Lrp5, encoding low-density lipoprotein receptor-related protein 5, is a co-receptor in the canonical WNT-β-catenin signaling pathway. It is crucial for the formation and maintenance of the human skeleton's homeostasis, and also plays roles in other biological processes such as the regulation of blood-retina barrier function, cardiomyocyte proliferation, and may be related to cell proliferation and invasion in ameloblastoma [1,3,6,7,8].

Loss-of-function variants of Lrp5 cause osteoporosis-pseudoglioma syndrome (OPPG), characterized by congenital blindness and severe childhood-onset osteoporosis. In mouse models, loss of Lrp5 leads to defective osteoblast function and low bone mass, while gain-of-function mutations result in high bone mass phenotypes. For instance, the G171V mutation preventing Dkk from binding to Lrp5 increases its function, leading to high bone mass due to uncoupling of bone formation and resorption. Also, Lrp5 may enhance bone formation by inhibiting tryptophan hydroxylase 1 expression in the duodenum, thus affecting serum serotonin levels which in turn regulate osteoblast proliferation [1,2,4,5].

In conclusion, Lrp5 is essential for skeletal morphogenesis, regulating bone mass through its role in the WNT-β-catenin signaling pathway. Insights from Lrp5-related mouse models have provided valuable information on skeletal disorders like OPPG, high-bone-mass disorders, and may also contribute to understanding other related pathologies such as those in the heart and retina [1,2,4,6,7].