Wnt co-receptors Lrp5 and Lrp6 differentially mediate Wnt3a signaling in osteoblasts
Abstract
Wnt3a is a major regulator of bone metabolism however, very few of its target genes are known in bone. Wnt3a preferentially signals through transmembrane receptors Frizzled and co-receptors Lrp5/6 to activate the canonical signaling pathway. Previous studies have shown that the canonical Wnt co-receptors Lrp5 and Lrp6 also play an essential role in normal postnatal bone homeostasis, yet, very little is known about specific contributions by these co-receptors in Wnt3a-dependent signaling. We used high-throughput sequencing technology to identify target genes regulated by Wnt3a in osteoblasts and to elucidate the role of Lrp5 and Lrp6 in mediating Wnt3a signaling. Our study identified 782 genes regulated by Wnt3a in primary calvarial osteoblasts. Wnt3a up-regulated the expression of several key regulators of osteoblast proliferation/ early stages of differentiation while inhibiting genes expressed in later stages of osteoblastogenesis. We also found that Lrp6 is the key mediator of Wnt3a signaling in osteoblasts and Lrp5 played a less significant role in mediating Wnt3a signaling.
- Publication Date:
- Research Org.:
- Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
- Sponsoring Org.:
- USDOE; LLNL Laboratory Directed Research and Development (LDRD) Program
- OSTI Identifier:
- 1410403
- Alternate Identifier(s):
- OSTI ID: 1458683
- Report Number(s):
- LLNL-JRNL-737141
Journal ID: ISSN 1932-6203; 10.1371/journal.pone.0188264
- Grant/Contract Number:
- AC52-07NA27344
- Resource Type:
- Published Article
- Journal Name:
- PLoS ONE
- Additional Journal Information:
- Journal Name: PLoS ONE Journal Volume: 12 Journal Issue: 11; Journal ID: ISSN 1932-6203
- Publisher:
- Public Library of Science
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES; osteoblasts; gene expression; Wnt signaling cascade; gene regulation; osteoblast differentiation; bone development; MAPK signaling cascades; gene targeting
Citation Formats
Sebastian, Aimy, Hum, Nicholas R., Murugesh, Deepa K., Hatsell, Sarah, Economides, Aris N., Loots, Gabriela G., and Kim, ed., Jung-Eun. Wnt co-receptors Lrp5 and Lrp6 differentially mediate Wnt3a signaling in osteoblasts. United States: N. p., 2017.
Web. doi:10.1371/journal.pone.0188264.
Sebastian, Aimy, Hum, Nicholas R., Murugesh, Deepa K., Hatsell, Sarah, Economides, Aris N., Loots, Gabriela G., & Kim, ed., Jung-Eun. Wnt co-receptors Lrp5 and Lrp6 differentially mediate Wnt3a signaling in osteoblasts. United States. https://doi.org/10.1371/journal.pone.0188264
Sebastian, Aimy, Hum, Nicholas R., Murugesh, Deepa K., Hatsell, Sarah, Economides, Aris N., Loots, Gabriela G., and Kim, ed., Jung-Eun. Mon .
"Wnt co-receptors Lrp5 and Lrp6 differentially mediate Wnt3a signaling in osteoblasts". United States. https://doi.org/10.1371/journal.pone.0188264.
@article{osti_1410403,
title = {Wnt co-receptors Lrp5 and Lrp6 differentially mediate Wnt3a signaling in osteoblasts},
author = {Sebastian, Aimy and Hum, Nicholas R. and Murugesh, Deepa K. and Hatsell, Sarah and Economides, Aris N. and Loots, Gabriela G. and Kim, ed., Jung-Eun},
abstractNote = {Wnt3a is a major regulator of bone metabolism however, very few of its target genes are known in bone. Wnt3a preferentially signals through transmembrane receptors Frizzled and co-receptors Lrp5/6 to activate the canonical signaling pathway. Previous studies have shown that the canonical Wnt co-receptors Lrp5 and Lrp6 also play an essential role in normal postnatal bone homeostasis, yet, very little is known about specific contributions by these co-receptors in Wnt3a-dependent signaling. We used high-throughput sequencing technology to identify target genes regulated by Wnt3a in osteoblasts and to elucidate the role of Lrp5 and Lrp6 in mediating Wnt3a signaling. Our study identified 782 genes regulated by Wnt3a in primary calvarial osteoblasts. Wnt3a up-regulated the expression of several key regulators of osteoblast proliferation/ early stages of differentiation while inhibiting genes expressed in later stages of osteoblastogenesis. We also found that Lrp6 is the key mediator of Wnt3a signaling in osteoblasts and Lrp5 played a less significant role in mediating Wnt3a signaling.},
doi = {10.1371/journal.pone.0188264},
journal = {PLoS ONE},
number = 11,
volume = 12,
place = {United States},
year = {Mon Nov 27 00:00:00 EST 2017},
month = {Mon Nov 27 00:00:00 EST 2017}
}
Free Publicly Available Full Text
Publisher's Version of Record
https://doi.org/10.1371/journal.pone.0188264
https://doi.org/10.1371/journal.pone.0188264
Other availability
Search WorldCat to find libraries that may hold this journal
Cited by: 23 works
Citation information provided by
Web of Science
Web of Science
Figures / Tables:
Table 1 : Part 1: Top 25 up- and down-regulated genes.
