First Author | Shim JH | Year | 2013 |
Journal | J Clin Invest | Volume | 123 |
Issue | 9 | Pages | 4010-22 |
PubMed ID | 23945236 | Mgi Jnum | J:201597 |
Mgi Id | MGI:5514448 | Doi | 10.1172/JCI69443 |
Citation | Shim JH, et al. (2013) Schnurri-3 regulates ERK downstream of WNT signaling in osteoblasts. J Clin Invest 123(9):4010-22 |
abstractText | 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 GSK3beta. 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. |