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Sci Transl Med. 2018 Nov 7;10(466). pii: eaau7137. doi: 10.1126/scitranslmed.aau7137.

Wnt1 is an Lrp5-independent bone-anabolic Wnt ligand.

Author information

1
Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
2
Department of Orthodontics, University Medical Center Hamburg-Eppendorf, D 20246 Hamburg, Germany.
3
Center for Molecular Neurobiology Hamburg, University Medical Center Hamburg-Eppendorf, D 20251 Hamburg, Germany.
4
Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), D 69120 Heidelberg, Germany.
5
Institute for Translational Immunology and Research Center for Immunotherapy, University Medical Center, Johannes Gutenberg University, D 55131 Mainz, Germany.
6
Institute of Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, D 13353 Berlin, Germany.
7
Berlin-Brandenburg Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, D 13353 Berlin, Germany.
8
Max Planck Institute for Molecular Genetics, D 14195 Berlin, Germany.
9
Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. j.david@uke.de schinke@uke.de amling@uke.de.

Abstract

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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