All figures and tables
(10 total)
Save to My Library
You must Sign In or Create an Account in order to save documents to your library.
Works referenced in this record:
Epidermal Growth Factor Receptor (EGFR) Signaling Promotes Proliferation and Survival in Osteoprogenitors by Increasing Early Growth Response 2 (EGR2) Expression
journal, May 2013
- Chandra, Abhishek; Lan, Shenghui; Zhu, Ji
- Journal of Biological Chemistry, Vol. 288, Issue 28
Biphasic effects of transforming growth factor β on bone morphogenetic protein-induced osteoblast differentiation
journal, May 2011
- de Gorter, David JJ; van Dinther, Maarten; Korchynskyi, Olexandr
- Journal of Bone and Mineral Research, Vol. 26, Issue 6
Glucocorticoid-dependent Wnt signaling by mature osteoblasts is a key regulator of cranial skeletal development in mice
journal, January 2009
- Zhou, H.; Mak, W.; Kalak, R.
- Development, Vol. 136, Issue 3
Wnt-Lrp5 Signaling Regulates Fatty Acid Metabolism in the Osteoblast
journal, March 2015
- Frey, Julie L.; Li, Zhu; Ellis, Jessica M.
- Molecular and Cellular Biology, Vol. 35, Issue 11
Wnt10b Increases Postnatal Bone Formation by Enhancing Osteoblast Differentiation
journal, August 2007
- Bennett, Christina N.; Ouyang, Hongjiao; Ma, Yanfei L.
- Journal of Bone and Mineral Research, Vol. 22, Issue 12
TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions
journal, January 2013
- Kim, Daehwan; Pertea, Geo; Trapnell, Cole
- Genome Biology, Vol. 14, Issue 4
TopHat: discovering splice junctions with RNA-Seq
journal, March 2009
- Trapnell, Cole; Pachter, Lior; Salzberg, Steven L.
- Bioinformatics, Vol. 25, Issue 9
Wnt 3a promotes proliferation and suppresses osteogenic differentiation of adult human mesenchymal stem cells
journal, January 2004
- Boland, Genevieve M.; Perkins, Geraldine; Hall, David J.
- Journal of Cellular Biochemistry, Vol. 93, Issue 6
E2F1 effects on osteoblast differentiation and mineralization are mediated through up-regulation of frizzled-1
journal, October 2013
- Yu, Shibing; Yerges-Armstrong, Laura M.; Chu, Yanxia
- Bone, Vol. 56, Issue 2
Trimmomatic: a flexible trimmer for Illumina sequence data
journal, April 2014
- Bolger, Anthony M.; Lohse, Marc; Usadel, Bjoern
- Bioinformatics, Vol. 30, Issue 15
Lrp5 and Lrp6 Exert Overlapping Functions in Osteoblasts during Postnatal Bone Acquisition
journal, May 2013
- Riddle, Ryan C.; Diegel, Cassandra R.; Leslie, Julie M.
- PLoS ONE, Vol. 8, Issue 5
Wnt11 Promotes Osteoblast Maturation and Mineralization through R-spondin 2
journal, February 2009
- Friedman, Michael S.; Oyserman, Sivan M.; Hankenson, Kurt D.
- Journal of Biological Chemistry, Vol. 284, Issue 21
Regulation of bone mass by Wnt signaling
journal, May 2006
- Krishnan, V.
- Journal of Clinical Investigation, Vol. 116, Issue 5
Loss of wnt/β-catenin signaling causes cell fate shift of preosteoblasts from osteoblasts to adipocytes
journal, October 2012
- Song, Lige; Liu, Minlin; Ono, Noriaki
- Journal of Bone and Mineral Research, Vol. 27, Issue 11
BMP-2 Controls Alkaline Phosphatase Expression and Osteoblast Mineralization by a Wnt Autocrine Loop
journal, October 2003
- Rawadi, Georges; Vayssière, Béatrice; Dunn, Fred
- Journal of Bone and Mineral Research, Vol. 18, Issue 10
TGF-β and BMP Signaling in Osteoblast Differentiation and Bone Formation
journal, January 2012
- Chen, Guiqian; Deng, Chuxia; Li, Yi-Ping
- International Journal of Biological Sciences, Vol. 8, Issue 2
Building bone to reverse osteoporosis and repair fractures
journal, February 2008
- Khosla, Sundeep; Westendorf, Jennifer J.; Oursler, Merry Jo
- Journal of Clinical Investigation, Vol. 118, Issue 2
Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks
journal, March 2012
- Trapnell, Cole; Roberts, Adam; Goff, Loyal
- Nature Protocols, Vol. 7, Issue 3
TGF-β and BMP signaling in osteoblast, skeletal development, and bone formation, homeostasis and disease
journal, April 2016
- Wu, Mengrui; Chen, Guiqian; Li, Yi-Ping
- Bone Research, Vol. 4, Issue 1
featureCounts: an efficient general purpose program for assigning sequence reads to genomic features
journal, November 2013
- Liao, Y.; Smyth, G. K.; Shi, W.
