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

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.

Pubmed ID: 22886088


  • Collette NM
  • Genetos DC
  • Economides AN
  • Xie L
  • Shahnazari M
  • Yao W
  • Lane NE
  • Harland RM
  • Loots GG


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

August 28, 2012

Associated Grants

  • Agency: NIAMS NIH HHS, Id: AR057547
  • Agency: NIDDK NIH HHS, Id: DK075730
  • Agency: NICHD NIH HHS, Id: HD47853
  • Agency: NIAMS NIH HHS, Id: R01 AR043052
  • Agency: NIAMS NIH HHS, Id: R01 AR061366
  • Agency: NIDDK NIH HHS, Id: R01 DK075730

Mesh Terms

  • Age Factors
  • Animals
  • Bone Remodeling
  • Craniofacial Abnormalities
  • Enhancer Elements, Genetic
  • Female
  • Femur
  • Gene Deletion
  • Glycoproteins
  • Hyperostosis
  • Lac Operon
  • MEF2 Transcription Factors
  • Male
  • Mandible
  • Mice
  • Mice, Transgenic
  • Myogenic Regulatory Factors
  • Osteochondrodysplasias
  • Osteocytes
  • Osteosclerosis
  • Signal Transduction
  • Skull
  • Syndactyly
  • Transcriptional Activation