University of Oulu

Movérare-Skrtic, S., Nilsson, K.H., Henning, P., Funck-Brentano, T., Nethander, M., Rivadeneira, F., Nunes, G.C., Koskela, A., Tuukkanen, J., Tuckermann, J., Perret, C., Souza, P.P.C., Lerner, U.H. and Ohlsson, C. (2019), Osteoblast‐derived NOTUM reduces cortical bone mass in mice and the NOTUM locus is associated with bone mineral density in humans. The FASEB Journal, 33: 11163-11179. doi:10.1096/fj.201900707R

Osteoblast‐derived NOTUM reduces cortical bone mass in mice and the NOTUM locus is associated with bone mineral density in humans

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Author: Movérare-Skrtic, Sofia1; Nilsson, Karin H.1; Henning, Petra1;
Organizations: 1Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Centre for Bone and Arthritis Research at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
2Department of Internal Medicine, Erasmus University Rotterdam, Rotterdam, The Netherlands
3Bone Biology Research Group, School of Dentistry, São Paulo State University (UNESP), Araraquara, Brazil
4Department of Anatomy and Cell Biology, Faculty of Medicine, Institute of Cancer Research and Translational Medicine, University of Oulu, Oulu, Finland
5Institute of General Zoology and Endocrinology, University of Ulm, Ulm, Germany
6INSERM, Unité 1016, Institut Cochin, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
7Equipe Labellisée Ligue Nationale contre le Cancer, Paris, France
8School of Dentistry, Federal University of Goiás, Goiânia, Brazil
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.8 MB)
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Language: English
Published: Federation of American Society for Experimental Biology, 2019
Publish Date: 2020-02-26


Osteoporosis is a common skeletal disease, affecting millions of individuals worldwide. Currently used osteoporosis treatments substantially reduce vertebral fracture risk, whereas nonvertebral fracture risk, mainly caused by reduced cortical bone mass, has only moderately been improved by the osteoporosis drugs used, defining an unmet medical need. Because several wingless‐type MMTV integration site family members (WNTs) and modulators of WNT activity are major regulators of bone mass, we hypothesized that NOTUM, a secreted WNT lipase, might modulate bone mass via an inhibition of WNT activity. To characterize the possible role of endogenous NOTUM as a physiologic modulator of bone mass, we developed global, cell‐specific, and inducible Notum‐inactivated mouse models. Notum expression was high in the cortical bone in mice, and conditional Notum inactivation revealed that osteoblast lineage cells are the principal source of NOTUM in the cortical bone. Osteoblast lineage–specific Notum inactivation increased cortical bone thickness via an increased periosteal circumference. Inducible Notum inactivation in adult mice increased cortical bone thickness as a result of increased periosteal bone formation, and silencing of Notum expression in cultured osteoblasts enhanced osteoblast differentiation. Large‐scale human genetic analyses identified genetic variants mapping to the NOTUM locus that are strongly associated with bone mineral density (BMD) as estimated with quantitative ultrasound in the heel. Thus, osteoblast‐derived NOTUM is an essential local physiologic regulator of cortical bone mass via effects on periosteal bone formation in adult mice, and genetic variants in the NOTUM locus are associated with BMD variation in adult humans. Therapies targeting osteoblast‐derived NOTUM may prevent nonvertebral fractures.

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Series: The FASEB journal
ISSN: 0892-6638
ISSN-E: 1530-6860
ISSN-L: 0892-6638
Volume: 33
Issue: 10
Pages: 11163 - 11179
DOI: 10.1096/fj.201900707R
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Funding: This study was supported by the Swedish Research Council, the Swedish Foundation for Strategic Research, the Swedish state under the agreement between the Swedish government and the county councils, the ALF‐agreement in Gothenburg (Grants 238261, 226481, and 237551), the IngaBritt and Arne Lundberg Foundation, the Royal 80 Year Fund of King Gustav V, the Torsten and Ragnar Söderberg's Foundation, the Knut and Alice Wallenberg Foundation, the Novo Nordisk Foundation, and São Paulo Research Foundation (Grant 2014/05283‐3). J.T. was supported by the Deutsche Forschungsgemeinschaft (DFG) Collaborative Research Centre (CRC) 1149, and G.C.N. was supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES; Finance Code 001). S.M.‐S. and K.H.N. share first authorship.
Copyright information: © FASEB. This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) ( which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.