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

• Published in: iScience Vol. 20; no. C; pp. 205 - 215
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.10.2019; Elsevier
• Subjects: Biological Sciences; Cell Biology; Molecular Biology; Molecular Biology; Biological Sciences; Cell Biology
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2019.09.023

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. [Display omitted] •Missense mutation in the third beta-propeller of Lrp4 improve bone properties•The R1170W mutation in Lrp4 interferes with sclerostin inhibition in vivo•The R1170W Lrp4 mutation alters the bone wasting effects of mechanical disuse Biological Sciences; Molecular Biology; Cell Biology