NOTUM inhibition increases endocortical bone formation and bone strength View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-12

AUTHORS

Robert Brommage, Jeff Liu, Peter Vogel, Faika Mseeh, Andrea Y. Thompson, David G. Potter, Melanie K. Shadoan, Gwenn M. Hansen, Sabrina Jeter-Jones, Jie Cui, Dawn Bright, Jennifer P. Bardenhagen, Deon D. Doree, Sofia Movérare-Skrtic, Karin H. Nilsson, Petra Henning, Ulf H. Lerner, Claes Ohlsson, Arthur T. Sands, James E. Tarver, David R. Powell, Brian Zambrowicz, Qingyun Liu

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. More... »

PAGES

2

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41413-018-0038-3

DOI

http://dx.doi.org/10.1038/s41413-018-0038-3

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1111061186

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30622831


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