Loots, Gabrieal G., Keller, Hansjoerg, Leupin, Olivier, Murugesh, Deepa, 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
Related URLs:	http://www.ncbi.nlm.nih.gov/pubmed?term=...
Related URLs:	http://www.ncbi.nlm.nih.gov/pubmed?term=...
Date Deposited:	13 Oct 2015 13:14
Last Modified:	13 Oct 2015 13:14
URI:	https://oak.novartis.com/id/eprint/5898