title: Fibrillin-1 directly regulates osteoclast formation and function by a dual mechanism.
abstract: Mutations in the fibrillin-1 gene give rise to a number of heritable disorders, which are all characterized by various malformations of bone as well as manifestations in other tissues. However, the role of fibrillin-1 in the development and homeostasis of bone is not well understood. Here, we examined the role of fibrillin-1 in regulating osteoclast differentiation from primary bone-marrow-derived precursors and monocytic RAW 264.7 cells. The soluble N-terminal half of fibrillin-1 (rFBN1-N) strongly inhibited osteoclastogenesis, whereas the C-terminal half (rFBN1-C) did not. By contrast, when rFBN1-N was immobilized on calcium phosphate, it did not affect osteoclastogenesis but modulated osteoclast resorptive activity, which was evident by a larger number of smaller resorption pits. Using a panel of recombinant sub-fragments spanning rFBN1-N, we localized an osteoclast inhibitory activity to the 63 kDa subfragment rF23 comprising the N-terminal region of fibrillin-1. Osteoclastic resorption led to the generation of small fibrillin-1 fragments that were similar to those identified in human vertebral bone extracts. rF23, but not rFBN1-N, was found to inhibit the expression of cathepsin K, matrix metalloproteinase 9 and Dcstamp in differentiating osteoclasts. rFBN1-N, but not rF23, exhibited interaction with RANKL. Excess RANKL rescued the inhibition of osteoclastogenesis by rFBN1-N. By contrast, rF23 disrupted RANKL-induced Ca(2+) signaling and activation of transcription factor NFATc1. These studies highlight a direct dual inhibitory role of N-terminal fibrillin-1 fragments in osteoclastogenesis, the sequestration of RANKL and the inhibition of NFATc1 signaling, demonstrating that osteoclastic degradation of fibrillin-1 provides a potent negative feedback that limits osteoclast formation and function.
authors.affiliation: Faculty of Dentistry, McGill University, 3640 rue University, Montreal, Quebec, Canada, H3A 0C7.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Tiedemann
authors.forename: Iris
authors.initials: I
authors.lastname: Boraschi-Diaz
authors.forename: Irina
authors.initials: I
authors.lastname: Rajakumar
authors.forename: Jasvir
authors.initials: J
authors.lastname: Kaur
authors.forename: Peter
authors.initials: P
authors.lastname: Roughley
authors.forename: Dieter P
authors.initials: DP
authors.lastname: Reinhardt
authors.forename: Svetlana V
authors.initials: SV
authors.lastname: Komarova
mesh_terms: D000293:Adolescent; D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D000071838:Fibrillin-1; D000071837:Fibrillins; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D054392:Adipokines
chemical_list: D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; C000605722:FBN1 protein, human; D054392:Adipokines; C000605724:Fbn1 protein, mouse
keywords: Calcium signaling; Fibrillin; NFATc1; Osteoclastogenesis; RANKL
references.citation: Dev Cell. 2002 Dec;3(6):889-901
references.pmid: 12479813
references.citation: J Cell Biol. 2010 Sep 20;190(6):1107-21
references.pmid: 20855508
references.citation: Cell Mol Life Sci. 2007 Sep;64(18):2437-46
references.pmid: 17585369
references.citation: J Cell Biol. 1995 May;129(4):1165-76
references.pmid: 7744963
references.citation: Br J Rheumatol. 1995 Feb;34(2):126-31
references.pmid: 7704457
references.citation: J Biol Chem. 1996 Aug 9;271(32):19489-96
references.pmid: 8702639
references.citation: J Cell Biochem. 2008 Apr 15;103(6):1707-17
references.pmid: 18231993
references.citation: Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6158-63
references.pmid: 15073337
references.citation: J Biol Chem. 2002 Dec 27;277(52):50795-804
references.pmid: 12399449
references.citation: J Mol Biol. 1996 Apr 26;258(1):104-16