- Bioinformatics, Vol. 30, Issue 7
Fibroblast growth factor receptor 1 signaling in the osteo-chondrogenic cell lineage regulates sequential steps of osteoblast maturation
journal, August 2006
- Jacob, Anne L.; Smith, Craig; Partanen, Juha
- Developmental Biology, Vol. 296, Issue 2
Ectopic Expression of SOX9 in Osteoblasts Alters Bone Mechanical Properties
journal, December 2011
- Liang, Bojian; Cotter, Meghan M.; Chen, Dongxing
- Calcified Tissue International, Vol. 90, Issue 2
Wnt Signaling Inhibits Osteoclast Differentiation by Activating Canonical and Noncanonical cAMP/PKA Pathways: Wnt INHIBITS OC DIFFERENTIATION BY CANONICAL/NONCANONICAL PATHWAYS
journal, August 2015
- Weivoda, Megan M.; Ruan, Ming; Hachfeld, Christine M.
- Journal of Bone and Mineral Research, Vol. 31, Issue 1
Predominant role of PDGF receptor transactivation in Wnt3a-induced osteoblastic cell proliferation
journal, January 2013
- Caverzasio, Joseph; Biver, Emmanuel; Thouverey, Cyril
- Journal of Bone and Mineral Research, Vol. 28, Issue 2
Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method
journal, December 2001
- Livak, Kenneth J.; Schmittgen, Thomas D.
- Methods, Vol. 25, Issue 4
Transcriptional control of Sost in bone
journal, March 2017
- Sebastian, Aimy; Loots, Gabriela G.
- Bone, Vol. 96
Cbfa1 -independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor
journal, April 2002
- Kato, Masaki; Patel, Millan S.; Levasseur, Regis
- The Journal of Cell Biology, Vol. 157, Issue 2
Mutations in WNT1 Cause Different Forms of Bone Fragility
journal, April 2013
- Keupp, Katharina; Beleggia, Filippo; Kayserili, Hülya
- The American Journal of Human Genetics, Vol. 92, Issue 4
SOST Inhibits Prostate Cancer Invasion
journal, November 2015
- Hudson, Bryan D.; Hum, Nicholas R.; Thomas, Cynthia B.
- PLOS ONE, Vol. 10, Issue 11
An LDL-receptor-related protein mediates Wnt signalling in mice
journal, September 2000
- Pinson, Kathleen I.; Brennan, Jane; Monkley, Susan
- Nature, Vol. 407, Issue 6803
The complex world of WNT receptor signalling
journal, November 2012
- Niehrs, Christof
- Nature Reviews Molecular Cell Biology, Vol. 13, Issue 12
Activation of non-canonical Wnt/JNK pathway by Wnt3a is associated with differentiation fate determination of human bone marrow stromal (mesenchymal) stem cells
journal, September 2011
- Qiu, Weimin; Chen, Li; Kassem, Moustapha
- Biochemical and Biophysical Research Communications, Vol. 413, Issue 1
Wnt Proteins Promote Bone Regeneration
journal, April 2010
- Minear, S.; Leucht, P.; Jiang, J.
- Science Translational Medicine, Vol. 2, Issue 29
Gene array analysis of Wnt-regulated genes in C3H10T1/2 cells
journal, April 2005
- Jackson, Amanda; Vayssière, Béatrice; Garcia, Teresa
- Bone, Vol. 36, Issue 4
edgeR: a Bioconductor package for differential expression analysis of digital gene expression data
journal, November 2009
- Robinson, M. D.; McCarthy, D. J.; Smyth, G. K.
- Bioinformatics, Vol. 26, Issue 1
Pin1-mediated Modification Prolongs the Nuclear Retention of β-Catenin in Wnt3a-induced Osteoblast Differentiation
journal, January 2016
- Shin, Hye-Rim; Islam, Rabia; Yoon, Won-Joon
- Journal of Biological Chemistry, Vol. 291, Issue 11
Vitamin D endocrine system and osteoblasts
journal, February 2014
- van Driel, Marjolein; van Leeuwen, Johannes P. T. M.
