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  Wnt1 is an Lrp5-independent bone-anabolic Wnt ligand

Luther, J., Yorgan, T. A., Rolvien, T., Ulsamer, L., Koehne, T., Liao, N., et al. (2018). Wnt1 is an Lrp5-independent bone-anabolic Wnt ligand. Science Translational Medicine, 10(466): eaau7137. doi:10.1126/scitranslmed.aau7137.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0003-5A3A-8 Version Permalink: http://hdl.handle.net/21.11116/0000-0003-5A3B-7
Genre: Journal Article

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© 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
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 Creators:
Luther, Julia, Author
Yorgan, Timur Alexander, Author
Rolvien, Tim, Author
Ulsamer, Lorenz, Author
Koehne, Till, Author
Liao, Nannan, Author
Keller, Daniela, Author
Vollersen, Nele, Author
Teufel, Stefan, Author
Neven, Mona, Author
Peters, Stephanie, Author
Schweizer, Michaela, Author
Trumpp, Andreas, Author
Rosigkeit, Sebastian, Author
Bockamp, Ernesto, Author
Mundlos, Stefan1, 2, 3, Author              
Kornak, Uwe1, 2, 3, Author              
Oheim, Ralf, Author
Amling, Michael, Author
Schinke, Thorsten, Author
David, Jean-Pierre, Author more..
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              
2Institute of Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, D 13353 Berlin, Germany, ou_persistent22              
3Berlin-Brandenburg Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, D 13353 Berlin, Germany, ou_persistent22              

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 Abstract: Wnt signaling is important for proper embryonic development, shaping cell fate and migration, stem cell renewal, and organ and tissue formation. Here, Luther et al. investigated the role of Wnt1 in osteoporosis. Patients with early-onset osteoporosis and with WNT1 mutations had low bone turnover and high fracture rates, and loss of Wnt1 activity caused fracture and osteoporosis in mice. Inducing Wnt1 in bone-forming cells increased bone mass in aged mice, and this process did not require Lrp5, a co-receptor involved in Wnt signaling. This study identifies Wnt1 as an anabolic (bone building) factor and suggests that it might be a therapeutic target for osteoporosis.WNT1 mutations in humans are associated with a new form of osteogenesis imperfecta and with early-onset osteoporosis, suggesting a key role of WNT1 in bone mass regulation. However, the general mode of action and the therapeutic potential of Wnt1 in clinically relevant situations such as aging remain to be established. Here, we report the high prevalence of heterozygous WNT1 mutations in patients with early-onset osteoporosis. We show that inactivation of Wnt1 in osteoblasts causes severe osteoporosis and spontaneous bone fractures in mice. In contrast, conditional Wnt1 expression in osteoblasts promoted rapid bone mass increase in developing young, adult, and aged mice by rapidly increasing osteoblast numbers and function. Contrary to current mechanistic models, loss of Lrp5, the co-receptor thought to transmit extracellular WNT signals during bone mass regulation, did not reduce the bone-anabolic effect of Wnt1, providing direct evidence that Wnt1 function does not require the LRP5 co-receptor. The identification of Wnt1 as a regulator of bone formation and remodeling provides the basis for development of Wnt1-targeting drugs for the treatment of osteoporosis.

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Language(s): eng - English
 Dates: 2018-11-07
 Publication Status: Published online
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 Identifiers: DOI: 10.1126/scitranslmed.aau7137
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Title: Science Translational Medicine
Source Genre: Journal
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Pages: - Volume / Issue: 10 (466) Sequence Number: eaau7137 Start / End Page: - Identifier: -