title: Ameloblastin modulates osteoclastogenesis through the integrin/ERK pathway.
abstract: Proteins of the extracellular matrix often have multiple functions to facilitate complex tasks ranging from signaling to structural support. Here we have focused on the function of one of the matrix proteins expressed in bones and teeth, the matrix adhesion protein ameloblastin (AMBN). Transgenic mice with 5-fold elevated AMBN levels in mandibles suffered from root cementum resorption, delamination, and reduced alveolar bone thickness. AMBN gain of function also resulted in a significant reduction in trabecular bone volume and bone mass dentistry in 42 days postnatal mouse jaws. In an in vitro model of osteoclastogenesis, AMBN modulated osteoclast differentiation from bone marrow derived monocytes (BMMCs), and dramatically increased osteoclast numbers and resorption pits. Furthermore, AMBN more than doubled BMMC adhesion, accelerated cell spreading, and promoted podosome belt and actin ring formation. These effects were associated with elevated ERK1/2 and AKT phosphorylation as well as higher expression of osteoclast activation related genes. Blocking integrin α2β1 and ERK 1/2 pathways alleviated the effects of AMBN on osteoclast differentiation. Together, our data indicate that AMBN increases osteoclast number and differentiation as well as mineralized tissue resorption by regulating cell adhesion and actin cytoskeleton polymerization, initiating integrin-dependent extracellular matrix signaling cascades and enhancing osteoclastogenesis.
authors: University of Illinois College of Dentistry, Brodie Laboratory for Craniofacial Genetics, Department of Oral Biology, USA.
authors: Xuanyu
authors: X
authors: Lu
authors: University of Illinois College of Dentistry, Brodie Laboratory for Craniofacial Genetics, Department of Oral Biology, USA.
authors: Yoshihiro
authors: Y
authors: Ito
authors: University of Illinois College of Dentistry, Brodie Laboratory for Craniofacial Genetics, Department of Oral Biology, USA.|University of Illinois College of Dentistry, Brodie Laboratory for Craniofacial Genetics, Department of Orthodontics, USA.
authors: Phimon
authors: P
authors: Atsawasuwan
authors: University of Illinois College of Dentistry, Brodie Laboratory for Craniofacial Genetics, Department of Oral Biology, USA.
authors: Smit
authors: S
authors: Dangaria
authors: University of Illinois College of Dentistry, Brodie Laboratory for Craniofacial Genetics, Department of Oral Biology, USA.
authors: Xiulin
authors: X
authors: Yan
authors: University of Illinois College of Dentistry, Brodie Laboratory for Craniofacial Genetics, Department of Oral Biology, USA.
authors: Tuojiang
authors: T
authors: Wu
authors: University of Illinois College of Dentistry, Brodie Laboratory for Craniofacial Genetics, Department of Orthodontics, USA.
authors: Carla A
authors: CA
authors: Evans
authors: University of Illinois College of Dentistry, Brodie Laboratory for Craniofacial Genetics, Department of Oral Biology, USA.|University of Illinois College of Dentistry, Brodie Laboratory for Craniofacial Genetics, Department of Orthodontics, USA.
