The Genetics of Low-Density Lipoprotein Receptor-Related Protein 5 in Bone: A Story of Extremes

Abstract

A few years ago, human genetic studies provided compelling evidence that the low-density lipoprotein receptor-related protein 5 (LRP5) is involved in the regulation of bone homeostasis because pathogenic LRP5 mutations were found in monogenic conditions with abnormal bone density. On the one hand, the osteoporosis pseudoglioma syndrome results from loss of function of LRP5, whereas on the other hand, gain-of-function mutations in LRP5 cause conditions with an increased bone density. On the molecular level, these types of mutations result in disturbed (respectively, decreased and increased) canonical Wnt signaling, an important metabolic pathway in osteoblasts during embryonic and postnatal osteogenesis. This signaling cascade is activated by binding of Wnt ligand to the Frizzled/LRP5 receptor complex. In addition to the involvement of LRP5 in conditions with extreme bone phenotypes, the genetic profile of this gene has also been shown to contribute to the determination of bone density in the general population. Quite a number of studies already demonstrated that common polymorphic variants in LRP5 are associated with bone mineral density and consequently osteoporosis, a multifactorial trait with low bone mass and porous bone structure. These genetic studies together with results obtained from in vitro and in vivo studies emphasize the importance of LRP5 and canonical Wnt signaling in the regulation of bone homeostasis. Therefore, unraveling the exact mechanisms of this signaling cascade has become an important area in bone research. This review focuses on the genetics of LRP5 and summarizes the findings on monogenic bone conditions as well as the current knowledge of its involvement in the pathogenesis of osteoporosis.