LRP5, encoding the low-density lipoprotein receptor-related protein 5, is a co-receptor in the canonical WNT-β-catenin signaling pathway [1,3,5]. It is crucial for the formation and maintenance of human skeletal homeostasis, playing a fundamental role in regulating embryonic development, injury repair and potentially the pathogenesis of human diseases [1,3]. Genetically engineered mouse models have been instrumental in studying its function [2].

Loss-of-function variants of LRP5 in humans cause osteoporosis-pseudoglioma syndrome (OPPG), characterized by congenital blindness and severe childhood-onset osteoporosis [1,5]. In mice, Lrp5 deletion leads to defective osteoblast function and low bone mass [2]. Conversely, gain-of-function variants are associated with high bone mass phenotypes in both humans and potentially in relevant mouse models [1,4,5,8]. Additionally, Lrp5 may enhance bone formation by inhibiting tryptophan hydroxylase 1 expression in the duodenum, affecting serotonin levels, as seen in Lrp5(- / -) mice [6]. In the heart, Lrp5 is required for neonatal heart regeneration by regulating cardiomyocyte proliferation, and its deletion disrupts myocardial regeneration after injury in mice [7].

In conclusion, LRP5 is essential for skeletal development and homeostasis, as well as for neonatal heart regeneration. Insights from gene knockout mouse models have been key in understanding its role in osteoporosis-related diseases and heart regeneration, providing potential therapeutic targets for these conditions [1,2,5,7].

References:

1. Littman, Jake, Yang, Wentian, Olansen, Jon, Phornphutkul, Chanika, Aaron, Roy K. 2023. LRP5, Bone Mass Polymorphisms and Skeletal Disorders. In Genes, 14, . doi:10.3390/genes14101846. https://pubmed.ncbi.nlm.nih.gov/37895195/

2. Williams, Bart O. 2017. LRP5: From bedside to bench to bone. In Bone, 102, 26-30. doi:10.1016/j.bone.2017.03.044. https://pubmed.ncbi.nlm.nih.gov/28341377/

3. Ren, Qian, Chen, Jiongcheng, Liu, Youhua. 2021. LRP5 and LRP6 in Wnt Signaling: Similarity and Divergence. In Frontiers in cell and developmental biology, 9, 670960. doi:10.3389/fcell.2021.670960. https://pubmed.ncbi.nlm.nih.gov/34026761/

4. De Mattia, Giammarco, Maffi, Michele, Mosca, Marta, Mazzantini, Maurizio. 2023. LRP5 high bone mass (Worth-type autosomal dominant endosteal hyperostosis): case report and historical review of the literature. In Archives of osteoporosis, 18, 112. doi:10.1007/s11657-023-01319-6. https://pubmed.ncbi.nlm.nih.gov/37659026/

5. Levasseur, Régis, Lacombe, Didier, de Vernejoul, Marie Christine. . LRP5 mutations in osteoporosis-pseudoglioma syndrome and high-bone-mass disorders. In Joint bone spine, 72, 207-14. doi:. https://pubmed.ncbi.nlm.nih.gov/15850991/

6. Yadav, Vijay K, Ducy, Patricia. . Lrp5 and bone formation : A serotonin-dependent pathway. In Annals of the New York Academy of Sciences, 1192, 103-9. doi:10.1111/j.1749-6632.2009.05312.x. https://pubmed.ncbi.nlm.nih.gov/20392224/

7. Zhou, Huixing, Zhang, Fulei, Wu, Yahan, Zhou, Liping, Chen, Yi-Han. 2022. LRP5 regulates cardiomyocyte proliferation and neonatal heart regeneration by the AKT/P21 pathway. In Journal of cellular and molecular medicine, 26, 2981-2994. doi:10.1111/jcmm.17311. https://pubmed.ncbi.nlm.nih.gov/35429093/

8. Zhao, Dichen, Sun, Lei, Zheng, Wenbin, Xing, Xiaoping, Li, Mei. 2023. Novel mutation in LRP5 gene cause rare osteosclerosis: cases studies and literature review. In Molecular genetics and genomics : MGG, 298, 683-692. doi:10.1007/s00438-023-02008-2. https://pubmed.ncbi.nlm.nih.gov/36971833/