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 language | English (US) |
|---|---|
| Pages (from-to) | 14092-14097 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 109 |
| Issue number | 35 |
| DOIs | |
| State | Published - Aug 28 2012 |
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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 journal › Article
}
TY - JOUR
T1 - Targeted deletion of Sost distal enhancer increases bone formation and bone mass
AU - Collette, Nicole M.
AU - Genetos, Damian C
AU - Economides, Aris N.
AU - Xie, LiQin
AU - Shahnazari, Mohammad
AU - Yao, Wei
AU - Lane, Nancy E
AU - Harland, Richard M.
AU - Loots, Gabriela G.
PY - 2012/8/28
Y1 - 2012/8/28
N2 - 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.
AB - 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.
KW - Osteocytes
UR - http://www.scopus.com/inward/record.url?scp=84865552981&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84865552981&partnerID=8YFLogxK
U2 - 10.1073/pnas.1207188109
DO - 10.1073/pnas.1207188109
M3 - Article
C2 - 22886088
AN - SCOPUS:84865552981
VL - 109
SP - 14092
EP - 14097
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 35
ER -