University of Oulu

Karin H. Nilsson, Petra Henning, Maha El Shahawy, Jianyao Wu, Antti Koskela, Juha Tuukkanen, Christine Perret, Ulf H. Lerner, Claes Ohlsson, and Sofia Movérare-Skrtic (2021) Osteocyte- and late osteoblast-derived NOTUM reduces cortical bone mass in mice. American Journal of Physiology-Endocrinology and Metabolism 2021 320:5, E967-E975,

Osteocyte- and late osteoblast-derived NOTUM reduces cortical bone mass in mice

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Author: Nilsson, Karin H.1; Henning, Petra1; El Shahawy, Maha1,2;
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 Oral Biology, Minia University, Minia, Egypt
3Department of Anatomy and Cell Biology, Faculty of Medicine, Institute of Cancer Research and Translational Medicine, University of Oulu, Oulu, Finl
4Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.9 MB)
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Language: English
Published: American Physiological Society, 2021
Publish Date: 2021-07-08


Osteoporosis is a common skeletal disease, with increased risk of fractures. Currently available osteoporosis treatments reduce the risk of vertebral fractures, mainly dependent on trabecular bone, whereas the effect on nonvertebral fractures, mainly dependent on cortical bone, is less pronounced. WNT signaling is a crucial regulator of bone homeostasis, and the activity of WNTs is inhibited by NOTUM, a secreted WNT lipase. We previously demonstrated that conditional inactivation of NOTUM in all osteoblast lineage cells increases the cortical but not the trabecular bone mass. The aim of the present study was to determine if NOTUM increasing cortical bone is derived from osteoblast precursors/early osteoblasts or from osteocytes/late osteoblasts. First, we demonstrated Notum mRNA expression in Dmp1-expressing osteocytes and late osteoblasts in cortical bone using in situ hybridization. We then developed a mouse model with inactivation of NOTUM in Dmp1-expressing osteocytes and late osteoblasts (Dmp1-creNotumflox/flox mice). We observed that the Dmp1-creNotumflox/flox mice displayed a substantial reduction of Notum mRNA in cortical bone, resulting in increased cortical bone mass and decreased cortical porosity in femur but no change in trabecular bone volume fraction in femur or in the lumbar vertebrae L5 in Dmp1-creNotumflox/flox mice as compared with control mice. In conclusion, osteocytes and late osteoblasts are the principal source of NOTUM in cortical bone, and NOTUM derived from osteocytes/late osteoblasts reduces cortical bone mass. These findings demonstrate that inhibition of osteocyte/late osteoblast-derived NOTUM might be an interesting pharmacological target to increase cortical bone mass and reduce nonvertebral fracture risk.

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Series: American journal of physiology. Endocrinology and metabolism
ISSN: 0193-1849
ISSN-E: 1522-1555
ISSN-L: 0193-1849
Volume: 320
Issue: 5
Pages: E967 - E975
DOI: 10.1152/ajpendo.00565.2020
Type of Publication: A1 Journal article – refereed
Field of Science: 1184 Genetics, developmental biology, physiology
3111 Biomedicine
3121 General medicine, internal medicine and other clinical medicine
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 the Adlerbertska Research Foundation.
Copyright information: © 2021 The Authors. Licensed under Creative Commons Attribution CC-Y 4.0. Published by the American Physiological Society.