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NOTUM inhibition increases endocortical bone formation and bone strength
Robert Brommage1,2, Jeff Liu1,3, Peter Vogel1,4
11Lexicon Pharmaceuticals, The Woodlands, TX USA.
Bone Research
|January 10, 2019
Summary
Inhibiting NOTUM, a WNT lipase, significantly increased cortical bone thickness and strength in mice. This discovery offers a promising new anabolic therapy for preventing non-vertebral osteoporotic fractures.
Area of Science:
- Bone Biology and Osteoporosis Research
- Drug Discovery and Development
Background:
- Non-vertebral osteoporotic fractures cause significant disability, mortality, and healthcare costs.
- Current osteoporosis treatments effectively reduce vertebral fractures but not non-vertebral ones.
- Cortical bone properties are critical for non-vertebral bone strength.
Purpose of the Study:
- To identify novel therapeutic targets for osteoporosis by examining cortical bone in knockout mouse strains.
- To investigate the role of NOTUM (a WNT lipase) in regulating cortical bone mass and strength.
Main Methods:
- Phenotyping cortical bone in 3,366 mouse strains with global knockouts of druggable genes.
- Assessing NOTUM expression in bone cells (osteoblasts and osteoclasts).
- Developing and testing small molecules and a neutralizing antibody to inhibit NOTUM lipase activity in rodent models.
Main Results:
- Cortical bone thickness was significantly increased in mice lacking NOTUM.
- NOTUM is highly expressed in cortical bone and osteoblasts.
- NOTUM inhibition via small molecules or antibody increased cortical bone thickness and strength in rodents, stimulating endocortical bone formation.
Conclusions:
- NOTUM is a key regulator of cortical bone mass and strength.
- Inhibiting NOTUM activity represents a potential novel anabolic therapeutic strategy for osteoporosis.
- Targeting NOTUM may be effective in preventing non-vertebral fractures by enhancing cortical bone strength.
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