Compositions and methods for bone formation and remodeling

US8367822B2 · kind B2 · utility

Assignee

• ENZO THERAPEUTICS, INC. · US

Inventors

• Dianqing (Dan) Wu · Cheshire, US
• Dakai Liu · South Setauket, US
• James J. Donegan · Amesbury, US

Key dates

• Filing date: Nov 14, 2006
• Grant date: Feb 5, 2013
• Expiry date: Dec 29, 2029

Classification

• Technology area (CPC C): Chemistry; Metallurgy
• CPC primary: C09B19/005
• WIPO field: Pharmaceuticals
• WIPO sector: Chemistry

Abstract

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 paracr…