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.

Bone Development: NOTUM inhibition stimulates bone formation

NOTUM is an enzyme that inactivates WNT proteins (which play a key role in early tissue development), and inhibiting NOTUM has been found to increase the formation of endocortical bone (within the cortex, the hard exterior of bone) and enhance bone strength. Existing therapies for osteoporosis (condition causing bone to become weak and brittle) are effective in reducing vertebral, but not non-vertebral, fractures. A team headed by Robert Brommage at Lexicon Pharmaceuticals, Texas aimed to identify novel osteoporosis drug targets in mice. Following inhibition of NOTUM activity, the authors observed increased cortical bone thickness and strength at multiple skeletal sites through stimulation of endocortical bone formation. The team concluded that inhibiting NOTUM activity has good potential as a new therapeutic strategy and could be beneficial in preventing non-vertebral osteoporotic fractures.

Details

Title
NOTUM inhibition increases endocortical bone formation and bone strength
Author
Brommage, Robert 1   VIAFID ORCID Logo  ; Liu, Jeff 2 ; Vogel, Peter 3 ; Mseeh Faika 4 ; Thompson, Andrea Y 5 ; Potter, David G 6 ; Shadoan, Melanie K 7 ; Hansen, Gwenn M 8 ; Jeter-Jones, Sabrina 4 ; Cui Jie 9 ; Bright, Dawn 5 ; Bardenhagen, Jennifer P 4 ; Doree, Deon D 10 ; Movérare-Skrtic Sofia 11 ; Nilsson, Karin H 11 ; Henning, Petra 11 ; Lerner, Ulf H 11 ; Ohlsson Claes 11 ; Sands, Arthur T 8 ; Tarver, James E 12 ; Powell, David R 5 ; Zambrowicz, Brian 13 ; Liu, Qingyun 14 

 Lexicon Pharmaceuticals, The Woodlands, USA (GRID:grid.417425.1) ; University of Gothenburg, Centre for Bone and Arthritis Research, Gothenburg, Sweden (GRID:grid.8761.8) (ISNI:0000 0000 9919 9582) 
 Lexicon Pharmaceuticals, The Woodlands, USA (GRID:grid.417425.1) ; Biogen, Cambridge, MA, USA (GRID:grid.417832.b) (ISNI:0000 0004 0384 8146) 
 Lexicon Pharmaceuticals, The Woodlands, USA (GRID:grid.417425.1) ; St. Jude Children’s Research Hospital, Memphis, USA (GRID:grid.240871.8) (ISNI:0000 0001 0224 711X) 
 Lexicon Pharmaceuticals, The Woodlands, USA (GRID:grid.417425.1) ; MD Anderson Cancer Center, Houston, USA (GRID:grid.240145.6) (ISNI:0000 0001 2291 4776) 
 Lexicon Pharmaceuticals, The Woodlands, USA (GRID:grid.417425.1) 
 Lexicon Pharmaceuticals, The Woodlands, USA (GRID:grid.417425.1) ; Bethyl Laboratories, Montgomery, USA (GRID:grid.417425.1) 
 Lexicon Pharmaceuticals, The Woodlands, USA (GRID:grid.417425.1) ; Merck, Rahway, USA (GRID:grid.453555.7) 
 Lexicon Pharmaceuticals, The Woodlands, USA (GRID:grid.417425.1) ; Nurix, San Francisco, USA (GRID:grid.417425.1) 
 Lexicon Pharmaceuticals, The Woodlands, USA (GRID:grid.417425.1) ; Wntrix, Houston, USA (GRID:grid.417425.1) 
10  Lexicon Pharmaceuticals, The Woodlands, USA (GRID:grid.417425.1) ; PRA Health Sciences, Raleigh, USA (GRID:grid.419301.e) (ISNI:0000 0004 0467 423X) 
11  The Sahlgrenska Academy at University of Gothenburg, Centre for Bone and Arthritis Research, Institute of Medicine, Gothenburg, Sweden (GRID:grid.8761.8) (ISNI:0000 0000 9919 9582) 
12  Lexicon Pharmaceuticals, The Woodlands, USA (GRID:grid.417425.1) ; University of Pennsylvania, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972) 
13  Lexicon Pharmaceuticals, The Woodlands, USA (GRID:grid.417425.1) ; Regeneron Pharmaceuticals, Tarrytown, USA (GRID:grid.418961.3) (ISNI:0000 0004 0472 2713) 
14  Lexicon Pharmaceuticals, The Woodlands, USA (GRID:grid.417425.1) ; University of Texas, Houston, USA (GRID:grid.267308.8) (ISNI:0000 0000 9206 2401) 
Publication year
2019
Publication date
Jan 2019
Publisher
Springer Nature B.V.
ISSN
20954700
e-ISSN
20956231
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2164542672
Copyright
This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.