LGR4 is a receptor for RANKL and negatively regulates osteoclast differentiation and bone resorption

Nature Medicine

Volumn 22, Issue 5, 2016, Pages 539-546

  Luo, Jian ^a   Yang, Zhengfeng ^a   Ma, Yu ^a   Yue, Zhiying ^a   Lin, Hongyu ^a   Qu, Guojun ^a   Huang, Jinping ^a   Dai, Wentao ^b   Li, Chenghai ^a   Zheng, Chunbing ^a   Xu, Leqin ^a   Chen, Huaqing ^a   Wang, Jiqiu ^c   Li, Dali ^a   Siwko, Stefan ^d   Penninger, Josef M ^e   Ning, Guang ^c   Xiao, Jianru ^a,f   Liu, Mingyao ^a,d  

^a EAST CHINA NORMAL UNIVERSITY   (China)

^b SHANGHAI CENTER FOR BIOINFORMATION TECHNOLOGY   (China)

^c SHANGHAI JIAO TONG UNIVERSITY   (China)

^d TEXAS A AND M HEALTH SCIENCE CENTER   (United States)

^e ERICH SCHMID INSTITUTE OF MATERIALS SCIENCE   (Austria)

^f SECOND MILITARY MEDICAL UNIVERSITY   (China)

Author keywords

[No Author keywords available]

Indexed keywords

GLYCOGEN SYNTHASE KINASE 3BETA; LEUCINE RICH REPEAT CONTAINING G PROTEIN COUPLED RECEPTOR 4; OSTEOCLAST DIFFERENTIATION FACTOR; PROTEIN; TRANSCRIPTION FACTOR NFAT; UNCLASSIFIED DRUG; CALCIUM; G PROTEIN COUPLED RECEPTOR; GUANINE NUCLEOTIDE BINDING PROTEIN ALPHA SUBUNIT; LGR4 PROTEIN, HUMAN; LGR4 PROTEIN, MOUSE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; BONE EROSION; BONE MASS; CALCIUM TRANSPORT; CELL COUNT; CELL SIZE; CELL SURFACE; CONTROLLED STUDY; HUMAN; HUMAN CELL; MOUSE; NONHUMAN; OSTEOCLAST ACTIVITY; OSTEOCLASTOGENESIS; OSTEOLYSIS; OSTEOPOROSIS; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN EXPRESSION; PROTEIN PROTEIN INTERACTION; SIGNAL TRANSDUCTION; SURFACE AREA; ANIMAL; BONE DEVELOPMENT; BONE REMODELING; CELL CULTURE; CHROMATIN IMMUNOPRECIPITATION; ENZYME LINKED IMMUNOSORBENT ASSAY; FLOW CYTOMETRY; FLUORESCENCE IMAGING; GENETICS; HEK293 CELL LINE; IMMUNOPRECIPITATION; KNOCKOUT MOUSE; METABOLISM; MICRO-COMPUTED TOMOGRAPHY; MOLECULAR DOCKING; MONONUCLEAR CELL; OSTEOCLASTOMA; RAW 264.7 CELL LINE; REAL TIME POLYMERASE CHAIN REACTION; SURFACE PLASMON RESONANCE; WESTERN BLOTTING;

ANIMALS; BLOTTING, WESTERN; BONE REMODELING; BONE RESORPTION; CALCIUM; CELLS, CULTURED; CHROMATIN IMMUNOPRECIPITATION; ENZYME-LINKED IMMUNOSORBENT ASSAY; FLOW CYTOMETRY; GIANT CELL TUMOR OF BONE; GLYCOGEN SYNTHASE KINASE 3 BETA; GTP-BINDING PROTEIN ALPHA SUBUNITS, GQ-G11; HEK293 CELLS; HUMANS; IMMUNOPRECIPITATION; LEUKOCYTES, MONONUCLEAR; MICE; MICE, KNOCKOUT; MOLECULAR DOCKING SIMULATION; NFATC TRANSCRIPTION FACTORS; OPTICAL IMAGING; OSTEOGENESIS; OSTEOPOROSIS; RANK LIGAND; RAW 264.7 CELLS; REAL-TIME POLYMERASE CHAIN REACTION; RECEPTORS, G-PROTEIN-COUPLED; SIGNAL TRANSDUCTION; SURFACE PLASMON RESONANCE; X-RAY MICROTOMOGRAPHY;