- BoneKEy Reports, Vol. 3
Crucial roles of canonical Runx2-dependent pathway on Wnt1-induced osteoblastic differentiation of human periodontal ligament fibroblasts
journal, January 2015
- Kook, Sung-Ho; Heo, Jung Sun; Lee, Jeong-Chae
- Molecular and Cellular Biochemistry, Vol. 402, Issue 1-2
An experimental model of partial insulin-like growth factor-1 deficiency in mice
journal, September 2013
- Castilla-Cortazar, I.; Guerra, L.; Puche, J. E.
- Journal of Physiology and Biochemistry, Vol. 70, Issue 1
BEDTools: a flexible suite of utilities for comparing genomic features
journal, January 2010
- Quinlan, Aaron R.; Hall, Ira M.
- Bioinformatics, Vol. 26, Issue 6
Decreased BMD and Limb Deformities in Mice Carrying Mutations in Both Lrp5 and Lrp6
journal, September 2004
- Holmen, Sheri L.; Giambernardi, Troy A.; Zylstra, Cassandra R.
- Journal of Bone and Mineral Research, Vol. 19, Issue 12
CCN1/Cyr61 Is Regulated by the Canonical Wnt Signal and Plays an Important Role in Wnt3A-Induced Osteoblast Differentiation of Mesenchymal Stem Cells
journal, March 2006
- Si, W.; Kang, Q.; Luu, H. H.
- Molecular and Cellular Biology, Vol. 26, Issue 8
Regulation of osteoblastogenesis and bone mass by Wnt10b
journal, February 2005
- Bennett, C. N.; Longo, K. A.; Wright, W. S.
- Proceedings of the National Academy of Sciences, Vol. 102, Issue 9
FGF18 is required for normal cell proliferation and differentiation during osteogenesis and chondrogenesis
journal, April 2002
- Ohbayashi, N.
- Genes & Development, Vol. 16, Issue 7
High Bone Density Due to a Mutation in LDL-Receptor–Related Protein 5
journal, May 2002
- Boyden, Lynn M.; Mao, Junhao; Belsky, Joseph
- New England Journal of Medicine, Vol. 346, Issue 20
ToppGene Suite for gene list enrichment analysis and candidate gene prioritization
journal, May 2009
- Chen, J.; Bardes, E. E.; Aronow, B. J.
- Nucleic Acids Research, Vol. 37, Issue Web Server
High-bone-mass-producing mutations in the Wnt signaling pathway result in distinct skeletal phenotypes
journal, November 2011
- Niziolek, Paul J.; Farmer, Takeisha L.; Cui, Yajun
- Bone, Vol. 49, Issue 5
Mechanotransduction in bone tissue: The A214V and G171V mutations in Lrp5 enhance load-induced osteogenesis in a surface-selective manner
journal, September 2012
- Niziolek, Paul J.; Warman, Matthew L.; Robling, Alexander G.
- Bone, Vol. 51, Issue 3
voom: precision weights unlock linear model analysis tools for RNA-seq read counts
journal, January 2014
- Law, Charity W.; Chen, Yunshun; Shi, Wei
- Genome Biology, Vol. 15, Issue 2
Wnt Protein Signaling Reduces Nuclear Acetyl-CoA Levels to Suppress Gene Expression during Osteoblast Differentiation
journal, April 2016
- Karner, Courtney M.; Esen, Emel; Chen, Jiakun
- Journal of Biological Chemistry, Vol. 291, Issue 25
The Wnt Co-receptor LRP5 Is Essential for Skeletal Mechanotransduction but Not for the Anabolic Bone Response to Parathyroid Hormone Treatment
journal, June 2006
- Sawakami, Kimihiko; Robling, Alexander G.; Ai, Minrong
- Journal of Biological Chemistry, Vol. 281, Issue 33
LDL Receptor-Related Protein 5 (LRP5) Affects Bone Accrual and Eye Development
journal, November 2001
- Gong, Yaoqin; Slee, Roger B.; Fukai, Naomi
- Cell, Vol. 107, Issue 4
Platelet-derived growth factor promotes osteoblast proliferation by activating G-protein-coupled receptor kinase interactor-1
journal, July 2014
- Wu, You; Zhang, Ying; Yin, Qingshui
- Molecular Medicine Reports, Vol. 10, Issue 3
Downregulation of ErbB3 by Wnt3a contributes to wnt-induced osteoblast differentiation in mesenchymal cells
journal, April 2012
- Jullien, Nicolas; Maudinet, Adrien; Leloutre, Benjamin
- Journal of Cellular Biochemistry, Vol. 113, Issue 6
Figures/Tables have been extracted from DOE-funded journal article accepted manuscripts.