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.
Highlights
Musculoskeletal diseases are common causes of severe pain and physical disability and their prevalence will increase with the aging of society.[1]
Cortical bone, comprising 80% of skeletal mass, is a major determinant of bone strength and non-vertebral fracture susceptibility, and marrow cavity expansion from endocortical bone loss with age is a major contributor to osteoporosis.[5,6,7,8,9,10]
NOTUM inhibition increases endocortical bone formation We evaluated the mechanism by which NOTUM inhibition increased cortical bone thickness
Summary
Musculoskeletal diseases are common causes of severe pain and physical disability and their prevalence will increase with the aging of society.[1]. Screening gene function in vivo is a powerful approach to discovering novel drug targets.[13,14] Lexicon performed the largest high-throughput phenotypic screening (HTS) campaign to date (4 656 genes) of gene function in mice to identify novel drug targets for various diseases. Besides dentin formation defects, histological examination of 40 soft tissues from Notum−/− mice (N = 8) at 40 weeks of age drug target, NOTUM, a lipase that inactivates WNTs by cleaving the palmitoleate moiety essential for Frizzled receptor binding and activation.[26,27,28] Notum−/− mice have normal trabecular bone mass, but elevated cortical bone thickness and strength. Increased cortical bone mass and strength were observed in both Notum−/− mice and Notum+/− mice compared with wild-
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