An international consortium of 62 clinicians and scientists led by Howard Hughes Medical Institute investigator Matthew Warman reported the discovery of the cause of the inherited disorder, osteoporosis-pseudoglioma syndrome (OPPG).
Studies of families with OPPG led the researchers to mutations in a completely unsuspected gene called LDL receptor-related protein 5 (LRP5), which codes for a protein whose precise cellular function remains unknown.
Although the researchers were able to identify the region of the genome that apparently harboured the gene mutation responsible for OPPG, they did not zero in on the gene responsible until a good working draft of the human genome sequence became available. This led the research team to LRP5.
According to Warman, genetic studies in several families revealed different types of mutations that eliminated function of the protein produced by LRP5. The scientists then showed in mice that the LRP5 gene was expressed in bone-forming cells, called osteoblasts, and that the gene's activity appeared to increase during differentiation of cells into osteoblasts during bone formation.
Despite these discoveries, one key piece of information was still missing. "We needed to know which signalling pathway was affected by the loss of the LRP5 protein," said Warman. One clue arose from the fact that a relative of LRP5, called LRP6, had been shown to function in a signalling pathway involving a protein called Wnt.
"It was known that the Wnt family of growth factors is involved in many different developmental processes, such as brain and limb patterning," said Warman. "But I do not think anyone had directly implicated Wnts in determining the quantity of bone that is formed."
In addition to implicating LRP5 in bone density, "a second surprise was that carriers of single LRP5 mutations - who have half the normal complement of functional LRP5 genes - also showed reduced bone mass when compared to normal individuals. Thus, LRP5 appears to be something like a bone thermostat that controls the level of bone mineralisation," said Warman.
These findings suggest that enhancing the function of the LRP5-signaling pathway could increase bone density, not only in people suffering rare, severe bone disorders such as OPPG, but also for people with subtler deficiencies in bone mass.
Item provided courtesy of the Howard Hughes Medical Institute.
