TGF-β regulates sclerostin expression via the ECR5 enhancer

Gabriela G. Loots, Hansjoerg Keller, Olivier Leupin, Deepa Murugesh, Nicole M. Collette, Damian C Genetos

Research output: Contribution to journalArticle

38 Scopus citations

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 123 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.

Original languageEnglish (US)
Pages (from-to)663-669
Number of pages7
JournalBone
Volume50
Issue number3
DOIs
StatePublished - Mar 2012

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Keywords

  • Bone
  • ECR5
  • Osteoblast
  • Sost
  • Transforming growth factor-beta
  • Wnt

ASJC Scopus subject areas

  • Physiology
  • Endocrinology, Diabetes and Metabolism
  • Histology

Cite this

Loots, G. G., Keller, H., Leupin, O., Murugesh, D., Collette, N. M., & Genetos, D. C. (2012). TGF-β regulates sclerostin expression via the ECR5 enhancer. Bone, 50(3), 663-669. https://doi.org/10.1016/j.bone.2011.11.016