Targeted deletion of Sost distal enhancer increases bone formation and bone mass

Nicole M. Collette, Damian C Genetos, Aris N. Economides, LiQin Xie, Mohammad Shahnazari, Wei Yao, Nancy E Lane, Richard M. Harland, Gabriela G. Loots

Research output: Contribution to journalArticle

70 Citations (Scopus)

Abstract

The Wnt antagonist Sost has emerged as a key regulator of bone homeostasis through the modulation of Lrp4/5/6 Wnt coreceptors. In humans, lack of Sclerostin causes sclerosteosis and van Buchem (VB) disease, two generalized skeletal hyperostosis disorders that result from hyperactive Wnt signaling. Unlike sclerosteosis, VB patients lack SOST coding mutations but carry a homozygous 52 kb noncoding deletion that is essential for the transcriptional activation of SOST in bone. We recently identified a putative bone enhancer, ECR5, in the VB deletion region, and showed that the transcriptional activity of ECR5 is controlled by Mef2C transcription factor in vitro. Here we report that mice lacking ECR5 or Mef2C through Col1-Cre osteoblast/osteocyte-specific ablation result in high bone mass (HBM) due to elevated bone formation rates. We conclude that the absence of the Sost-specific long-range regulatory element ECR5 causes VB disease in rodents, and that Mef2C is the main transcription factor responsible for ECR5-dependent Sost transcriptional activation in the adult skeleton.

Original languageEnglish (US)
Pages (from-to)14092-14097
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number35
DOIs
StatePublished - Aug 28 2012

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Osteogenesis
Osteochondrodysplasias
Bone and Bones
Transcriptional Activation
Transcription Factors
Hyperostosis
Osteocytes
Osteoblasts
Skeleton
Rodentia
Homeostasis
Mutation
Sclerosteosis

Keywords

  • Osteocytes

ASJC Scopus subject areas

  • General

Cite this

Targeted deletion of Sost distal enhancer increases bone formation and bone mass. / Collette, Nicole M.; Genetos, Damian C; Economides, Aris N.; Xie, LiQin; Shahnazari, Mohammad; Yao, Wei; Lane, Nancy E; Harland, Richard M.; Loots, Gabriela G.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 35, 28.08.2012, p. 14092-14097.

Research output: Contribution to journalArticle

Collette, Nicole M. ; Genetos, Damian C ; Economides, Aris N. ; Xie, LiQin ; Shahnazari, Mohammad ; Yao, Wei ; Lane, Nancy E ; Harland, Richard M. ; Loots, Gabriela G. / Targeted deletion of Sost distal enhancer increases bone formation and bone mass. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 35. pp. 14092-14097.
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