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Notum Deletion From Late-Stage Skeletal Cells Increases Cortical Bone Formation and Potentiates Skeletal Effects of

Roy B Choi1, Whitney A Bullock1, April M Hoggatt1

  • 1Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA.

Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research
|July 5, 2021
PubMed

Insights

Notum, a Wnt signaling inhibitor, is an osteocyte-active suppressor of cortical bone formation. Dual inhibition of Notum and sclerostin significantly improved bone properties, suggesting therapeutic potential for skeletal health.

Area of Science:

  • Skeletal biology
  • Molecular signaling
  • Bone homeostasis

Background:

  • Wnt signaling is crucial for skeletal development and maintenance.
  • Notum, an enzyme, inhibits Wnt signaling by removing a key modification.
  • Targeting Notum offers a potential strategy for enhancing skeletal health.

Purpose of the Study:

  • To identify the specific cell types mediating Notum's skeletal effects.
  • To investigate the combined effects of Notum and sclerostin inhibition on bone.
  • To explore Notum's impact on other signaling pathways in bone.

Main Methods:

  • Generation of global and conditional Notum-deficient mouse models (Notum-/- , Prx1-Cre, Dmp1-Cre).
  • Assessment of cortical bone properties in Notum-deficient mice.
  • Combined genetic and pharmacologic inhibition of Notum and sclerostin.
  • Wnt and Shh signaling reporter assays in cell models.

Main Results:

  • Global and late-stage Notum deficiency increased cortical bone properties.
  • Dual inhibition of Notum and sclerostin yielded synergistic improvements in cortical bone.
  • Notum suppressed Wnt signaling but also enhanced Shh signaling independently.
  • Notum acts on osteocytes to suppress cortical bone formation.

Conclusions:

  • Notum is an osteocyte-specific suppressor of cortical bone formation.
  • Combined Notum and sclerostin inhibition presents a promising therapeutic approach for bone health.
  • Notum's influence extends to multiple signaling pathways regulating bone homeostasis.
Keywords:
ANABOLICSNOTUMOSTEOCYTESPARACRINE PATHWAYSWNT SIGNALING

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