Schnurri-3 and its interaction with ERK and WNT signaling

Glimcher's group previously documented that mice deficient in Schnurri-3 (SHN3 or HIVEP3) exhibit increased bone formation.1 Schnurri proteins are large zinc finger proteins that are critical for the regulation of bone mass. In this study the same group used transgenic mice to investigate how SHN3 behaves in osteoblasts, with the intention of informing therapeutic development.2

A series of experiments revealed that SHN3 damped down activity of extracellular signal-regulated kinase (ERK), an effect mediated by a D-domain motif in the SHN3 protein. This inhibition was shown to occur downstream of WNT signaling in osteoblasts, reducing osteoblast differentiation.

Several observations were interesting from a potential therapeutic viewpoint. A knockin mutation that blocked interaction between SHN3 and ERK led to hyperactivity of osteoblasts in vivo. The osteosclerotic phenotype of Shn3 knockout mice was partially rescued by crossing them with mice lacking expression of low-density lipoprotein receptor-related protein 5. In the mouse strain Shn3^KD, which bore a doxycycline-inducible Shn3 shRNA construct, adult mice had increased bone mass compared to wild-type mice.

Editor's comment: These findings warrant further investigation in terms of developing new therapeutics for osteoporosis. However, it remains to be shown that the potentially therapeutic effects of manipulating Shn3 are specific to mice, or whether they can be extrapolated to humans.