title: Transforming growth factor-beta inhibits CCAAT/enhancer-binding protein expression and PPARgamma activity in unloaded bone marrow stromal cells.
abstract: The molecular mechanisms regulating the adipogenic differentiation of bone marrow stromal cells in vivo remain largely unknown. In this study, we investigated the regulatory effects of transforming growth factor beta-2 (TGF-beta2) on transcription factors involved in adipogenic differentiation induced by hind limb suspension in rat bone marrow stromal cells in vivo. Time course real-time quantitative reverse-transcription polymerase chain reaction (RT-PCR) analysis of gene expression showed that skeletal unloading progressively increases the expression of CCAAT/enhancer-binding protein (C/EBP)alpha and C/EBPbeta alpha at 5 days in bone marrow stromal cells resulting in increased peroxisome proliferator-activated receptor gamma (PPARgamma2) transcripts at 7 days. TGF-beta2 administration in unloaded rats corrected the rise in C/EBPalpha and C/EBPbeta transcripts induced by unloading in bone marrow stromal cells. This resulted in inhibition of PPARgamma2 expression that was associated with increased Runx2 expression. Additionally, the inhibition of C/EBPalpha and C/EBPbeta expression by TGF-beta2 was associated with increased PPARgamma serine phosphorylation in bone marrow stromal cells, a mechanism that inhibits PPARgamma transactivating activity. The sequential inhibitory effect of TGF-beta2 on C/EBPalpha, C/EBPbeta, and PPARgamma2 resulted in reduced LPL expression and abolition of bone marrow stromal cell adipogenic differentiation, which contributed to prevent bone loss induced by skeletal unloading. We conclude that TGF-beta2 inhibits the excessive adipogenic differentiation of bone marrow stromal cells induced by skeletal unloading by inhibiting C/EBPalpha, C/EBPbeta, and PPARgamma expression and activity, which provides a sequential mechanism by which TGF-beta2 regulates adipogenic differentiation of bone marrow stromal cells in vivo.
authors.affiliation: Unit 606 INSERM, Laboratory of Osteoblast Biology and Pathology, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Ahdjoudj
authors.forename: K
authors.initials: K
authors.lastname: Kaabeche
authors.forename: X
authors.initials: X
authors.lastname: Holy
authors.forename: O
authors.initials: O
authors.lastname: Fromigué
authors.forename: D
authors.initials: D
authors.lastname: Modrowski
authors.forename: E
authors.initials: E
authors.lastname: Zérath
authors.forename: P J
authors.initials: PJ
authors.lastname: Marie
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology* / Q000378:metabolism; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D008297:Male; D047495:PPAR gamma / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017154:Stromal Cells / Q000166:cytology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053781:Transforming Growth Factor beta2
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D047495:PPAR gamma; D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2