title: NFAT signaling in osteoblasts regulates the hematopoietic niche in the bone microenvironment.
abstract: Osteoblasts support hematopoietic cell development, including B lymphopoiesis. We have previously shown that the nuclear factor of activated T cells (NFAT) negatively regulates osteoblast differentiation and bone formation. Interestingly, in smooth muscle, NFAT has been shown to regulate the expression of vascular cellular adhesion molecule-1 (VCAM-1), a mediator of cell adhesion and signaling during leukocyte development. To examine whether NFAT signaling in osteoblasts regulates hematopoietic development in vivo, we generated a mouse model expressing dominant-negative NFAT driven by the 2.3 kb fragment of the collagen-αI promoter to disrupt NFAT activity in osteoblasts (dnNFAT(OB)). Bone histomorphometry showed that dnNFAT(OB) mice have significant increases in bone volume (44%) and mineral apposition rate (131%) and decreased trabecular thickness (18%). In the bone microenvironment, dnNFAT(OB) mice displayed a significant increase (87%) in Lineage(-)cKit(+)Sca-1(+) (LSK) cells and significant decreases in B220(+)CD19(-)IgM(-) pre-pro-B cells (41%) and B220(+)CD19(+)IgM(+) immature B cells (40%). Concurrent with these findings, LSK cell differentiation into B220(+) cells was inhibited when cocultured on differentiated primary osteoblasts harvested from dnNFAT(OB) mice. Gene expression and protein levels of VCAM-1 in osteoblasts decreased in dnNFAT(OB) mice compared to controls. These data suggest that osteoblast-specific NFAT activity mediates early B lymphopoiesis, possibly by regulating VCAM-1 expression on osteoblasts.
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Sesler
authors.forename: Majd
authors.initials: M
authors.lastname: Zayzafoon
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000378:metabolism*; D002454:Cell Differentiation; D060833:Cellular Microenvironment / Q000502:physiology; D005260:Female; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010012:Osteogenesis / Q000502:physiology; D015398:Signal Transduction; D055153:Stem Cell Niche / Q000502:physiology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D050778:NFATC Transcription Factors; D019010:Vascular Cell Adhesion Molecule-1
references.citation: Ann N Y Acad Sci. 2006 Apr;1068:564-7
references.pmid: 16831953
references.citation: Cytokine Growth Factor Rev. 1999 Mar;10(1):41-60
references.pmid: 10379911
references.citation: Stem Cells. 2008 Aug;26(8):2042-51
references.pmid: 18499897
references.citation: Blood. 2010 Apr 22;115(16):3239-48
references.pmid: 20154218
references.citation: J Biol Chem. 2007 Nov 30;282(48):35318-27
references.pmid: 17884821
references.citation: J Biol Chem. 2005 Feb 25;280(8):7049-59
references.pmid: 15590632
references.citation: EMBO Mol Med. 2012 Apr;4(4):269-82
references.pmid: 22311511
references.citation: Birth Defects Res C Embryo Today. 2010 Dec;90(4):229-42
references.pmid: 21181885
references.citation: Cell Stem Cell. 2007 Aug 16;1(2):204-17
references.pmid: 18371351
references.citation: J Biol Chem. 2011 Feb 11;286(6):4576-88
references.pmid: 21131365
references.citation: Hum Reprod. 2012 Jul;27(7):1955-65
references.pmid: 22495096
references.citation: J Bone Miner Res. 2012 Jul;27(7):1451-61
references.pmid: 22434688
references.citation: J Cell Biol. 1995 Jun;129(5):1421-32
references.pmid: 7775585
references.citation: Nature. 2003 Oct 23;425(6960):841-6
references.pmid: 14574413
references.citation: Blood. 2007 May 1;109(9):3706-12
references.pmid: 17227831
references.citation: Nat Immunol. 2006 Apr;7(4):333-7
references.pmid: 16550195
references.citation: Nature. 2003 Oct 23;425(6960):836-41
references.pmid: 14574412
references.citation: Bone. 2007 Jun;40(6):1502-16
references.pmid: 17392048
references.citation: Nat Immunol. 2013 Feb;14(2):127-35
references.pmid: 23263556
references.citation: J Immunol. 1999 Nov 15;163(10):5656-65
references.pmid: 10553096
references.citation: Proc Natl Acad Sci U S A. 2005 Nov 22;102(47):17130-5
references.pmid: 16286645
references.citation: Physiology (Bethesda). 2005 Oct;20:349-56
references.pmid: 16174874
references.citation: Mol Immunol. 2007 Mar;44(7):1606-12
references.pmid: 17067679
references.citation: Blood. 2004 May 1;103(9):3258-64
references.pmid: 14726388
references.citation: J Mol Cell Cardiol. 2012 Aug;53(2):223-32
references.pmid: 22668785
references.citation: Bone. 2009 Sep;45(3):579-89
references.pmid: 19463978
references.citation: Haematologica. 2011 Nov;96(11):1580-8
references.pmid: 21750088
references.citation: Nat Med. 2005 Aug;11(8):880-5
references.pmid: 16041384
references.citation: Mol Cell Biol. 1999 Mar;19(3):2300-7
references.pmid: 10022916
references.citation: J Biol Chem. 2013 Jan 4;288(1):624-32
references.pmid: 23166323
references.citation: PLoS Comput Biol. 2010 Sep 09;6(9):
references.pmid: 20838577
references.citation: J Biol Chem. 2006 Jul 21;281(29):20503-20
references.pmid: 16627481
references.citation: Arterioscler Thromb Vasc Biol. 2009 Feb;29(2):225-31
references.pmid: 19023090
references.citation: Dev Cell. 2006 Jun;10(6):771-82
references.pmid: 16740479
references.citation: Nat Rev Immunol. 2010 Sep;10(9):645-56
references.pmid: 20725108
references.citation: J Cell Biol. 1991 Aug;114(3):557-65
references.pmid: 1713592
references.citation: PLoS One. 2010 May 27;5(5):e10853
references.pmid: 20523730
references.citation: Nat Rev Immunol. 2005 Jun;5(6):472-84
references.pmid: 15928679