DR. JIE ZHANG, M.D
Medical Practice at Madison Ave, Memphis, TN

8637506, Jan 28, 2014

May 19, 2004

10/849067

Dianqing Wu - Chesire CT, US
Yazhou Zhang - Farmington CT, US
Peng Liu - West Hartford CT, US
Xiaofeng Li - West Hartford CT, US
Jie Zhang - Memphis TN, US
Jufang Shan - Memphis TN, US
Dean Engelhardt - New York NY, US

Enzo Biochem, Inc. - Farmingdale NY
University of Connecticut - Farmington CT
St. Jude's Childrens Hospital - Memphis TN

A61K 31/535, C07C 50/18

5142298, 552208

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.