Endothelial Notch activity promotes angiogenesis and osteogenesis in bone

Nature. 2014 Mar 20;507(7492):376-380. doi: 10.1038/nature13146. Epub 2014 Mar 12.

Abstract

Blood vessel growth in the skeletal system and osteogenesis seem to be coupled, suggesting the existence of molecular crosstalk between endothelial and osteoblastic cells. Understanding the nature of the mechanisms linking angiogenesis and bone formation should be of great relevance for improved fracture healing or prevention of bone mass loss. Here we show that vascular growth in bone involves a specialized, tissue-specific form of angiogenesis. Notch signalling promotes endothelial cell proliferation and vessel growth in postnatal long bone, which is the opposite of the well-established function of Notch and its ligand Dll4 in the endothelium of other organs and tumours. Endothelial-cell-specific and inducible genetic disruption of Notch signalling in mice not only impaired bone vessel morphology and growth, but also led to reduced osteogenesis, shortening of long bones, chondrocyte defects, loss of trabeculae and decreased bone mass. On the basis of a series of genetic experiments, we conclude that skeletal defects in these mutants involved defective angiocrine release of Noggin from endothelial cells, which is positively regulated by Notch. Administration of recombinant Noggin, a secreted antagonist of bone morphogenetic proteins, restored bone growth and mineralization, chondrocyte maturation, the formation of trabeculae and osteoprogenitor numbers in endothelial-cell-specific Notch pathway mutants. These findings establish a molecular framework coupling angiogenesis, angiocrine signals and osteogenesis, which may prove significant for the development of future therapeutic applications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Blood Vessels / growth & development
  • Bone Development / drug effects
  • Bone and Bones / blood supply*
  • Bone and Bones / cytology
  • Bone and Bones / drug effects
  • Bone and Bones / metabolism*
  • Calcification, Physiologic / drug effects
  • Carrier Proteins / administration & dosage
  • Carrier Proteins / metabolism
  • Carrier Proteins / pharmacology
  • Cell Proliferation
  • Chondrocytes / cytology
  • Chondrocytes / drug effects
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / metabolism*
  • Female
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neovascularization, Physiologic*
  • Osteogenesis* / drug effects
  • Receptors, Notch / metabolism*
  • Signal Transduction / genetics

Substances

  • Carrier Proteins
  • Receptors, Notch
  • noggin protein