Schnurri-3 regulates ERK downstream of WNT signaling in osteoblasts.

TitleSchnurri-3 regulates ERK downstream of WNT signaling in osteoblasts.
Publication TypeJournal Article
Year of Publication2013
AuthorsShim J-H, Greenblatt MB, Zou W, Huang Z, Wein MN, Brady N, Hu D, Charron J, Brodkin HR, Petsko GA, Zaller D, Zhai B, Gygi S, Glimcher LH, Jones DC
JournalJ Clin Invest
Date Published2013 Sep 3
KeywordsAmino Acid Motifs, Amino Acid Sequence, Animals, beta Catenin, Bone and Bones, DNA-Binding Proteins, Extracellular Signal-Regulated MAP Kinases, Glycogen Synthase Kinase 3, HEK293 Cells, Humans, Mesenchymal Stromal Cells, Mice, Mice, Inbred C57BL, Mice, Transgenic, Molecular Sequence Data, Osteoblasts, Osteogenesis, Osteoporosis, Protein Structure, Tertiary, Wnt Signaling Pathway

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.

Alternate JournalJ. Clin. Invest.
PubMed ID23945236
PubMed Central IDPMC3754267
Grant ListHD055601 / HD / NICHD NIH HHS / United States
K99AR055668 / AR / NIAMS NIH HHS / United States
T32 CA070083 / CA / NCI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States