Schnurri-3 regulates ERK downstream of WNT signaling in osteoblasts

J Clin Invest. 2013 Sep;123(9):4010-22. doi: 10.1172/JCI69443. Epub 2013 Aug 15.


Mice deficient in Schnurri-3 (SHN3; also known as HIVEP3) display increased bone formation, but harnessing this observation for therapeutic benefit requires an improved understanding of how SHN3 functions in osteoblasts. Here we identified SHN3 as a dampener of ERK activity that functions in part downstream of WNT signaling in osteoblasts. A D-domain motif within SHN3 mediated the interaction with and inhibition of ERK activity and osteoblast differentiation, and knockin of a mutation in Shn3 that abolishes this interaction resulted in aberrant ERK activation and consequent osteoblast hyperactivity in vivo. Additionally, in vivo genetic interaction studies demonstrated that crossing to Lrp5(-/-) mice partially rescued the osteosclerotic phenotype of Shn3(-/-) mice; mechanistically, this corresponded to the ability of SHN3 to inhibit ERK-mediated suppression of GSK3β. Inducible knockdown of Shn3 in adult mice resulted in a high-bone mass phenotype, providing evidence that transient blockade of these pathways in adults holds promise as a therapy for osteoporosis.

Publication types

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

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Bone and Bones / metabolism
  • Bone and Bones / pathology
  • Bone and Bones / physiopathology
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / physiology*
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • HEK293 Cells
  • Humans
  • Mesenchymal Stem Cells
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Molecular Sequence Data
  • Osteoblasts / metabolism*
  • Osteogenesis
  • Osteoporosis / drug therapy
  • Osteoporosis / metabolism
  • Protein Structure, Tertiary
  • Wnt Signaling Pathway*
  • beta Catenin / metabolism


  • DNA-Binding Proteins
  • Schnurri-3 protein, mouse
  • beta Catenin
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Extracellular Signal-Regulated MAP Kinases
  • Glycogen Synthase Kinase 3