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TGFb Regulates Sclerostin Expression via the ECR5 enhancer

Loots, Gabrieal G. and Keller, Hansjoerg and Leupin, Olivier and Murugesh, Deepa and Collette, Nicole M. and Genetos, Damian C. (2011) TGFb Regulates Sclerostin Expression via the ECR5 enhancer. Bone, 50 (3). pp. 663-669. ISSN 8756-3282

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-β1-β2-β3 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-β1 targeted the Sost bone enhancer ECR5 and did not affect the transcriptional activity of the
endogenous Sost promoter. These results indicate that TGF-β1 controls Sost transcription in mature osteoblasts,
suggesting that sclerostin may mediate the inhibitory effect of TGF-β upon osteoblast differentiaion.

Item Type: Article
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Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14
URI: https://oak.novartis.com/id/eprint/5898

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