EID: 84963610126     PISSN: 10788956     EISSN: 1546170X     Source Type: Journal    
DOI: 10.1038/nm.4076     Document Type: Article

References (44)

1. Kong, Y.Y., et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397, 315-323 (1999
2. Hanada, R., Hanada, T., Sigl, V., Schramek, D., & Penninger, J.M. RANKL/RANK-beyond bones. J. Mol. Med. 89, 647-656 (2011
3. Fata, J.E., et al. The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell 103, 41-50 (2000
4. Jones, D.H., et al. Regulation of cancer cell migration and bone metastasis by RANKL. Nature 440, 692-696 (2006
5. Gonzalez-Suarez, E., et al. RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature 468, 103-107 (2010
6. Tan, W., et al. Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature 470, 548-553 (2011
7. Schramek, D., et al. Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer. Nature 468, 98-102 (2010
8. Kiechl, S., et al. Blockade of receptor activator of nuclear factor-?B (RANKL) signaling improves hepatic insulin resistance and prevents development of diabetes mellitus. Nat. Med. 19, 358-363 (2013
9. Hanada, R., et al. Central control of fever and female body temperature by RANKL/RANK. Nature 462, 505-509 (2009
10. Simonet, W.S., et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89, 309-319 (1997
11. Lacey, D.L., et al. Bench to bedside: elucidation of the OPG-RANK-RANKL pathway and the development of denosumab. Nat. Rev. Drug Discov. 11, 401-419 (2012
12. Weng, J., et al. Deletion of G protein-coupled receptor 48 leads to ocular anterior segment dysgenesis (ASD) through down-regulation of Pitx2. Proc. Natl. Acad. Sci. USA 105, 6081-6086 (2008
13. Luo, J., et al. Regulation of bone formation and remodeling by G-protein-coupled receptor 48. Development 136, 2747-2756 (2009
14. Carmon, K.S., Gong, X., Lin, Q., Thomas, A., & Liu, Q. R-spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt/beta-catenin signaling. Proc. Natl. Acad. Sci. USA 108, 11452-11457 (2011
15. De Lau, W., et al. Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. Nature 476, 293-297 (2011
16. Styrkarsdottir, U., et al. Nonsense mutation in the LGR4 gene is associated with several human diseases and other traits. Nature 497, 517-520 (2013
17. Abe, E., et al. TSH is a negative regulator of skeletal remodeling. Cell 115, 151-162 (2003
18. Sun, L., et al. FSH directly regulates bone mass. Cell 125, 247-260 (2006
19. Du, B., et al. Lgr4/Gpr48 negatively regulates TLR2/4-Associated pattern recognition and innate immunity by targeting CD14 expression. J. Biol. Chem. 288, 15131-15141 (2013
20. Wang, Y., et al. Lgr4 regulates mammary gland development and stem cell activity through the pluripotency transcription factor Sox2. Stem Cells 31, 1921-1931 (2013
21. Wang, J., et al. Ablation of LGR4 promotes energy expenditure by driving white-to-brown fat switch. Nat. Cell Biol. 15, 1455-1463 (2013
22. Gao, Y., et al. Up-regulation of GPR48 induced by down-regulation of p27Kip1 enhances carcinoma cell invasiveness and metastasis. Cancer Res. 66, 11623-11631 (2006
23. Wu, J., et al. GPR48, a poor prognostic factor, promotes tumor metastasis and activates ?-catenin/TCF signaling in colorectal cancer. Carcinogenesis 34, 2861-2869 (2013
