The mechanism by which the high bone mass (HBM) mutation (G171V) of the Wntcoreceptor LRP5 regulates the canonical Wnt signaling was investigated. Themutation was previously shown to reduce Dkk protein-1-mediated antagonism,suggesting that the first YWTD repeat domain where G171 is located may beresponsible for Dkk protein-mediated antagonism. However, we found that thethird YWTD repeat, but not the first repeat domain, is required for DKK1-mediated antagonism. Instead, we found that the G171V mutation disrupted theinteraction of LRP5 with Mesd, a chaperon protein for LRP5/6 molecules on thecell surface. Although the reduction in the level of cell surface LRP5molecules led to a reduction in Wnt signaling in a paracrine paradigm, themutation did not appear to affect the activity of coexpressed Wnt in anautocrine paradigm. Together with the observation that osteoblast cellsproduce autocrine canonical Wnt, Wnt7b, and that osteocytes produce paracrineDkk1, we believe that the G171V mutation may cause an increase in Wnt activityin osteoblastls by reducing the numnber of targets for paracrine Dkk1 toantagonize without affecting the activity of autocrine Wnt.
