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

Journal Article · · Bone
 [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)
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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.

Research Organization:
Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
Sponsoring Organization:
USDOE
Grant/Contract Number:
AC52-07NA27344
OSTI ID:
1377785
Alternate ID(s):
OSTI ID: 1396354
Report Number(s):
LLNL-JRNL-691137; PII: S8756328216302472
Journal Information:
Bone, Vol. 92, Issue C; ISSN 8756-3282
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 15 works
Citation information provided by
Web of Science

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Mechanical Stimulation of Bone in Vivo Reduces Osteocyte Expression of Sost/Sclerostin journal December 2007
Sclerostin antibody inhibits skeletal deterioration due to reduced mechanical loading journal March 2013
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A 52-kb deletion in theSOST-MEOX1 intergenic region on 17q12-q21 is associated with van Buchem disease in the Dutch population journal May 2002
Genomic deletion of a long-range bone enhancer misregulates sclerostin in Van Buchem disease journal June 2005
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SOST is a target gene for PTH in bone journal August 2005
Prostaglandin E2 Signals Through PTGER2 to Regulate Sclerostin Expression journal March 2011
Pro-Inflammatory Cytokines TNF-Related Weak Inducer of Apoptosis (TWEAK) and TNFα Induce the Mitogen-Activated Protein Kinase (MAPK)-Dependent Expression of Sclerostin in Human Osteoblasts* journal August 2009
Postnatal β-catenin deletion from Dmp1-expressing osteocytes/osteoblasts reduces structural adaptation to loading, but not periosteal load-induced bone formation journal July 2016
Fluid Flow Induction of Cyclo-Oxygenase 2 Gene Expression in Osteoblasts Is Dependent on an Extracellular Signal-Regulated Kinase Signaling Pathway journal February 2002
Control of the SOST Bone Enhancer by PTH Using MEF2 Transcription Factors journal August 2007

Cited By (7)

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
Sost deficiency leads to reduced mechanical strains at the tibia midshaft in strain-matched in vivo loading experiments in mice journal April 2018
Molecular and cellular mechanisms underlying the evolution of form and function in the amniote jaw journal August 2019
Lrp4 Mediates Bone Homeostasis and Mechanotransduction through Interaction with Sclerostin In Vivo journal October 2019
FGF and TGFβ signaling link form and function during jaw development and evolution journal December 2018
Sost deficiency led to a greater cortical bone formation response to mechanical loading and altered gene expression text January 2017

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
Sost
Sclerostin
Mechanotransduction
ECR5
Enhancer
Skeleton
Disuse