename: Chunbing
authors.initials: C
authors.lastname: Zheng
authors.affiliation: East China Normal University and Shanghai Changzheng Hospital Joint Research Center for Orthopedic Oncology, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
authors.forename: Leqin
authors.initials: L
authors.lastname: Xu
authors.affiliation: East China Normal University and Shanghai Changzheng Hospital Joint Research Center for Orthopedic Oncology, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
authors.forename: Huaqing
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jiqiu
authors.initials: J
authors.lastname: Wang
authors.affiliation: East China Normal University and Shanghai Changzheng Hospital Joint Research Center for Orthopedic Oncology, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
authors.forename: Dali
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Molecular and Cellular Medicine, Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Siwko
authors.affiliation: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Josef M
authors.identifier: 0000-0002-8194-3777
authors.initials: JM
authors.lastname: Penninger
authors.affiliation: Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Ning
authors.affiliation: East China Normal University and Shanghai Changzheng Hospital Joint Research Center for Orthopedic Oncology, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.|Department of Orthopedic Oncology, Shanghai Changzheng Hospital, The Second Military Medical University, Shanghai, China.
authors.forename: Jianru
authors.initials: J
authors.lastname: Xiao
authors.affiliation: East China Normal University and Shanghai Changzheng Hospital Joint Research Center for Orthopedic Oncology, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.|Department of Molecular and Cellular Medicine, Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas, USA.
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016723:Bone Remodeling / Q000235:genetics*; D001862:Bone Resorption / Q000235:genetics*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D018212:Giant Cell Tumor of Bone / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D007963:Leukocytes, Mononuclear; D051379:Mice; D018345:Mice, Knockout; D062105:Molecular Docking Simulation; D050778:NFATC Transcription Factors / Q000378:metabolism; D061848:Optical Imaging; D010012:Osteogenesis / Q000235:genetics*; D010024:Osteoporosis / Q000235:genetics / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism*; D000067996:RAW 264.7 Cells; D060888:Real-Time Polymerase Chain Reaction; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D015398:Signal Transduction; D020349:Surface Plasmon Resonance; D055114:X-Ray Microtomography
chemical_list: C411562:LGR4 protein, human; C496200:LGR4 protein, mouse; D050778:NFATC Transcription Factors; D053245:RANK Ligand; D043562:Receptors, G-Protein-Coupled; D000071679:Glycogen Synthase Kinase 3 beta; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D002118:Calcium