Schnurri-3 regulates ERK downstream of WNT signaling in osteoblasts
Jae-Hyuck Shim, … , Laurie H. Glimcher, Dallas C. Jones
Jae-Hyuck Shim, … , Laurie H. Glimcher, Dallas C. Jones
Published August 15, 2013
Citation Information: J Clin Invest. 2013;123(9):4010-4022. https://doi.org/10.1172/JCI69443.
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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

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Figure 6

Inducible knockdown of SHN3 increases bone mass in adult mice.

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Inducible knockdown of SHN3 increases bone mass in adult mice. (A) 8-wee...
(A) 8-week-old WT and Shn3KD mice were fed DOX-containing chow for 6 weeks, and total RNA was extracted from long bones for RT-PCR analysis. Values are normalized to Hprt. (B) 8-week-old WT and Shn3KD mice were fed PBS- or DOX-containing chow for 6 weeks. Femurs from 14-week-old mice were analyzed by μCT. Shown are bone volume fraction, trabecular number, midshaft bone volume fraction (M.BV/TV), and cortical thickness. (C) 8-week-old WT and Shn3KD mice were fed DOX-containing chow for 6 weeks, and femurs from 14-week-old mice were analyzed by histomorphometric analysis. (D) 18-week-old WT and Shn3KD mice were fed DOX-containing chow for 6 weeks, and femurs from 24-week-old mice were analyzed by μCT. Results are presented as mean + SD. *P < 0.05, **P < 0.005, ***P < 0.0005, Student’s t test.