The high bone mass family--the role of Wnt/Lrp5 signaling in the regulation of bone mass.

A G171V mutation in the low-density lipoprotein receptor-related protein 5 (LRP5) was identified as causal for an autosomal dominant high bone mass trait in a single human family. A transgenic mouse line was produced that carries this mutation and develops a high bone mass phenotype that recapitulates the human phenotype. LRP5 is a co-receptor for Wnt and we have investigated the potential role of this gene/protein and the Wnt signaling pathway in mediating the bone formation response to mechanical loading. The G171V mutation results in an increased responsiveness of bone to mechanical load and reduces the threshold of load required to elicit a response. Our studies have shown that the Wnt signaling pathway is activated in response to mechanical loading and this response is greatly enhanced in the presence of the G171V mutation. Additionally, this mutation results in increased transcription of osteoprotegerin (OPG) in response to loading. Thus, the mutation appears to have direct effects at the level of the osteoblast and may also result in a reduction in osteoclastogenesis. The identification of LRP5/Wnt signaling in bone mechanosensation has resulted in a new paradigm for understanding bone formation. Hopefully, knowledge gained from these studies will result in new therapies for treating osteoporosis.