title: Anti-interleukin-6 receptor antibody prevents systemic bone mass loss via reducing the number of osteoclast precursors in bone marrow in a collagen-induced arthritis model.
abstract: Systemic bone loss is a hallmark of rheumatoid arthritis (RA). Inflammatory cytokines such as interleukin (IL)-6 promote bone resorption by osteoclasts. Sphingosine-1-phosphate (S1P) controls the migration of osteoclast precursor cells (OCPs) between the blood and bone marrow, in part via S1P receptors (S1PR1 and S1PR2) expressed on the surface of OCPs. OCPs (CD11b(+) Gr-1(low+med) ) isolated from bone marrow of DBA/1J mice were stimulated with IL-6. S1P-directed chemotaxis of OCPs was evaluated using a transwell plate. mRNA expression of S1PR1 and S1PR2 was measured. DBA/1J mice were immunized with bovine type II collagen (days 0 and 21) and anti-mouse IL-6 receptor antibody (MR16-1) was administered on days 0 and/or 21. Trabecular bone volume was analysed using micro-computed tomography. The percentage of OCPs in tibial bone marrow and S1PR1 and S1PR2 mRNA expression in OCPs were measured. IL-6 stimulation significantly decreased S1P-directed chemotaxis of OCPs. IL-6 induced S1PR2 mRNA expression, but not S1PR1 mRNA expression, in OCPs. Bone volume was significantly lower in arthritic mice than in non-arthritic control mice on day 35. Treatment of immunized mice with MR16-1 significantly inhibited bone loss. In MR16-1-treated mice, the percentage of OCPs and expression of S1PR2 mRNA was each decreased compared with arthritic mice on day 14, but not on day 35. IL-6 increased the number of OCPs in tibial bone marrow via up-regulating S1PR2, thus playing a crucial role in systemic bone loss induced by inflammation.
authors.affiliation: Product Research Department, Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical Co. Ltd, Gotemba, Shizuoka, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Tanaka
authors.forename: Misato
authors.initials: M
authors.lastname: Hashizume
authors.forename: Masahiko
authors.initials: M
authors.lastname: Mihara
authors.forename: Hiroto
authors.initials: H
authors.lastname: Yoshida
authors.forename: Miho
authors.initials: M
authors.lastname: Suzuki
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Matsumoto
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology; D001169:Arthritis, Experimental / Q000276:immunology*; D015519:Bone Density / Q000276:immunology; D001854:Bone Marrow Cells; D001862:Bone Resorption / Q000276:immunology / Q000378:metabolism* / Q000517:prevention & control; D002465:Cell Movement; D003094:Collagen; D015870:Gene Expression; D007249:Inflammation / Q000276:immunology; D015850:Interleukin-6 / Q000502:physiology*; D008246:Lysophospholipids / Q000378:metabolism; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000502:physiology*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D000081025:Sphingosine-1-Phosphate Receptors; D013234:Stem Cells / Q000166:cytology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015850:Interleukin-6; D008246:Lysophospholipids; D012333:RNA, Messenger; D019947:Receptors, Interleukin-6; D049349:Receptors, Lysosphingolipid; C556330:S1pr1 protein, mouse; D000081025:Sphingosine-1-Phosphate Receptors; C577686:interleukin-6, mouse; C533955:sphingosine-1-phosphate receptor-2, mouse; C060506:sphingosine 1-phosphate; D003094:Collagen; C502936:tocilizumab; D013110:Sphingosine
keywords: collagen-induced arthritis; interleukin-6; osteoclast; sphingosine-1-phosphate receptor 2
references.citation: Acad Radiol. 2003 Oct;10(10):1153-8
references.pmid: 14587633
references.citation: Nature. 1999 Jan 28;397(6717):315-23
references.pmid: 9950424
references.citation: J Exp Med. 2010 Dec 20;207(13):2793-8
references.pmid: 21135136
references.citation: Calcif Tissue Int. 1997 Dec;61(6):493-8
references.pmid: 9383277
references.citation: Invest Radiol. 2002 Jan;37(1):40-6
references.pmid: 11753153
references.citation: Arthritis Res Ther. 2009;11(6):R185
references.pmid: 20003278
references.citation: Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1566-71
references.pmid: 10677500
references.citation: J Cell Biochem. 2002;87(4):386-93
references.pmid: 12397598
references.citation: Nat Med. 2009 Apr;15(4):417-24
references.pmid: 19330010
references.citation: Arthritis Rheum. 2010 Jan;62(1):33-43
references.pmid: 20039425
references.citation: Blood. 2000 Jul 15;96(2):671-5
references.pmid: 10887133
references.citation: Arthritis Res Ther. 2004;6(3):R220-31
references.pmid: 15142268
references.citation: Immunol Lett. 2002 Dec 3;84(3):231-40
references.pmid: 12413742
references.citation: Genes Dev. 1999 Sep 15;13(18):2412-24
references.pmid: 10500098
references.citation: Nat Rev Rheumatol. 2009 Dec;5(12):667-76
references.pmid: 19884898
references.citation: Ann Rheum Dis. 2013 Mar;72(3):396-400
references.pmid: 22586162
references.citation: J Immunol. 2010 May 1;184(9):4717-24
references.pmid: 20357249
references.citation: Rheumatol Int. 2011 Jan;31(1):127-31
references.pmid: 20658238
references.citation: EMBO J. 1991 Dec;10(13):4025-31
references.pmid: 1721867
references.citation: Nature. 2009 Mar 26;458(7237):524-8
references.pmid: 19204730
references.citation: J Immunol. 2007 Mar 15;178(6):3437-46
references.pmid: 17339438
references.citation: Arthritis Rheum. 2006 Nov;54(11):3551-63
references.pmid: 17075861
references.citation: Nat Immunol. 2007 Dec;8(12):1295-301
references.pmid: 18026082
references.citation: Proc Natl Acad Sci U S A. 1982 May;79(10):3325-9
references.pmid: 6954482
references.citation: Cell. 1998 Apr 17;93(2):165-76
references.pmid: 9568710
references.citation: J Immunol. 2009 Dec 15;183(12):7825-31
references.pmid: 19923448
references.citation: Arthritis Rheum. 2008 May;58(5):1332-42
references.pmid: 18438854
references.citation: J Biol Chem. 2005 Apr 22;280(16):16163-9
references.pmid: 15722361
references.citation: Pathol Res Pract. 2012 Feb 15;208(2):82-8
references.pmid: 22244964
references.citation: Semin Arthritis Rheum. 2012 Oct;42(2):131-9
references.pmid: 22397953
references.citation: Bone. 2005 May;36(5):840-53
references.pmid: 15794931
references.citation: J Clin Endocrinol Metab. 2012 Aug;97(8):E1421-8
references.pmid: 22679064
references.citation: Clin Rheumatol. 2002 May;21(2):150-8
references.pmid: 12086167
references.citation: J Bone Miner Res. 1996 Jan;11(1):88-95
references.pmid: 8770701
references.citation: Calcif Tissue Int. 2011 Feb;88(2):87-95
references.pmid: 21140260
references.citation: Calcif Tissue Int. 1996 Jan;58(1):24-9
references.pmid: 8825235
references.citation: J Bone Miner Res. 2003 Aug;18(8):1404-18
references.pmid: 12929930