title: Feedback inhibition of osteoclastogenesis during inflammation by IL-10, M-CSF receptor shedding, and induction of IRF8.
abstract: Inflammation plays a key role in excessive bone loss in conditions such as rheumatoid arthritis and periodontitis. An important paradigm in immunology is that inflammatory factors activate feedback inhibition mechanisms to restrain inflammation and limit associated tissue damage. We hypothesized that inflammatory factors would activate similar feedback mechanisms to restrain bone loss in inflammatory settings. We have identified three mechanisms that inhibit osteoclastogenesis and are induced by inflammatory factors such as toll-like receptor ligands and cytokines; downregulation of expression of costimulatory molecules such as TREM-2; induction of shedding, and thereby inactivation of the M-CSF receptor c-Fms, leading to decreased RANK transcription; and induction of transcriptional repressors such as interferon regulatory factor 8. It is likely that these mechanisms work in a complementary and cooperative manner to fine tune the extent of osteoclastogenesis in inflammatory settings, and their augmentation may represent an alternative therapeutic approach to suppress bone resorption.
authors.affiliation: Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, New York, USA. ivashkivl@hss.edu
authors.forename: Lionel B
authors.initials: LB
authors.lastname: Ivashkiv
authors.forename: Baohong
authors.initials: B
authors.lastname: Zhao
authors.forename: Kyung-Hyun
authors.initials: KH
authors.lastname: Park-Min
authors.forename: Masamichi
authors.initials: M
authors.lastname: Takami
mesh_terms: D000818:Animals; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D025461:Feedback, Physiological / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D050835:Interferon Regulatory Factors / Q000096:biosynthesis* / Q000235:genetics; D016753:Interleukin-10 / Q000502:physiology*; D010010:Osteoclasts / Q000473:pathology / Q000502:physiology*; D010012:Osteogenesis / Q000502:physiology*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D000099185:Interferon Regulatory Factor-8
chemical_list: D050835:Interferon Regulatory Factors; D016753:Interleukin-10; D016186:Receptor, Macrophage Colony-Stimulating Factor; D011971:Receptors, Immunologic; D000099185:Interferon Regulatory Factor-8; C473367:TREML2 protein, human
references.citation: J Immunol. 2002 Aug 1;169(3):1516-23
references.pmid: 12133979
references.citation: J Exp Med. 2000 Jan 17;191(2):275-86
references.pmid: 10637272
references.citation: J Immunol. 2010 Nov 15;185(10):5926-34
references.pmid: 20935210
references.citation: J Biol Chem. 2006 Apr 28;281(17):11846-55
references.pmid: 16461346
references.citation: J Exp Med. 2003 Aug 18;198(4):645-51
references.pmid: 12913093
references.citation: J Immunol. 1999 Jun 15;162(12):7417-25
references.pmid: 10358195
references.citation: J Endocrinol. 2009 Jun;201(3):309-20
references.pmid: 19443863
references.citation: J Immunol. 2009 Dec 1;183(11):7223-33
references.pmid: 19890054
references.citation: Nat Rev Rheumatol. 2009 Dec;5(12):667-76
references.pmid: 19884898
references.citation: Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6158-63
references.pmid: 15073337
references.citation: J Bone Miner Res. 2009 Jul;24(7):1142-1146
references.pmid: 19558316
references.citation: Arthritis Res Ther. 2006;8(1):201
references.pmid: 16356195
references.citation: J Bone Miner Res. 2011 Jan;26(1):182-92
references.pmid: 20715177
references.citation: Curr Opin Rheumatol. 2006 Jul;18(4):427-32
references.pmid: 16763465
references.citation: J Immunol. 2009 Aug 1;183(3):1862-70
references.pmid: 19587010
references.citation: J Exp Med. 2003 Aug 18;198(4):669-75
references.pmid: 12925681
references.citation: Arthritis Res Ther. 2011 Jul 28;13(4):234
references.pmid: 21861861
references.citation: Eur J Immunol. 2011 Sep;41(9):2477-81
references.pmid: 21952800
references.citation: J Dent Res. 2006 Jul;85(7):596-607
references.pmid: 16798858
references.citation: Arthritis Rheum. 2010 Feb;62(2):402-13
references.pmid: 20112358
references.citation: J Immunol. 2009 Aug 15;183(4):2444-55
references.pmid: 19625651
references.citation: J Bone Miner Res. 2004 Feb;19(2):207-13
references.pmid: 14969390
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 3;104(27):11394-9
references.pmid: 17592115
references.citation: Nat Med. 2009 Sep;15(9):1066-71
references.pmid: 19718038
references.citation: Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1566-71
references.pmid: 10677500
references.citation: J Clin Invest. 2009 Oct;119(10):3024-34
references.pmid: 19770515
references.citation: Trends Mol Med. 2008 Jun;14(6):245-53
references.pmid: 18468489
references.citation: Nat Rev Rheumatol. 2009 Oct;5(10):578-82
references.pmid: 19798034
references.citation: Nature. 2004 Apr 15;428(6984):758-63
references.pmid: 15085135
references.citation: J Bone Miner Res. 2002 Jul;17(7):1211-8
references.pmid: 12096834
references.citation: Immunol Rev. 2005 Dec;208:30-49
references.pmid: 16313339
references.citation: J Biol Chem. 2009 May 1;284(18):12512-23
references.pmid: 19258321
references.citation: FASEB J. 2002 Mar;16(3):274-82
references.pmid: 11874977
references.citation: J Exp Med. 2005 Sep 5;202(5):589-95
references.pmid: 16147974
references.citation: Proc Natl Acad Sci U S A. 2011 Jan 25;108(4):1573-8
references.pmid: 21220349
references.citation: J Biol Chem. 2006 Apr 14;281(15):10073-80
references.pmid: 16484229
references.citation: Arch Biochem Biophys. 2008 May 15;473(2):139-46
references.pmid: 18395508
references.citation: Nat Rev Immunol. 2005 Jun;5(6):446-58
references.pmid: 15928677
references.citation: J Immunol. 2010 Jul 15;185(2):1265-73
references.pmid: 20543106
references.citation: Cell. 2001 Feb 23;104(4):487-501
references.pmid: 11239407
references.citation: Nat Med. 2007 Feb;13(2):156-63
references.pmid: 17237793
references.citation: Endocr Rev. 2008 Jun;29(4):403-40
references.pmid: 18451259
references.citation: J Clin Invest. 2005 Feb;115(2):282-90
references.pmid: 15668736
references.citation: J Interferon Cytokine Res. 2002 Jan;22(1):145-52
references.pmid: 11846985
references.citation: J Bone Miner Res. 2010 Apr;25(4):809-18
references.pmid: 19839765