skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Sost, independent of the non-coding enhancer ECR5, is required for bone mechanoadaptation

Abstract

Here, sclerostin ( Sost) is a negative regulator of bone formation that acts upon the Wnt signaling pathway. Sost is mechanically regulated at both mRNA and protein level such that loading represses and unloading enhances Sost expression, in osteocytes and in circulation. The non-coding evolutionarily conserved enhancer ECR5 has been previously reported as a transcriptional regulatory element required for modulating Sost expression in osteocytes. Here we explored the mechanisms by which ECR5, or several other putative transcriptional enhancers regulate Sost expression, in response to mechanical stimulation. We found that in vivo ulna loading is equally osteoanabolic in wildtype and Sost –/– mice, although Sost is required for proper distribution of load-induced bone formation to regions of high strain. Using Luciferase reporters carrying the ECR5 non-coding enhancer and heterologous or homologous h SOST promoters, we found that ECR5 is mechanosensitive in vitro and that ECR5-driven Luciferase activity decreases in osteoblasts exposed to oscillatory fluid flow. Yet, ECR5–/– mice showed similar magnitude of load-induced bone formation and similar periosteal distribution of bone formation to high-strain regions compared to wildtype mice. Further, we found that in contrast to Sost–/– mice, which are resistant to disuse-induced bone loss, ECR5–/– mice lose bone upon unloadingmore » to a degree similar to wildtype control mice. ECR5 deletion did not abrogate positive effects of unloading on Sost, suggesting that additional transcriptional regulators and regulatory elements contribute to load-induced regulation of Sost.« less

Authors:
 [1];  [2];  [2];  [3];  [4];  [5];  [3]
  1. Indiana Univ. School of Medicine, Indianapolis, IN (United States); Indiana Univ./Purdue Univ. at Indianapolis, Indianapolis, IN (United States)
  2. Indiana Univ. School of Medicine, Indianapolis, IN (United States)
  3. Univ. of California, Davis, CA (United States)
  4. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
  5. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Univ. of California at Merced, Merced, CA (United States)
Publication Date:
Research Org.:
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1377785
Alternate Identifier(s):
OSTI ID: 1396354
Report Number(s):
LLNL-JRNL-691137
Journal ID: ISSN 8756-3282; PII: S8756328216302472
Grant/Contract Number:  
AC52-07NA27344
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Bone
Additional Journal Information:
Journal Volume: 92; Journal Issue: C; Journal ID: ISSN 8756-3282
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Sost; Sclerostin; Mechanotransduction; ECR5; Enhancer; Skeleton; Disuse

Citation Formats

Robling, Alexander G., Kang, Kyung Shin, Bullock, Whitney A., Foster, William H., Murugesh, Deepa, Loots, Gabriela G., and Genetos, Damian C. Sost, independent of the non-coding enhancer ECR5, is required for bone mechanoadaptation. United States: N. p., 2016. Web. doi:10.1016/j.bone.2016.09.001.
Robling, Alexander G., Kang, Kyung Shin, Bullock, Whitney A., Foster, William H., Murugesh, Deepa, Loots, Gabriela G., & Genetos, Damian C. Sost, independent of the non-coding enhancer ECR5, is required for bone mechanoadaptation. United States. https://doi.org/10.1016/j.bone.2016.09.001
Robling, Alexander G., Kang, Kyung Shin, Bullock, Whitney A., Foster, William H., Murugesh, Deepa, Loots, Gabriela G., and Genetos, Damian C. Sun . "Sost, independent of the non-coding enhancer ECR5, is required for bone mechanoadaptation". United States. https://doi.org/10.1016/j.bone.2016.09.001. https://www.osti.gov/servlets/purl/1377785.
@article{osti_1377785,
title = {Sost, independent of the non-coding enhancer ECR5, is required for bone mechanoadaptation},
author = {Robling, Alexander G. and Kang, Kyung Shin and Bullock, Whitney A. and Foster, William H. and Murugesh, Deepa and Loots, Gabriela G. and Genetos, Damian C.},
abstractNote = {Here, sclerostin (Sost) is a negative regulator of bone formation that acts upon the Wnt signaling pathway. Sost is mechanically regulated at both mRNA and protein level such that loading represses and unloading enhances Sost expression, in osteocytes and in circulation. The non-coding evolutionarily conserved enhancer ECR5 has been previously reported as a transcriptional regulatory element required for modulating Sost expression in osteocytes. Here we explored the mechanisms by which ECR5, or several other putative transcriptional enhancers regulate Sost expression, in response to mechanical stimulation. We found that in vivo ulna loading is equally osteoanabolic in wildtype and Sost–/– mice, although Sost is required for proper distribution of load-induced bone formation to regions of high strain. Using Luciferase reporters carrying the ECR5 non-coding enhancer and heterologous or homologous hSOST promoters, we found that ECR5 is mechanosensitive in vitro and that ECR5-driven Luciferase activity decreases in osteoblasts exposed to oscillatory fluid flow. Yet, ECR5–/– mice showed similar magnitude of load-induced bone formation and similar periosteal distribution of bone formation to high-strain regions compared to wildtype mice. Further, we found that in contrast to Sost–/– mice, which are resistant to disuse-induced bone loss, ECR5–/– mice lose bone upon unloading to a degree similar to wildtype control mice. ECR5 deletion did not abrogate positive effects of unloading on Sost, suggesting that additional transcriptional regulators and regulatory elements contribute to load-induced regulation of Sost.},
doi = {10.1016/j.bone.2016.09.001},
url = {https://www.osti.gov/biblio/1377785}, journal = {Bone},
issn = {8756-3282},
number = C,
volume = 92,
place = {United States},
year = {2016},
month = {9}
}

Journal Article:

Citation Metrics:
Cited by: 6 works
Citation information provided by
Web of Science

Save / Share:

Works referencing / citing this record:

Sost deficiency leads to reduced mechanical strains at the tibia midshaft in strain-matched in vivo loading experiments in mice
journal, April 2018


Sost deficiency leads to reduced mechanical strains at the tibia midshaft in strain-matched in vivo loading experiments in mice
journal, April 2018


Expression of a Degradation‐Resistant β‐Catenin Mutant in Osteocytes Protects the Skeleton From Mechanodeprivation‐Induced Bone Wasting
journal, August 2019


Conditional Activation of NF‐κB Inducing Kinase (NIK) in the Osteolineage Enhances Both Basal and Loading‐Induced Bone Formation
journal, July 2019


Molecular and cellular mechanisms underlying the evolution of form and function in the amniote jaw
journal, August 2019