title: Suppression of autophagy by FIP200 deletion leads to osteopenia in mice through the inhibition of osteoblast terminal differentiation.
abstract: Autophagy is a conserved lysosomal degradation process that has important roles in both normal human physiology and disease. However, the function of autophagy in bone homeostasis is not well understood. Here, we report that autophagy is activated during osteoblast differentiation. Ablation of focal adhesion kinase family interacting protein of 200 kD (FIP200), an essential component of mammalian autophagy, led to multiple autophagic defects in osteoblasts including aberrantly increased p62 expression, deficient LC3-II conversion, defective autophagy flux, absence of GFP-LC3 puncta in FIP200-null osteoblasts expressing transgenic GFP-LC3, and absence of autophagosome-like structures by electron microscope examination. Osteoblast-specific deletion of FIP200 led to osteopenia in mice. Histomorphometric analysis revealed that the osteopenia was the result of cell-autonomous effects of FIP200 deletion on osteoblasts. FIP200 deletion led to defective osteoblast terminal differentiation in both primary bone marrow and calvarial osteoblasts in vitro. Interestingly, both proliferation and differentiation were not adversely affected by FIP200 deletion in early cultures. However, FIP200 deletion led to defective osteoblast nodule formation after initial proliferation and differentiation. Furthermore, treatment with autophagy inhibitors recapitulated the effects of FIP200 deletion on osteoblast differentiation. Taken together, these data identify FIP200 as an important regulator of bone development and reveal a novel role of autophagy in osteoblast function through its positive role in supporting osteoblast nodule formation and differentiation.
authors: Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, MI, USA.
authors: Fei
authors: F
authors: Liu
authors: Fang
authors: F
authors: Fang
authors: Hebao
authors: H
authors: Yuan
authors: Dongye
authors: D
authors: Yang
authors: Yongqiang
authors: Y
authors: Chen
authors: Linford
authors: L
authors: Williams
authors: Steven A
authors: SA
authors: Goldstein
authors: Paul H
authors: PH
authors: Krebsbach
authors: Jun-Lin
authors: JL
authors: Guan
mesh_terms: D000818:Animals; D001343:Autophagy; D000071183:Autophagy-Related Proteins; D001851:Bone Diseases, Metabolic / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D002454:Cell Differentiation; D017353:Gene Deletion; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology*; D010012:Osteogenesis; D010641:Phenotype
chemical_list: D000071183:Autophagy-Related Proteins; D047908:Intracellular Signaling Peptides and Proteins; C428743:Rb1cc1 protein, mouse
keywords: AUTOPHAGY; BONE DEVELOPMENT; DIFFERENTIATION; MOUSE; OSTEOBLAST
references: Cell. 2007 Dec 14;131(6):1149-63
references: 18083104
references: Nature. 2013 Feb 14;494(7436):201-6
references: 23364696
references: Genes Dev. 2011 Jul 15;25(14):1510-27
references: 21764854
references: Autophagy. 2007 Jan-Feb;3(1):4-9
references: 16929167
references: Int J Dev Biol. 2004 Sep;48(7):645-53
references: 15470637
references: J Bone Miner Res. 2010 Nov;25(11):2479-88
references: 20564240
references: Autophagy. 2008 Apr;4(3):309-14
references: 18188005
references: Nature. 2008 Jul 10;454(7201):232-5
references: 18454133
references: Dev Cell. 2008 Sep;15(3):344-357
references: 18804433
references: Nature. 2007 Jun 28;447(7148):1121-5
references: 17589504
references: Mol Cancer Res. 2011 Sep;9(9):1232-41
references: 21807966
references: PLoS One. 2010 Apr 01;5(4):e9979
references: 20376313
references: FASEB J. 2011 Oct;25(10):3366-76
references: 21705669
references: Science. 2010 Dec 3;330(6009):1344-8
references: 21127245
references: J Cell Biol. 2005 May 9;169(3):425-34
references: 15866887
references: J Immunol. 2009 Apr 1;182(7):4046-55
references: 19299702
references: Cell Signal. 2008 May;20(5):787-94
references: 18036779
references: J Biol Chem. 2009 May 1;284(18):12297-305
references: 19258318
