NOTUM inhibition increases endocortical bone formation and bone strength PMID: 30622831

ADC Targets in Oncology

2026-04-10

NOTUM inhibition increases endocortical bone formation and bone strength

Bone Res. 2019 Jan 8;7:2. doi: 10.1038/s41413-018-0038-3.

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

Affiliations

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.