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NOTUM inhibition increases endocortical bone formation and bone strength

Journal article
Authors Robert Brommage
J. Liu
P. Vogel
F. Mseeh
A. Y. Thompson
D. G. Potter
M. K. Shadoan
G. M. Hansen
S. Jeter-Jones
J. Cui
D. Bright
J. P. Bardenhagen
D. D. Doree
Sofia Moverare-Skrtic
Karin H. Nilsson
Petra Henning
Ulf H Lerner
Claes Ohlsson
A. T. Sands
J. E. Tarver
D. R. Powell
B. Zambrowicz
Q. Y. Liu
Published in Bone Research
Volume 7
ISSN 2095-4700
Publication year 2019
Published at Centre for Bone and Arthritis Research
Language en
Links dx.doi.org/10.1038/s41413-018-0038-...
Keywords non-vertebral fractures, cortical-bone, lining cells, non-hip, osteoclastogenesis, romosozumab, mutations, dysplasia, fragility, database, Cell Biology
Subject categories Rheumatology and Autoimmunity

Abstract

The disability, mortality and costs caused by non-vertebral osteoporotic fractures are enormous. Existing osteoporosis therapies are highly effective at reducing vertebral but not non-vertebral fractures. Cortical bone is a major determinant of non-vertebral bone strength. To identify novel osteoporosis drug targets, we phenotyped cortical bone of 3 366 viable mouse strains with global knockouts of druggable genes. Cortical bone thickness was substantially elevated in Notum(-/-) mice. NOTUM is a secreted WNT lipase and we observed high NOTUM expression in cortical bone and osteoblasts but not osteoclasts. Three orally active small molecules and a neutralizing antibody inhibiting NOTUM lipase activity were developed. They increased cortical bone thickness and strength at multiple skeletal sites in both gonadal intact and ovariectomized rodents by stimulating endocortical bone formation. Thus, inhibition of NOTUM activity is a potential novel anabolic therapy for strengthening cortical bone and preventing non-vertebral fractures.

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