references.pmid: 8613981
references.citation: J Clin Invest. 2011 Sep;121(9):3505-16
references.pmid: 21841309
references.citation: J Bone Miner Res. 2001 Oct;16(10):1787-94
references.pmid: 11585342
references.citation: Hum Mol Genet. 2010 Dec 15;19(24):4790-8
references.pmid: 20871099
references.citation: J Biol Chem. 2000 Apr 21;275(16):12339-45
references.pmid: 10766875
references.citation: Joint Bone Spine. 2006 Dec;73(6):733-5
references.pmid: 17056292
references.citation: J Bone Miner Res. 1995 Oct;10(10):1550-5
references.pmid: 8686512
references.citation: Osteoporos Int. 1999;10(6):475-9
references.pmid: 10663348
references.citation: J Biol Chem. 2010 Oct 29;285(44):34126-33
references.pmid: 20729550
references.citation: Curr Top Dev Biol. 2006;75:93-123
references.pmid: 16984811
references.citation: Bone. 2008 Aug;43(2):386-93
references.pmid: 18502714
references.citation: J Biol Chem. 2005 Mar 25;280(12):11404-12
references.pmid: 15657057
references.citation: Bone. 2011 Feb;48(2):202-11
references.pmid: 20849994
references.citation: J Biol Chem. 2003 Dec 5;278(49):49271-8
references.pmid: 14504271
references.citation: FEBS Lett. 2012 Jul 4;586(14):2003-15
references.pmid: 22641039
references.citation: J Biol Chem. 2004 Jul 30;279(31):32924-31
references.pmid: 15161917
references.citation: Osteoporos Int. 2007 Dec;18(12):1565-81
references.pmid: 17694399
references.citation: J Biol Chem. 2007 Mar 23;282(12):8935-46
references.pmid: 17255108
references.citation: J Biol Chem. 2011 Sep 16;286(37):32810-23
references.pmid: 21784848
references.citation: Gene. 2009 Oct 15;446(2):90-8
references.pmid: 19563866
references.citation: Matrix Biol. 2002 Dec;21(8):637-46
references.pmid: 12524050
references.citation: J Biol Chem. 2001 Oct 26;276(43):39661-6
references.pmid: 11481325
references.citation: Nat Genet. 2003 Mar;33(3):407-11
references.pmid: 12598898
references.citation: PLoS One. 2012;7(10):e48629
references.pmid: 23119075
references.citation: Immunol Rev. 2009 Sep;231(1):241-56
references.pmid: 19754901
references.citation: Endocr Rev. 2005 Oct;26(6):743-74
references.pmid: 15901668
references.citation: J Cell Biol. 2001 Jul 23;154(2):275-81
references.pmid: 11470817
references.citation: Ann N Y Acad Sci. 2010 Mar;1192:253-6
references.pmid: 20392244
references.citation: J Biol Chem. 2002 Feb 8;277(6):4565-72
references.pmid: 11726670
references.citation: Nature. 2004 Apr 15;428(6984):758-63
references.pmid: 15085135
references.citation: Annu Rev Med. 2000;51:481-510
references.pmid: 10774478
references.citation: Biochim Biophys Acta. 1993 Mar 24;1181(1):15-22
references.pmid: 8457600
references.citation: J Biol Chem. 2002 Oct 25;277(43):41147-56
references.pmid: 12171919
references.citation: Hum Mol Genet. 2000 Aug 12;9(13):1987-94
references.pmid: 10942427
references.citation: Matrix Biol. 2011 Jan;30(1):43-52
references.pmid: 20970500
references.citation: J Biol Chem. 2001 Sep 21;276(38):36035-42
references.pmid: 11461921
references.citation: Cell. 2008 Mar 7;132(5):794-806
references.pmid: 18329366
references.citation: Rheumatology (Oxford). 2000 Mar;39(3):307-9
references.pmid: 10788540
references.citation: J Histochem Cytochem. 1997 Aug;45(8):1069-82
references.pmid: 9267468
references.citation: Calcif Tissue Int. 1997 Apr;60(4):358-60
references.pmid: 9075633
references.citation: J Histochem Cytochem. 1991 Jan;39(1):59-69
references.pmid: 1983874
references.citation: Bone. 2000 Jul;27(1):61-7
references.pmid: 10865210
references.citation: J Biol Chem. 2008 May 16;283(20):13874-88
references.pmid: 18339631
references.citation: Am J Med Genet C Semin Med Genet. 2012 Aug 15;160C(3):145-53
references.pmid: 22791552
references.citation: J Biol Chem. 2009 Nov 27;284(48):33662-70
references.pmid: 19801662