references: J Exp Med. 2011 Mar 14;208(3):455-67
references: 21339326
references: J Biol Chem. 2010 Jan 29;285(5):3499-509
references: 19940130
references: Nature. 2004 Dec 23;432(7020):1032-6
references: 15525940
references: Science. 2008 Jul 4;321(5885):117-20
references: 18599786
references: Cell. 2008 Jan 11;132(1):27-42
references: 18191218
references: J Exp Med. 2007 Jan 22;204(1):25-31
references: 17190837
references: Development. 2006 Aug;133(16):3231-44
references: 16854976
references: Blood. 2010 Dec 2;116(23):4806-14
references: 20716775
references: Nat Cell Biol. 2011 May;13(5):589-98
references: 21478857
references: Curr Opin Cell Biol. 2010 Apr;22(2):132-9
references: 20056399
references: Cells Tissues Organs. 2011;194(2-4):274-8
references: 21597271
references: J Biol Chem. 2007 May 18;282(20):14845-52
references: 17395594
references: Blood. 2009 Jul 2;114(1):157-64
references: 19417210
references: Trends Endocrinol Metab. 2010 Jun;21(6):369-74
references: 20223679
references: Mol Cancer Ther. 2011 Nov;10(11):2135-45
references: 21903606
references: Cell. 2011 Nov 11;147(4):728-41
references: 22078875
references: J Bone Miner Res. 2004 Sep;19(9):1497-505
references: 15312250
references: Proc Natl Acad Sci U S A. 2007 Jun 19;104(25):10619-24
references: 17537919
references: Nature. 2006 Jun 15;441(7095):880-4
references: 16625205
references: J Bone Miner Res. 2003 Aug;18(8):1497-505
references: 12929939
references: J Cell Biol. 2000 Apr 17;149(2):423-30
references: 10769033
references: J Cell Biol. 2006 Oct 9;175(1):121-33
references: 17015619
references: Nat Cell Biol. 2010 Sep;12(9):823-30
references: 20811354
references: J Clin Invest. 2009 Nov;119(11):3329-39
references: 19855132
references: Nature. 2006 Jun 15;441(7095):885-9
references: 16625204
references: J Bone Miner Res. 1987 Dec;2(6):595-610
references: 3455637
references: Science. 2011 May 20;332(6032):966-70
references: 21512002
references: Biogerontology. 2012 Feb;13(1):21-35
references: 21461872
references: Dev Cell. 2011 Nov 15;21(5):966-74
references: 22055344
references: Bone. 2007 Apr;40(4):1135-43
references: 17275432
references: Cell. 2010 Feb 5;140(3):313-26
references: 20144757
references: Autophagy. 2009 Jan;5(1):85-7
references: 18981720
references: Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):19860-5
references: 19910529
references: Proc Natl Acad Sci U S A. 2010 Jul 20;107(29):12913-8
references: 20616007
references: Autophagy. 2009 Nov;5(8):1118-30
references: 19844159
references: Teratology. 1980 Dec;22(3):299-301
references: 6165088
references: Autophagy. 2009 Jul;5(5):625-35
references: 19276668
references: J Bone Miner Res. 1989 Feb;4(1):3-11
references: 2718776
references: J Cell Biol. 2008 May 5;181(3):497-510
references: 18443221
references: Bone. 2009 Dec;45(6):1104-16
references: 19651256
references: Bone. 2007 Jul;41(1):39-51
references: 17459803
references: Proc Natl Acad Sci U S A. 2010 Jan 12;107(2):832-7
references: 20080761
references: Mol Biol Cell. 2004 Mar;15(3):1101-11
references: 14699058
references: J Bone Miner Res. 2010 Jul;25(7):1572-80
references: 20200951
references: Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15077-82
references: 14657337
references: Nat Neurosci. 2013 May;16(5):532-42
references: 23542691
references: Nat Cell Biol. 2010 Sep;12(9):814-22
references: 20811353
references: J Bone Miner Res. 2012 Jul;27(7):1439-47
references: 22706899
references: J Hum Genet. 2010 Jul;55(7):441-7
references: 20448653
references: Mol Biol Cell. 2002 Sep;13(9):3178-91
references: 12221124
references: Bone. 2008 Jul;43(1):101-109
references: 18460422
references: Cell Cycle. 2009 Feb 1;8(3):391-3
references: 19177014
references: Adv Exp Med Biol. 2001;496:67-83
references: 11783627
references: Mol Biol Cell. 2009 Apr;20(7):1992-2003
references: 19225151
references: Mol Biol Cell. 2009 Apr;20(7):1981-91
references: 19211835
references: Cell. 2006 Feb 10;124(3):471-84
references: 16469695
references: J Orthop Res. 1990 Nov;8(6):833-42
references: 2213340