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Susan M. Ott, Editorial: Sclerostin and Wnt Signaling—The Pathway to Bone Strength, The Journal of Clinical Endocrinology & Metabolism, Volume 90, Issue 12, 1 December 2005, Pages 6741–6743, https://doi.org/10.1210/jc.2005-2370
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The realization that Wnt signaling was critical to bone strength came to those in the bone field suddenly and from several directions. Whereas a search of ASBMR (American Society for Bone and Mineral Research) abstracts about Wnt, LRP5 (low-density-lipoprotein-receptor-related protein 5), or Dickkopf (Dkk) returned a void in 2000, there were 111 reports at the most recent meetings. The various discoveries read like a story, with surprises, coincidences, and promise for a better treatment of osteoporosis.
In 1997 clinical investigators from Creighton University reported a kindred with high bone mass. The proband was an 18-yr-old girl who had back pain after an automobile accident. Radiographs showed dense but otherwise normal bones, and the bone mineral density was 5.6 sd values above average for age. Her mother had similarly dense bones with a bone density z-score of 4.98 but no skeletal symptoms. This led to an extended survey of this family whose members carried the “high bone mass” gene (1). Using linkage analysis, they demonstrated that the trait was located to a region on chromosome 11q12–13. Recombinant events in two of the individuals significantly refined the interval, and further analysis, including a search for mutations, revealed that the family members with high bone mass had a single point mutation in the LRP5 gene (2). This was not on any list of candidate genes involved in bone metabolism. Shortly afterward, an unrelated kindred was reported that carried the identical mutation, G171V, which was also associated with high bone density (3). In both studies, the inheritance was autosomal dominant. Meanwhile, another group of investigators discovered that a different mutation in the LRP5 gene caused the osteoporosis-pseudoglioma syndrome, a devastating disease manifested by multiple fractures and blindness, which was inherited as an autosomal recessive disorder. The heterozygotic carriers had low bone density and increased risk of fractures (4).
