Schnurri-3 regulates ERK downstream of WNT signaling in osteoblasts. Academic Article uri icon

Overview

abstract

  • 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 date

  • August 15, 2013

Research

keywords

  • DNA-Binding Proteins
  • Extracellular Signal-Regulated MAP Kinases
  • Osteoblasts
  • Wnt Signaling Pathway

Identity

PubMed Central ID

  • PMC3754267

Scopus Document Identifier

  • 84883531076

Digital Object Identifier (DOI)

  • 10.1016/j.stem.2012.02.003

PubMed ID

  • 23945236

Additional Document Info

volume

  • 123

issue

  • 9