title: TGF-β regulates sclerostin expression via the ECR5 enhancer.
abstract: Wnt signaling is critical for skeletal development and homeostasis. Sclerostin (Sost) has emerged as a potent inhibitor of Wnt signaling and, thereby, bone formation. Thus, strategies to reduce sclerostin expression may be used to treat osteoporosis or non-union fractures. Transforming growth factor-beta (TGF-β) elicits various effects upon the skeleton both in vitro and in vivo depending on the duration and timing of administration. In vitro and in vivo studies demonstrate that TGF-β increases osteoprogenitor differentiation but decreases matrix mineralization of committed osteoblasts. Because sclerostin decreases matrix mineralization, this study aimed to examine whether TGF-β achieves such inhibitory effects via transcriptional modulation of Sost. Using the UMR106.01 mature osteoblast cell line, we demonstrated that TGF-βTGF-β(1)-β(2)-β(3) and Activin A increase Sost transcript expression. Pharmacologic inhibition of Alk4/5/7 in vitro and in vivo decreased endogenous Sost expression, and siRNA against Alk4 and Alk5 demonstrated their requirement for endogenous Sost expression. TGF-β(1) targeted the Sost bone enhancer ECR5 and did not affect the transcriptional activity of the endogenous Sost promoter. These results indicate that TGF-β(1) controls Sost transcription in mature osteoblasts, suggesting that sclerostin may mediate the inhibitory effect of TGF-β upon osteoblast differentiation.
authors.affiliation: Biology and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, CA, USA.
authors.forename: Gabriela G
authors.initials: GG
authors.lastname: Loots
authors.forename: Hansjoerg
authors.initials: H
authors.lastname: Keller
authors.forename: Olivier
authors.initials: O
authors.lastname: Leupin
authors.forename: Deepa
authors.initials: D
authors.lastname: Murugesh
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Collette
authors.forename: Damian C
authors.initials: DC
authors.lastname: Genetos
mesh_terms: D028341:Activins / Q000494:pharmacology; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D004742:Enhancer Elements, Genetic / Q000187:drug effects*; D005819:Genetic Markers / Q000235:genetics*; D008297:Male; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000494:pharmacology; D011621:Pteridines / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; D010281:Parathyroid Hormone; D011621:Pteridines; C511004:SD-208; C486031:Sost protein, rat; D016212:Transforming Growth Factor beta; C422405:activin A; D028341:Activins