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 [1,2,3,4]. Beyond its role in the skeleton, it also participates in other biological processes such as regulating the blood-retina barrier function [6] and cardiomyocyte proliferation in neonatal heart regeneration [7].

Loss-of-function variants of Lrp5 cause osteoporosis-pseudoglioma syndrome (OPPG), characterized by congenital blindness and severe childhood-onset osteoporosis [1,4]. In mice, Lrp5 deficiency leads to defective osteoblast function and low bone mass [2]. The use of genetically engineered mouse models, like Lrp5 knockout (KO) or conditional knockout (CKO) mouse models, has provided insights into its role in skeletal homeostasis. For example, loss of Lrp5 function increases serum serotonin levels in mice and OPPG patients, suggesting a Wnt-independent pathway through which Lrp5 controls bone formation [5].

In conclusion, Lrp5 is essential for skeletal development and homeostasis, and its dysregulation is associated with skeletal disorders such as OPPG. Insights from Lrp5 KO/CKO mouse models have been crucial in understanding its role in these disease conditions, providing potential targets for the treatment of bone-related disorders.