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Notum Deletion From Late-Stage Skeletal Cells Increases Cortical Bone Formation and Potentiates Skeletal Effects of Sclerostin Inhibition |
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| Authors: | Roy B Choi Whitney A Bullock April M Hoggatt Daniel J Horan Emily Z Pemberton Jung Min Hong Xinjun Zhang Xi He Alexander G Robling |
| Affiliation: | 1. Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA Contribution: Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Writing - original draft, Writing - review & editing;2. Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA;3. Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA Contribution: Data curation, Formal analysis, Investigation, Resources, Supervision;4. Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA Contribution: Data curation, Formal analysis, Methodology;5. Division of Biomedical and Applied Sciences, Indiana University School of Dentistry, Indianapolis, IN, USA Contribution: Data curation, Formal analysis, Methodology, Validation;6. F. M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA Department of Neurology, Harvard Medical School, Boston, MA, USA Contribution: Investigation, Methodology, Resources, Validation;7. F. M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA Department of Neurology, Harvard Medical School, Boston, MA, USA Contribution: Conceptualization, Methodology, Resources, Writing - review & editing |
| Abstract: | Wnt signaling plays a vital role in the cell biology of skeletal patterning, differentiation, and maintenance. Notum is a secreted member of the α/β-hydrolase superfamily that hydrolyzes the palmitoleoylate modification on Wnt proteins, thereby disrupting Wnt signaling. As a secreted inhibitor of Wnt, Notum presents an attractive molecular target for improving skeletal health. To determine the cell type of action for Notum's effect on the skeleton, we generated mice with Notum deficiency globally (Notum−/−) and selectively (Notumf/f) in limb bud mesenchyme (Prx1-Cre) and late osteoblasts/osteocytes (Dmp1-Cre). Late-stage deletion induced increased cortical bone properties, similar to global mutants. Notum expression was enhanced in response to sclerostin inhibition, so dual inhibition (Notum/sclerostin) was also investigated using a combined genetic and pharmacologic approach. Co-suppression increased cortical properties beyond either factor alone. Notum suppressed Wnt signaling in cell reporter assays, but surprisingly also enhanced Shh signaling independent of effects on Wnt. Notum is an osteocyte-active suppressor of cortical bone formation that is likely involved in multiple signaling pathways important for bone homeostasis © 2021 American Society for Bone and Mineral Research (ASBMR). |
| Keywords: | ANABOLICS WNT SIGNALING NOTUM PARACRINE PATHWAYS OSTEOCYTES |