NOTUM inhibition increases endocortical bone formation and bone strength
| Autor: | Qingyun Liu, Sabrina Jeter-Jones, Dawn Bright, Sofia Movérare-Skrtic, Peter Vogel, Jeff Liu, David Potter, Arthur T. Sands, Faika Mseeh, Petra Henning, Ulf H. Lerner, Robert Brommage, David R. Powell, Karin H Nilsson, James E. Tarver, Claes Ohlsson, Andrea Y. Thompson, Gwenn M. Hansen, Jennifer Bardenhagen, Brian Zambrowicz, Melanie K. Shadoan, Jie Cui, Deon Doree |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Histology animal structures Anabolism Physiology Endocrinology Diabetes and Metabolism Osteoporosis 030209 endocrinology & metabolism Stimulation Article lcsh:Physiology 03 medical and health sciences 0302 clinical medicine Internal medicine medicine lcsh:QH301-705.5 Gene knockout lcsh:QP1-981 business.industry fungi Wnt signaling pathway medicine.disease Notum 030104 developmental biology medicine.anatomical_structure Endocrinology lcsh:Biology (General) Ovariectomized rat Cortical bone business |
| Zdroj: | Bone Research, Vol 7, Iss 1, Pp 1-12 (2019) Bone Research |
| ISSN: | 2095-6231 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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