Lrp4 Mediates Bone Homeostasis and Mechanotransduction through Interaction with Sclerostin In Vivo
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.
- Research Organization:
- Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
- Sponsoring Organization:
- USDOE; National Institutes of Health (NIH); Indiana Clinical and Translational Sciences Institute; NIH National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award
- Grant/Contract Number:
- AC52-07NA27344; AR070624; AR065971; AR069029; DK075730; AR053237; BX001478; BX003783; UL1TR002529
- OSTI ID:
- 1568899
- Alternate ID(s):
- OSTI ID: 1623686; OSTI ID: 1841843
- Report Number(s):
- LLNL-JRNL-791546; S258900421930361X; PII: S258900421930361X
- Journal Information:
- iScience, Journal Name: iScience Vol. 20 Journal Issue: C; ISSN 2589-0042
- Publisher:
- ElsevierCopyright Statement
- Country of Publication:
- Netherlands
- Language:
- English
Web of Science
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