Bullock, Whitney A.Hoggatt, April M.Horan, Daniel J.Elmendorf, Andrew J.Sato, Amy Y.Bellido, TeresitaLoots, Gabriela G.Pavalko, Fredrick M.Robling, Alexander G.2020-01-032020-01-032019-10-25Bullock, W. A., Hoggatt, A. M., Horan, D. J., Elmendorf, A. J., Sato, A. Y., Bellido, T., … Robling, A. G. (2019). Lrp4 Mediates Bone Homeostasis and Mechanotransduction through Interaction with Sclerostin In Vivo. iScience, 20, 205–215. doi:10.1016/j.isci.2019.09.023https://hdl.handle.net/1805/21730Wnt 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.en-USAttribution-NonCommercial-NoDerivatives 4.0 InternationalBiological SciencesCell BiologyMolecular BiologyArticle