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Title: 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.

Authors:
 [1];  [1];  [2];  [3];  [3]; ORCiD logo [1]
  1. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Physical and Life Sciences Directorate; Univ. of California, Merced, CA (United States). School of Natural Sciences
  2. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Physical and Life Sciences Directorate
  3. Regeneron Pharmaceuticals, Tarrytown, NY (United States)
Publication Date:
Research Org.:
Lawrence Livermore National Lab. (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; 890036
Grant/Contract Number:  
AC52-07NA27344
Resource Type:
Journal Article: Published Article
Journal Name:
PLoS ONE
Additional Journal Information:
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., and Loots, Gabriela G.. 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.. Wnt co-receptors Lrp5 and Lrp6 differentially mediate Wnt3a signaling in osteoblasts. United States. doi:10.1371/journal.pone.0188264.
Sebastian, Aimy, Hum, Nicholas R., Murugesh, Deepa K., Hatsell, Sarah, Economides, Aris N., and Loots, Gabriela G.. Mon . "Wnt co-receptors Lrp5 and Lrp6 differentially mediate Wnt3a signaling in osteoblasts". United States. doi: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.},
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}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record at 10.1371/journal.pone.0188264

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