The mass, density, and architecture of the skeleton are adapted to enable it to perform its mechanical, protective, and metabolic functions. Osteoporosis is a condition of lost adaptation characterized by decreased skeletal mass and density and increased skeletal fragility. Many diseases result in increased bone density, including osteopetrosis and Paget's disease, but deformities or bony lesions with decreased skeletal integrity usually accompany these conditions. We have identified a kindred with high bone mass (HBM) yet normally shaped bones. Linkage analysis localized the gene for the HBM trait to chromosome 11 (11q12-13). Subsequent physical mapping and mutation analysis have identified the cause as a point mutation in the LDL receptor-related protein 5 (Lrp5) gene that results in a valine substitution for glycine at position 171 in the protein. This protein is important in the Wnt signaling pathway. The authors have hypothesized that the Lrp5 gene/pathway is part of the mechanism by which bone senses mechanical load. Increased bone strength, HBM, and a phenotype resembling our human kindred develop in transgenic mice carrying the human Lrp5 gene with the HBM mutation. Recent data indicate that the HBM mutation reduces the threshold for response of the skeleton to mechanical load resulting in an overadaptation to normal mechanical loads. This discovery has opened the door to understanding one of the most important paradigms in bone biology, how bones respond and adapt to mechanical loading. Understanding the mechanosensation pathway and its regulation will lead us to new treatments for osteoporosis.
All Science Journal Classification (ASJC) codes
- Endocrinology, Diabetes and Metabolism