[HTML][HTML] Schnurri-3 regulates ERK downstream of WNT signaling in osteoblasts

JH Shim, MB Greenblatt, W Zou… - The Journal of …, 2013 - Am Soc Clin Investig
JH Shim, MB Greenblatt, W Zou, Z Huang, MN Wein, N Brady, D Hu, J Charron, HR Brodkin…
The Journal of clinical investigation, 2013Am Soc Clin Investig
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 …
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.
The Journal of Clinical Investigation