Sprouty1 is a critical regulatory switch of mesenchymal stem cell lineage allocation.
Development of bone and adipose tissue are linked processes arising from a common progenitor cell, but having an inverse relationship in disease conditions such as osteoporosis. Cellular differentiation of both tissues relies on growth factor cues, and we focus this study on Sprouty1 (Spry1), an inhibitor of growth factor signaling. We tested whether Spry1 can modify the development of fat cells through its activity in regulating growth factors known to be important for adipogenesis. We utilized conditional expression and genetic-null mouse models of Spry1 in adipocytes using the fatty acid binding promoter (aP2). Conditional deletion of Spry1 results in 10% increased body fat and decreased bone mass. This phenotype was rescued on Spry1 expression, which results in decreased body fat and increased bone mass. Ex vivo bone marrow experiments indicate Spry1 in bone marrow and adipose progenitor cells favors differentiation of osteoblasts at the expense of adipocytes by suppressing CEBP-beta and PPARgamma while up regulating TAZ. Age and gender-matched littermates expressing only Cre recombinase were used as controls. Spry1 is a critical regulator of adipocyte differentiation and mesenchymal stem cell (MSC) lineage allocation, potentially acting through regulation of CEBP-beta and TAZ.
Urs
Sumithra
S
Maine Medical Center Research Institute, 81 Research Dr., Scarborough, ME 04074, USA.
Venkatesh
Deepak
D
Tang
Yuefeng
Y
Henderson
Terry
T
Yang
Xuehui
X
Friesel
Robert E
RE
Rosen
Clifford J
CJ
Liaw
Lucy
L
D015502:Absorptiometry, Photon; D048868:Adaptor Proteins, Signal Transducing; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D050156:Adipogenesis / Q000235:genetics / Q000502:physiology; D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D006984:Hypertrophy / Q000235:genetics / Q000503:physiopathology; D015151:Immunoblotting; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics / Q000502:physiology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism; D055114:X-Ray Microtomography
D048868:Adaptor Proteins, Signal Transducing; D022782:CCAAT-Enhancer-Binding Protein-beta; D008565:Membrane Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; C425468:Spry1 protein, mouse; D051879:Twist-Related Protein 1; C067250:Twist1 protein, mouse
J Endocrinol. 2009 Nov;203(2):191-202
19423641
Dev Biol. 2008 Sep 1;321(1):64-76
18582454
J Biol Chem. 2002 Nov 29;277(48):46226-32
12270934
Am J Med. 2009 May;122(5):409-14
19375545
J Clin Invest. 2007 Mar;117(3):812-22
17304352
Angiogenesis. 2008;11(1):53-62
18219583
Curr Opin Rheumatol. 2008 Jul;20(4):429-34
18525356
Cell Cycle. 2006 Jan;5(2):176-9
16397409
Dev Cell. 2005 Feb;8(2):229-39
15691764
Proc Natl Acad Sci U S A. 2005 Aug 2;102(31):10993-8
16009937
Cell Prolif. 2008 Oct;41(5):803-12
18616697
Biochem Biophys Res Commun. 2008 Feb 8;366(2):471-5
18067853
Science. 2005 Aug 12;309(5737):1074-8
16099986
Am J Physiol Endocrinol Metab. 2009 Jan;296(1):E121-31
18940940
Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15712-7
14660788
J Clin Invest. 2004 Mar;113(6):846-55
15067317
Nat Cell Biol. 2008 Jul;10(7):837-48
18568018
Curr Stem Cell Res Ther. 2008 Sep;3(3):208-18
18782003
Nat Rev Mol Cell Biol. 2006 Dec;7(12):885-96
17139329
J Bone Miner Res. 2006 Jun;21(6):934-45
16753024
PLoS Genet. 2007 Apr 27;3(4):e64
17465682
J Steroid Biochem Mol Biol. 2009 Aug;116(1-2):86-92
19460432
Transgenic Res. 2006 Oct;15(5):647-53
16952017
FASEB J. 2006 Dec;20(14):2615-7
17068114
Biochem Biophys Res Commun. 2007 Jul 27;359(2):239-44
17543283
Nature. 2001 Aug 9;412(6847):647-51
11493923
J Anim Sci. 2004 Mar;82(3):905-15
15032449
Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14457-62
14603033
Mol Cell Biol. 2008 Apr;28(7):2426-36
18227151
Thromb Haemost. 2006 Sep;96(3):361-70
16953280
Nat Rev Mol Cell Biol. 2004 Jun;5(6):441-50
15173823
J Cell Physiol. 2007 Jan;210(1):1-6
17063460
Expert Rev Cardiovasc Ther. 2008 Mar;6(3):343-68
18327995