Submit a comment

Schnurri-3 regulates ERK downstream of WNT signaling in osteoblasts
Jae-Hyuck Shim, Matthew B. Greenblatt, Weiguo Zou, Zhiwei Huang, Marc N. Wein, Nicholas Brady, Dorothy Hu, Jean Charron, Heather R. Brodkin, Gregory A. Petsko, Dennis Zaller, Bo Zhai, Steven Gygi, Laurie H. Glimcher, Dallas C. Jones
Jae-Hyuck Shim, Matthew B. Greenblatt, Weiguo Zou, Zhiwei Huang, Marc N. Wein, Nicholas Brady, Dorothy Hu, Jean Charron, Heather R. Brodkin, Gregory A. Petsko, Dennis Zaller, Bo Zhai, Steven Gygi, Laurie H. Glimcher, Dallas C. Jones
View: Text | PDF
Research Article Bone biology

Schnurri-3 regulates ERK downstream of WNT signaling in osteoblasts

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.

Authors

Jae-Hyuck Shim, Matthew B. Greenblatt, Weiguo Zou, Zhiwei Huang, Marc N. Wein, Nicholas Brady, Dorothy Hu, Jean Charron, Heather R. Brodkin, Gregory A. Petsko, Dennis Zaller, Bo Zhai, Steven Gygi, Laurie H. Glimcher, Dallas C. Jones

×

Guidelines

The Editorial Board will only consider comments that are deemed relevant and of interest to readers. The Journal will not post data that have not been subjected to peer review; or a comment that is essentially a reiteration of another comment.

  • Comments appear on the Journal’s website and are linked from the original article’s web page.
  • Authors are notified by email if their comments are posted.
  • The Journal reserves the right to edit comments for length and clarity.
  • No appeals will be considered.
  • Comments are not indexed in PubMed.

Specific requirements

  • Maximum length, 400 words
  • Entered as plain text or HTML
  • Author’s name and email address, to be posted with the comment
  • Declaration of all potential conflicts of interest (even if these are not ultimately posted); see the Journal’s conflict-of-interest policy
  • Comments may not include figures
This field is required
This field is required
This field is required
This field is required
This field is required
This field is required