Anabolic actions of Notch on mature bone

Proc Natl Acad Sci U S A. 2016 Apr 12;113(15):E2152-61. doi: 10.1073/pnas.1603399113. Epub 2016 Mar 28.

Abstract

Notch controls skeletogenesis, but its role in the remodeling of adult bone remains conflicting. In mature mice, the skeleton can become osteopenic or osteosclerotic depending on the time point at which Notch is activated or inactivated. Using adult EGFP reporter mice, we find that Notch expression is localized to osteocytes embedded within bone matrix. Conditional activation of Notch signaling in osteocytes triggers profound bone formation, mainly due to increased mineralization, which rescues both age-associated and ovariectomy-induced bone loss and promotes bone healing following osteotomy. In parallel, mice rendered haploinsufficient in γ-secretase presenilin-1 (Psen1), which inhibits downstream Notch activation, display almost-absent terminal osteoblast differentiation. Consistent with this finding, pharmacologic or genetic disruption of Notch or its ligand Jagged1 inhibits mineralization. We suggest that stimulation of Notch signaling in osteocytes initiates a profound, therapeutically relevant, anabolic response.

Keywords: aging; osteoporosis; skeletal mineralization; therapeutic target.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Cells / cytology
  • Bone and Bones / diagnostic imaging
  • Bone and Bones / metabolism*
  • Calcification, Physiologic / physiology
  • Cells, Cultured
  • Female
  • Green Fluorescent Proteins / genetics
  • Jagged-1 Protein / genetics
  • Male
  • Mice, Transgenic
  • Osteoblasts / cytology
  • Osteoblasts / metabolism
  • Osteogenesis / physiology
  • Presenilin-1 / genetics
  • Receptors, Notch / metabolism*
  • Stromal Cells / cytology
  • Stromal Cells / metabolism
  • X-Ray Microtomography

Substances

  • Jag1 protein, mouse
  • Jagged-1 Protein
  • Presenilin-1
  • Receptors, Notch
  • enhanced green fluorescent protein
  • presenilin 1, mouse
  • Green Fluorescent Proteins