Schnurri-3 regulates ERK downstream of WNT signaling in osteoblasts.
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.
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York 10065, USA. jas2060@med.cornell.edu
Jae-Hyuck
JH
Shim
Matthew B
MB
Greenblatt
Weiguo
W
Zou
Zhiwei
Z
Huang
Marc N
MN
Wein
Nicholas
N
Brady
Dorothy
D
Hu
Jean
J
Charron
Heather R
HR
Brodkin
Gregory A
GA
Petsko
Dennis
D
Zaller
Bo
B
Zhai
Steven
S
Gygi
Laurie H
LH
Glimcher
Dallas C
DC
Jones
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006801:Humans; D059630:Mesenchymal Stem Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010006:Osteoblasts / Q000378:metabolism*; D010012:Osteogenesis; D010024:Osteoporosis / Q000188:drug therapy / Q000378:metabolism; D017434:Protein Structure, Tertiary; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
D004268:DNA-Binding Proteins; C510834:Schnurri-3 protein, mouse; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3