24. Joshi, P.A., et al. RANK signaling amplifies WNT-responsive mammary progenitors through R-SPONDIN1. Stem Cell Reports 5, 31-44 (2015
25. Wang, D., et al. Structural basis for R-spondin recognition by LGR4/5/6 receptors. Genes Dev. 27, 1339-1344 (2013
26. Deng, C., et al. Multi-functional norrin is a ligand for the LGR4 receptor. J. Cell Sci. 126, 2060-2068 (2013
27. Tang, X., et al. GPR116, an adhesion G-protein-coupled receptor, promotes breast cancer metastasis via the G?q-p63RhoGEF-Rho GTPase pathway. Cancer Res. 73, 6206-6218 (2013
28. Clapham, D.E. Calcium signaling. Cell 131, 1047-1058 (2007
29. Wu, X., et al. RANKL regulates Fas expression and Fas-mediated apoptosis in osteoclasts. J. Bone Miner. Res. 20, 107-116 (2005
30. Krönke, G., et al. R-spondin 1 protects against inflammatory bone damage during murine arthritis by modulating the Wnt pathway. Arthritis Rheum. 62, 2303-2312 (2010
31. Moon, J.B., et al. Akt induces osteoclast differentiation through regulating the GSK3?/NFATc1 signaling cascade. J. Immunol. 188, 163-169 (2012
32. Takeshita, S., et al. Osteoclast-secreted CTHRC1 in the coupling of bone resorption to formation. J. Clin. Invest. 123, 3914-3924 (2013
33. Mizuno, A., et al. Severe osteoporosis in mice lacking osteoclastogenesis inhibitory factor/osteoprotegerin. Biochem. Biophys. Res. Commun. 247, 610-615 (1998
34. Lacey, D.L., et al. Osteoprotegerin ligand modulates murine osteoclast survival in vitro and in vivo. Am. J. Pathol. 157, 435-448 (2000
35. Jimi, E., et al. Osteoclast differentiation factor acts as a multifunctional regulator in murine osteoclast differentiation and function. J. Immunol. 163, 434-442 (1999
36. Boyce, B.F. Advances in the regulation of osteoclasts and osteoclast functions. J. Dent. Res. 92, 860-867 (2013
37. Manolagas, S.C., & Parfitt, A.M. What old means to bone. Trends Endocrinol. Metab. 21, 369-374 (2010
38. Pierce, B.G., Hourai, Y., & Weng, Z. Accelerating protein docking in ZDOCK using an advanced 3D convolution library. PLoS One 6, e24657 (2011
39. Dai, W., et al. Improvement in low-homology template-based modeling by employing a model evaluation method with focus on topology. PLoS One 9, e89935 (2014
40. Li, C., et al. Maslinic acid suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss by regulating RANKL-mediated NF-?B and MAPK signaling pathways. J. Bone Miner. Res. 26, 644-656 (2011
41. Chu, G.C., et al. RANK- And c-Met-mediated signal network promotes prostate cancer metastatic colonization. Endocr. Relat. Cancer 21, 311-326 (2014
42. Wu, X., et al. Caffeic acid 3,4-dihydroxy-phenethyl ester suppresses receptor activator of NF-?B ligand-induced osteoclastogenesis and prevents ovariectomy-induced bone loss through inhibition of mitogen-Activated protein kinase/activator protein 1 and Ca2+nuclear factor of activated T-cells cytoplasmic 1 signaling pathways. J. Bone Miner. Res. 27, 1298-1308 (2012
43. McMichael, B.K., Meyer, S.M., & Lee, B.S. c-Src-mediated phosphorylation of thyroid hormone receptor-interacting protein 6 (TRIP6) promotes osteoclast sealing zone formation. J. Biol. Chem. 285, 26641-26651 (2010
44. Zhang, Z., et al. Ferroportin1 deficiency in mouse macrophages impairs iron homeostasis and inflammatory responses. Blood 118, 1912-1922 (2011