authors: Xianghong
authors: X
authors: Luan
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D001862:Bone Resorption / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D003746:Dental Enamel Proteins / Q000235:genetics / Q000378:metabolism*; D004848:Epithelium / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006801:Humans; D038982:Integrin alpha2beta1 / Q000378:metabolism*; D053547:Keratin-14 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D008963:Molar / Q000000981:diagnostic imaging / Q000254:growth & development / Q000378:metabolism / Q000648:ultrastructure; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics; D010513:Periodontal Ligament / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D053245:RANK Ligand / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011859:Radiography; D014092:Tooth Root / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D000199:Actins; C490890:Ambn protein, mouse; D003746:Dental Enamel Proteins; D038982:Integrin alpha2beta1; D053547:Keratin-14; D053245:RANK Ligand; D012333:RNA, Messenger; D051057:Proto-Oncogene Proteins c-akt
references: Science. 2002 May 31;296(5573):1652-3
references: 12040184
references: Am J Orthod Dentofacial Orthop. 2003 May;123(5):527-33
references: 12750671
references: J Periodontal Res. 2003 Feb;38(1):51-6
references: 12558937
references: Biochem Biophys Res Commun. 2005 Mar 18;328(3):728-38
references: 15694407
references: J Bone Miner Res. 2006 Oct;21(10):1657-65
references: 16995821
references: J Biol Chem. 1998 Oct 16;273(42):27268-74
references: 9765250
references: Lab Invest. 1976 Mar;34(3):235-49
references: 765622
references: Eur J Oral Sci. 1998 Oct;106(5):963-70
references: 9786327
references: Cytotechnology. 2008 Feb;56(2):71-9
references: 19002844
references: J Biol Chem. 1993 Aug 5;268(22):16737-45
references: 8344953
references: Eur J Oral Sci. 2011 Dec;119 Suppl 1:270-9
references: 22243256
references: J Biol Chem. 2009 Oct 2;284(40):27176-84
references: 19648121
references: J Biol Chem. 1996 Feb 23;271(8):4431-5
references: 8626794
references: J Periodontal Res. 2010 Oct;45(5):643-9
references: 20572923
references: Dev Dyn. 2006 May;235(5):1167-80
references: 16450392
references: Exp Cell Res. 1997 Dec 15;237(2):296-306
references: 9434625
references: Eur J Oral Sci. 1998 Jan;106 Suppl 1:324-30
references: 9541243
references: Dev Dyn. 2003 Dec;228(4):651-63
references: 14648842
references: Mol Cell Biol. 2010 Jul;30(13):3233-48
references: 20439493
references: Eur J Oral Sci. 2011 Dec;119 Suppl 1:254-60
references: 22243254
references: Am J Pathol. 2007 Feb;170(2):427-35
references: 17255310
references: Mol Cells. 2003 Apr 30;15(2):216-25
references: 12803485
references: J Periodontol. 2002 Nov;73(11):1377-91
references: 12479643
references: J Clin Invest. 2000 Feb;105(4):433-40
references: 10683372
references: Eur J Oral Sci. 2011 Dec;119 Suppl 1:280-5
references: 22243257
references: J Bone Miner Res. 1996 Jul;11(7):892-8
references: 8797108
references: Anal Biochem. 1987 Oct;166(1):1-13
references: 3314585
references: J Immunol. 2005 Jul 1;175(1):350-7
references: 15972668
references: Exp Cell Res. 2007 Oct 1;313(16):3616-23
references: 17673200
references: Science. 1999 Aug 13;285(5430):1028-32
references: 10446041
references: Int J Biochem Cell Biol. 2010 May;42(5):576-9
references: 20035895
references: Matrix Biol. 2000 May;19(2):97-105
references: 10842093
references: J Periodontal Res. 2010 Dec;45(6):809-14
references: 20572915
references: Mol Biol Cell. 2004 Dec;15(12):5231-41
references: 15371537
references: J Cell Biol. 2004 Dec 6;167(5):973-83
references: 15583034
references: IUBMB Life. 2005 Jun;57(6):389-95
references: 16012047
references: Mol Endocrinol. 1998 Dec;12(12):1955-62
references: 9849968
references: Exp Cell Res. 2010 Apr 15;316(7):1202-12
references: 20043904
references: Curr Biol. 1995 Sep 1;5(9):1000-2
references: 8542272
references: Science. 1995 Apr 14;268(5208):233-9
references: 7716514
references: Proteomics. 2010 May;10(9):1730-9
references: 20162559
references: Orthod Craniofac Res. 2009 Aug;12(3):236-42
references: 19627526
references: Eur J Oral Sci. 2010 Oct;118(5):451-9
references: 20831578
references: Eur J Cell Biol. 2006 Apr;85(3-4):195-202
references: 16546562
references: J Biol Chem. 2000 Apr 21;275(16):11993-2002
references: 10766830
references: Bone. 2005 Oct;37(4):578-88
references: 16054450
references: Bone. 2011 Feb;48(2):406-13
references: 20854943
references: Arch Histol Cytol. 1989 Mar;52(1):61-70
references: 2497762
references: Int J Dev Biol. 1996 Dec;40(6):1141-50
references: 9032019
references: Cells Tissues Organs. 2005;181(3-4):189-95
references: 16612084
references: J Neurosci. 1982 Aug;2(8):1157-75
references: 7108587
references: Eur J Oral Sci. 2006 Dec;114(6):504-11
references: 17184233
references: Eur J Oral Sci. 2006 May;114 Suppl 1:244-53; discussion 254-6, 381-2
references: 16674693