LRP5
Tóm tắt
Several lines of evidence have provided compelling support for low-density lipoprotein receptor-related protein 5 (LRP5) and the canonical Wnt/β-catenin signaling pathway as being important and essential for bone formation. Lrp 5 and its close homolog, Lrp6, are coreceptors with frizzled for Wnt proteins. Binding of Wnt proteins to Lrp5/6 and frizzled activates the Wnt/β-catenin signaling pathway. Mutations in Lrp5 have been shown to give rise to human diseases of low bone mass and loss of vision such as osteoporosis pseudoglioma syndrome (OPPG) and familial exudative vitreoretinopathy (FEVR) as well as several human conditions with increased bone mass and reduced fracture risk, such as the high bone mass (HBM) phenotype. Although it is well established that the Lrp5/6-Wnt canonical pathway is important in embryonic growth and development of the skeleton, its role in the adult skeleton is not clear. Accumulating evidence now supports an important role for Lrp5 in the response of the postnatal skeleton to mechanical load. Transgenic mice carrying the human HBM mutation (LRP5G171V) have increased sensitivity to load, and mice lacking Lrp5 do not respond to mechanical load. In vivo loading of LRP5G171V mice tibia results in increased osteoprotegerin (OPG) gene expression. Mice with either gain-or loss-of-function mutations in protein components of the canonical pathway below the level of Lrp5/6 develop high or low bone mass mainly as a consequence of altered OPG production by osteoblasts, which subsequently alters osteoclastogenesis. Thus, activation of the canonical Wnt signaling pathway apparently has multiple modes of action on bone cells to regulate bone mass. Given the clear importance of LRP5 in regulating bone mass, this gene/protein represents a potentially exciting new target for the development of anabolic agents to treat osteoporosis.
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