Bone-protective Functions of Netrin 1 Protein.
Netrin 1 was initially identified as an axon guidance factor, and recent studies indicate that it inhibits chemokine-directed monocyte migration. Despite its importance as a neuroimmune guidance cue, the role of netrin 1 in osteoclasts is largely unknown. Here we detected high netrin 1 levels in the synovial fluid of rheumatoid arthritis patients. Netrin 1 is potently expressed in osteoblasts and synovial fibroblasts, and IL-17 robustly enhances netrin 1 expression in these cells. The binding of netrin 1 to its receptor UNC5b on osteoclasts resulted in activation of SHP1, which inhibited VAV3 phosphorylation and RAC1 activation. This significantly impaired the actin polymerization and fusion, but not the differentiation of osteoclast. Strikingly, netrin 1 treatment prevented bone erosion in an autoimmune arthritis model and age-related bone destruction. Therefore, the netrin 1-UNC5b axis is a novel therapeutic target for bone-destructive diseases.
From the Laboratories of Host Defense and maruyama@biken.osaka-u.ac.jp.
Kenta
K
Maruyama
the Division of Brain Function, National Institute of Genetics, 1111 Yata, Mishima 411-8540, Japan.
Takahiko
T
Kawasaki
Experimental Immunology, World Premier Institute (WPI) Immunology Frontier Research Center (IFReC) and.
Masahide
M
Hamaguchi
the Department of the Control for Rheumatic Diseases, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
Motomu
M
Hashimoto
the Department of the Control for Rheumatic Diseases, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
Moritoshi
M
Furu
the Department of the Control for Rheumatic Diseases, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
Hiromu
H
Ito
the Department of the Control for Rheumatic Diseases, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
Takao
T
Fujii
the Division of Innate Immune Regulation, International Research and Development Center for Mucosal Vaccine, Institute for Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Naoki
N
Takemura
From the Laboratories of Host Defense and.
Thangaraj
T
Karuppuchamy
From the Laboratories of Host Defense and.
Takeshi
T
Kondo
From the Laboratories of Host Defense and.
Takumi
T
Kawasaki
From the Laboratories of Host Defense and.
Masahiro
M
Fukasaka
From the Laboratories of Host Defense and.
Takuma
T
Misawa
From the Laboratories of Host Defense and.|the Department of Inflammation Biology, Institute for Enzyme Research, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
Tatsuya
T
Saitoh
the Departments of Functional Genomics and Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8562, Japan, and.
Yutaka
Y
Suzuki
From the Laboratories of Host Defense and.|the European Molecular Biology Laboratory, Australian Regenerative Medicine Institute, Monash University, Victoria 3800, Australia.
Mikaël M
MM
Martino
From the Laboratories of Host Defense and.
Yutaro
Y
Kumagai
From the Laboratories of Host Defense and sakira@biken.osaka-u.ac.jp.|the Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
Shizuo
S
Akira
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008817:Mice, Mutant Strains; D009414:Nerve Growth Factors / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D000075386:Netrin Receptors; D000075388:Netrin-1; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics; D013583:Synovial Membrane / Q000378:metabolism* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; D000075386:Netrin Receptors; D009479:Neuropeptides; C000617353:Ntn1 protein, mouse; D051567:Proto-Oncogene Proteins c-vav; C484602:Rac1 protein, mouse; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; C496622:Vav3 protein, mouse; D000075388:Netrin-1; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D020830:rac1 GTP-Binding Protein
arthritis; cell fusion; interleukin 17A (IL-17 or IL-17A); netrin 1; osteoblast; osteoclast; osteoporosis; rheumatoid arthritis
Proc Natl Acad Sci U S A. 2005 Oct 11;102(41):14729-34
16203981
Am J Physiol Renal Physiol. 2013 May 1;304(9):F1187-97
23445618
Nat Immunol. 2009 Sep;10(9):965-72
19668221
Development. 2011 Jun;138(11):2153-69
21558366
Nat Med. 2012 Jul;18(7):1077-86
22660635
Dev Cell. 2002 Dec;3(6):889-901
12479813
Arthritis Res Ther. 2011 May 27;13(3):219
21635718
Dev Cell. 2010 Jan 19;18(1):77-89
20152179
FEBS Lett. 2014 Jun 27;588(14):2262-9
24846137
Immunity. 2012 Dec 14;37(6):1024-36
23200825
Nature. 2012 May 3;485(7396):69-74
22522930
Cell Metab. 2006 Aug;4(2):111-21
16890539
Nat Immunol. 2012 Jan 08;13(2):136-43
22231519
J Immunol. 2008 Oct 1;181(7):4742-51
18802077
J Exp Med. 2006 Nov 27;203(12):2673-82
17088434
Arthritis Res Ther. 2006;8(6):R172
17105652
J Exp Med. 2013 Sep 23;210(10):1947-60
23980096
Nat Med. 2006 Dec;12(12):1403-9
17128270
Expert Opin Drug Saf. 2013 Jul;12(4):507-22
23614635
J Exp Med. 2003 Apr 21;197(8):1029-35
12707301
Proc Natl Acad Sci U S A. 2009 Oct 6;106(40):17146-51
19721007
Cell. 1996 Dec 13;87(6):1001-14
8978605
FASEB J. 2009 Dec;23(12):4081-90
19667119
Brain Res. 2000 Sep 29;878(1-2):204-9
10996153
Nat Rev Mol Cell Biol. 2007 Apr;8(4):296-306
17356579
N Engl J Med. 2012 May 3;366(18):1734-6
22551134
Proc Natl Acad Sci U S A. 2008 Jun 24;105(25):8643-8
18552177
Nat Rev Rheumatol. 2012 Nov;8(11):656-64
23007741
Nat Med. 2014 Apr;20(4):377-84
24584118
Nat Med. 2012 Feb 19;18(3):405-12
22344299
J Immunol. 2006 Sep 15;177(6):3799-805
16951341
Cell. 1995 May 19;81(4):621-9
7758116
Ann N Y Acad Sci. 2011 Dec;1240:14-7
22172034
EMBO Mol Med. 2013 Dec;5(12):1821-34
24293316
Nat Protoc. 2010 Mar;5(3):550-60
20203670
Cell. 1994 Aug 12;78(3):425-35
8062385
Nature. 2013 May 23;497(7450):490-3
23644455
Arthritis Rheum. 2008 May;58(5):1299-309
18438830
Oncogene. 2004 Jul 22;23(33):5577-85
15122327
Lancet. 2011 Apr 9;377(9773):1276-87
21450337
Nat Immunol. 2010 Oct;11(10):936-44
20729857
J Immunol. 2011 Jan 1;186(1):549-55
21098235
Dev Cell. 2002 Apr;2(4):389-406
11970890
J Bone Miner Res. 2015 May;30(5):837-54
25483983
Genes Dev. 1997 Dec 15;11(24):3482-96
9407039
PLoS One. 2011;6(6):e20780
21695256
Clin Dev Immunol. 2013;2013:462152
24369474
J Immunol. 2003 Dec 15;171(12):6541-8
14662855
J Exp Med. 2005 Aug 1;202(3):345-51
16061724
J Exp Med. 2014 Jun 2;211(6):1037-48
24863066
J Biol Chem. 2012 Aug 17;287(34):29114-24
22773835
Science. 1994 Oct 21;266(5184):443-8
7939685
Bone. 1999 Sep;25(3):261-7
10495129