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Title: Lrp4 Mediates Bone Homeostasis and Mechanotransduction through Interaction with Sclerostin In Vivo

Abstract

Wnt signaling plays a key role in regulating bone remodeling. In vitro studies suggest that sclerostin's inhibitory action on Lrp5 is facilitated by the membrane-associated receptor Lrp4. We generated an Lrp4 R1170W knockin mouse model (Lrp4KI), based on a published mutation in patients with high bone mass (HBM). Lrp4KI mice have an HBM phenotype (assessed radiographically), including increased bone strength and formation. Overexpression of a Sost transgene had osteopenic effects in Lrp4-WT but not Lrp4KI mice. Conversely, sclerostin inhibition had blunted osteoanabolic effects in Lrp4KI mice. In a disuse-induced bone wasting model, Lrp4KI mice exhibit significantly less bone loss than wild-type (WT) mice. In summary, mice harboring the Lrp4-R1170W missense mutation recapitulate the human HBM phenotype, are less sensitive to altered sclerostin levels, and are protected from disuse-induced bone loss. Lrp4 is an attractive target for pharmacological targeting aimed at increasing bone mass and preventing bone loss due to disuse.

Authors:
; ; ; ; ; ; ; ; ORCiD logo
Publication Date:
Research Org.:
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Sponsoring Org.:
USDOE; National Institutes of Health (NIH); Indiana Clinical and Translational Sciences Institute; NIH National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award
OSTI Identifier:
1568899
Alternate Identifier(s):
OSTI ID: 1623686
Grant/Contract Number:  
AC52-07NA27344; AR070624; AR065971; AR069029; DK075730; AR053237; BX001478; BX003783; UL1TR002529
Resource Type:
Published Article
Journal Name:
iScience
Additional Journal Information:
Journal Name: iScience Journal Volume: 20 Journal Issue: C; Journal ID: ISSN 2589-0042
Publisher:
Elsevier
Country of Publication:
Netherlands
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Science & Technology - Other Topics

Citation Formats

Bullock, Whitney A., Hoggatt, April M., Horan, Daniel J., Elmendorf, Andrew J., Sato, Amy Y., Bellido, Teresita, Loots, Gabriela G., Pavalko, Fredrick M., and Robling, Alexander G. Lrp4 Mediates Bone Homeostasis and Mechanotransduction through Interaction with Sclerostin In Vivo. Netherlands: N. p., 2019. Web. doi:10.1016/j.isci.2019.09.023.
Bullock, Whitney A., Hoggatt, April M., Horan, Daniel J., Elmendorf, Andrew J., Sato, Amy Y., Bellido, Teresita, Loots, Gabriela G., Pavalko, Fredrick M., & Robling, Alexander G. Lrp4 Mediates Bone Homeostasis and Mechanotransduction through Interaction with Sclerostin In Vivo. Netherlands. doi:https://doi.org/10.1016/j.isci.2019.09.023
Bullock, Whitney A., Hoggatt, April M., Horan, Daniel J., Elmendorf, Andrew J., Sato, Amy Y., Bellido, Teresita, Loots, Gabriela G., Pavalko, Fredrick M., and Robling, Alexander G. Tue . "Lrp4 Mediates Bone Homeostasis and Mechanotransduction through Interaction with Sclerostin In Vivo". Netherlands. doi:https://doi.org/10.1016/j.isci.2019.09.023.
@article{osti_1568899,
title = {Lrp4 Mediates Bone Homeostasis and Mechanotransduction through Interaction with Sclerostin In Vivo},
author = {Bullock, Whitney A. and Hoggatt, April M. and Horan, Daniel J. and Elmendorf, Andrew J. and Sato, Amy Y. and Bellido, Teresita and Loots, Gabriela G. and Pavalko, Fredrick M. and Robling, Alexander G.},
abstractNote = {Wnt signaling plays a key role in regulating bone remodeling. In vitro studies suggest that sclerostin's inhibitory action on Lrp5 is facilitated by the membrane-associated receptor Lrp4. We generated an Lrp4 R1170W knockin mouse model (Lrp4KI), based on a published mutation in patients with high bone mass (HBM). Lrp4KI mice have an HBM phenotype (assessed radiographically), including increased bone strength and formation. Overexpression of a Sost transgene had osteopenic effects in Lrp4-WT but not Lrp4KI mice. Conversely, sclerostin inhibition had blunted osteoanabolic effects in Lrp4KI mice. In a disuse-induced bone wasting model, Lrp4KI mice exhibit significantly less bone loss than wild-type (WT) mice. In summary, mice harboring the Lrp4-R1170W missense mutation recapitulate the human HBM phenotype, are less sensitive to altered sclerostin levels, and are protected from disuse-induced bone loss. Lrp4 is an attractive target for pharmacological targeting aimed at increasing bone mass and preventing bone loss due to disuse.},
doi = {10.1016/j.isci.2019.09.023},
journal = {iScience},
number = C,
volume = 20,
place = {Netherlands},
year = {2019},
month = {10}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
DOI: https://doi.org/10.1016/j.isci.2019.09.023

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