Novel Regulators of Bone Formation

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Project Summary / Abstract Little is known about the regulation of postnatal bone formation. We have recently identified an adaptor protein called Schnurri-3 (Shn3, also KRC) that controls adult bone mass. Schnurri-3, a mammalian homologue of Drosophila Shn, is a potent and essential regulator of adult bone formation. Mice lacking Shn3 display an osteosclerotic phenotype with profoundly increased bone mass due to augmented osteoblast activity. Shn3 controls protein levels of Runx2, the principal regulator of osteoblast differentiation, by promoting its degradation. Shn3 promotes the formation of a complex between Runx2 and the E3 ubiquitin ligase WWP1. This complex inhibits Runx2 function due to the ability of WWP1 to promote Runx2 polyubiquitination and proteasome-dependent degradation. We have recent evidence that the cytokine TGF¿ intersects with the Shn3/WWP1 pathway and that this pathway has substrates in addition to Runx2. Thus, while our studies reveal an essential role for Shn3 as a regulator of postnatal bone mass, many questions about the function and mechanism of action of Shn3 and WWP1 in osteoblast biology remain. Here we propose to pursue our discovery of Shn3 as an essential regulator of bone formation We will interrogate its function, upstream inducers, substrates and downstream targets in the osteoblast. We have the following specific aims: 1) Investigate the upstream signals of Shn3 and WWP1 in the osteoblast. 2) Investigate the downstream substrates of Shn3 and WWP1 in the osteoblast Relevance Osteoporosis afflicts an estimated 10 million Americans over age 50 with 34 million Americans at risk and coupled with the aging of the American population leads to the prediction that the rate of osteoporosis related fractures may triple by the year 2020 unless we seek to improve the prevention, diagnosis, and treatment of bone disease. We have identified a novel pathway consisting of an adapter protein, Schnurri-3 and an E3 ligase WWP1 that control adult bone formation. These new proteins offer exciting targets for the development of anabolics that act at the level of the osteoblast to increase bone mass.