University of Connecticut

Enzo Biochem, Inc.

St. Jude's Childrens Hospital

Enzo Therapeutics, Inc.

Li, Xiaofeng

Liu, Peng

Zhang, Yazhou

Zhang, Jie

Shan, Jufang

Engelhardt, Dean

Jufang Shan

Jie Zheng

Jie Zhang

Dianqing Wu

Dean L Engelhardt

Xiaofeng Li

Yazhou Zhang

Peng Liu

Dean Engelhardt

The mechanism by which the high bone mass (HBM) mutation (G171V) of the Wnt coreceptor LRP5 regulates the canonical Wnt signaling was investigated. The mutation was previously shown to reduce Dkk protein-1-mediated antagonism, suggesting that the first YWTD repeat domain where G171 is located may be responsible for Dkk protein-mediated antagonism. However, we found that the third YWTD repeat, but not the first repeat domain, is required for DKK1-mediated antagonism. Instead, we found that the G171V mutation disrupted the interaction of LRP5 with Mesd, a chaperon protein for LRP5/6 that is required for the coreceptors' transport to cell surfaces, resulting in less LRP5 molecules on the cell surface. Although the reduction in the level of cell surface LRP5 molecules led to a reduction in Wnt signaling in a paracrine paradigm, the mutation did not appear to affect the activity of coexpressed Wnt in an autocrine paradigm. Together with the observation that osteoblast cells produce autocrine canonical Wnt, Wnt7b, and that osteocytes produce paracrine Dkk1, we believe that the G171V mutation may cause an increase in Wnt activity in osteoblasts by reducing the number of targets for paracrine Dkk1 to antagonize without affecting the activity of autocrine Wnt.

Compositions and methods for bone formation and remodeling

Growing community of inventors

Memphis, TN, United States of America

Jufang Shan