DOE PAGES 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 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 degreemore » 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:
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},
journal = {Bone},
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 referenced in this record:

Bone loss in response to long-term immobilisation
journal, August 1978


Reversibility of nontraumatic disuse osteoporosis during its active phase
journal, January 1986


Control of bone architecture by functional load bearing
journal, December 1992


Mechanical Stimulation of Bone in Vivo Reduces Osteocyte Expression of Sost/Sclerostin
journal, December 2007

  • Robling, Alexander G.; Niziolek, Paul J.; Baldridge, Lee A.
  • Journal of Biological Chemistry, Vol. 283, Issue 9
  • DOI: 10.1074/jbc.M705092200

Sclerostin antibody inhibits skeletal deterioration due to reduced mechanical loading
journal, March 2013

  • Spatz, Jordan M.; Ellman, Rachel; Cloutier, Alison M.
  • Journal of Bone and Mineral Research, Vol. 28, Issue 4
  • DOI: 10.1002/jbmr.1807

Sclerostin Mediates Bone Response to Mechanical Unloading Through Antagonizing Wnt/β-Catenin Signaling
journal, October 2009

  • Lin, Chuwen; Jiang, Xuan; Dai, Zhongquan
  • Journal of Bone and Mineral Research, Vol. 24, Issue 10
  • DOI: 10.1359/jbmr.090411

Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease
journal, February 2002


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

  • Staehling-Hampton, Karen; Proll, Sean; Paeper, Bryan W.
  • American Journal of Medical Genetics, Vol. 110, Issue 2
  • DOI: 10.1002/ajmg.10401

Genomic deletion of a long-range bone enhancer misregulates sclerostin in Van Buchem disease
journal, June 2005


Targeted deletion of Sost distal enhancer increases bone formation and bone mass
journal, August 2012

  • Collette, N. M.; Genetos, D. C.; Economides, A. N.
  • Proceedings of the National Academy of Sciences, Vol. 109, Issue 35
  • DOI: 10.1073/pnas.1207188109

TGF-β regulates sclerostin expression via the ECR5 enhancer
journal, March 2012


Targeted Deletion of the Sclerostin Gene in Mice Results in Increased Bone Formation and Bone Strength
journal, February 2008

  • Li, Xiaodong; Ominsky, Michael S.; Niu, Qing-Tian
  • Journal of Bone and Mineral Research, Vol. 23, Issue 6
  • DOI: 10.1359/jbmr.080216

Evidence for a skeletal mechanosensitivity gene on mouse chromosome 4
journal, December 2002

  • Robling, Alexander G.; Li, Jiliang; Shultz, Kathryn L.
  • The FASEB Journal, Vol. 17, Issue 2
  • DOI: 10.1096/fj.02-0393fje

Differential effect of steady versus oscillating flow on bone cells
journal, November 1998


Missense Mutations in LRP5 Associated with High Bone Mass Protect the Mouse Skeleton from Disuse- and Ovariectomy-Induced Osteopenia
journal, November 2015


Modulation of sclerostin expression by mechanical loading and bone morphogenetic proteins in osteogenic cells
journal, January 2009

  • Papanicolaou, Savvas E.; Phipps, Roger J.; Fyhrie, David P.
  • Biorheology, Vol. 46, Issue 5
  • DOI: 10.3233/BIR-2009-0550

Osteocyte-Derived Sclerostin Inhibits Bone Formation: Its Role in Bone Morphogenetic Protein and Wnt Signaling
journal, January 2008

  • ten Dijke, Peter; Krause, Carola; de Gorter, David J. J.
  • Journal of Bone and Joint Surgery, Vol. 90, Issue Supplement_1
  • DOI: 10.2106/JBJS.G.01183

Sclerostin Stimulates Osteocyte Support of Osteoclast Activity by a RANKL-Dependent Pathway
journal, October 2011


Sclerostin Antibody Treatment Increases Bone Formation, Bone Mass, and Bone Strength in a Rat Model of Postmenopausal Osteoporosis*
journal, April 2009

  • Li, Xiaodong; Ominsky, Michael S.; Warmington, Kelly S.
  • Journal of Bone and Mineral Research, Vol. 24, Issue 4
  • DOI: 10.1359/jbmr.081206

Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength
journal, January 2010

  • Ominsky, Michael S.; Vlasseros, Fay; Jolette, Jacquelin
  • Journal of Bone and Mineral Research, Vol. 25, Issue 5
  • DOI: 10.1002/jbmr.14

Inhibition of sclerostin by monoclonal antibody enhances bone healing and improves bone density and strength of nonfractured bones
journal, May 2011

  • Ominsky, Michael S.; Li, Chaoyang; Li, Xiaodong
  • Journal of Bone and Mineral Research, Vol. 26, Issue 5
  • DOI: 10.1002/jbmr.307

Inhibition of sclerostin by systemic treatment with sclerostin antibody enhances healing of proximal tibial defects in ovariectomized rats
journal, March 2012

  • McDonald, Michelle M.; Morse, Alyson; Mikulec, Kathy
  • Journal of Orthopaedic Research, Vol. 30, Issue 10
  • DOI: 10.1002/jor.22109

Effects of sclerostin antibody on healing of a non-critical size femoral bone defect
journal, August 2012

  • Jawad, Muhammad U.; Fritton, Kate E.; Ma, Ting
  • Journal of Orthopaedic Research, Vol. 31, Issue 1
  • DOI: 10.1002/jor.22186

Sclerostin Inhibition Prevents Spinal Cord Injury-Induced Cancellous Bone Loss: SCLEROSTIN ANTIBODY PREVENTS BONE LOSS AFTER SCI
journal, March 2015

  • Beggs, Luke A.; Ye, Fan; Ghosh, Payal
  • Journal of Bone and Mineral Research, Vol. 30, Issue 4
  • DOI: 10.1002/jbmr.2396

Unique regulation of SOST, the sclerosteosis gene, by BMPs and steroid hormones in human osteoblasts
journal, August 2004


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

  • Vincent, Cristina; Findlay, David M.; Welldon, Katie J.
  • Journal of Bone and Mineral Research, Vol. 24, Issue 8
  • DOI: 10.1359/jbmr.090305

Fluid Flow Induction of Cyclo-Oxygenase 2 Gene Expression in Osteoblasts Is Dependent on an Extracellular Signal-Regulated Kinase Signaling Pathway
journal, February 2002

  • Wadhwa, Sunil; Godwin, Stephen L.; Peterson, Donald R.
  • Journal of Bone and Mineral Research, Vol. 17, Issue 2
  • DOI: 10.1359/jbmr.2002.17.2.266

Control of the SOST Bone Enhancer by PTH Using MEF2 Transcription Factors
journal, August 2007

  • Leupin, Olivier; Kramer, Ina; Collette, Nicole M.
  • Journal of Bone and Mineral Research, Vol. 22, Issue 12
  • DOI: 10.1359/jbmr.070804

Works referencing / citing this record:

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

  • Bullock, Whitney A.; Hoggatt, April M.; Horan, Daniel J.
  • Journal of Bone and Mineral Research, Vol. 34, Issue 10
  • DOI: 10.1002/jbmr.3812

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

  • Davis, Jennifer L.; Cox, Linda; Shao, Christine
  • Journal of Bone and Mineral Research, Vol. 34, Issue 11
  • DOI: 10.1002/jbmr.3819

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

  • Albiol, Laia; Cilla, Myriam; Pflanz, David
  • Journal of The Royal Society Interface, Vol. 15, Issue 141
  • DOI: 10.1098/rsif.2018.0012

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