Low-density lipoprotein receptor-related protein 5 (LRP5) is a multifunctional transmembrane coreceptor that plays a pivotal role in development and disease. Wnt/β-catenin signaling is the primary downstream signaling pathway activated by LRP5. Furthermore, some LRP5 functions are mediated by noncanonical pathways, such as AKT/P21 and TGF-β/Smad signaling. Pathologically, both loss-of-function and gain-of-function mutations in LRP5 produce distinct phenotypes, ranging from osteoporosis-pseudoglioma syndrome to high bone mass disorders. Beyond the skeletal system, LRP5 has emerged as a key regulator of retinal angiogenesis, vascular integrity, renal tubular function, neurodevelopment, and lipid metabolism. Its physiological functions are highlighted by its ability to influence adipocyte differentiation, insulin sensitivity, and neuronal synaptic plasticity. Moreover, LRP5 displays a dual role in development and disease progression. Although it plays a protective role in acute injuries such as myocardial infarction and acute kidney injury, LRP5 also contributes to chronic pathologies such as tubulointerstitial fibrosis, polycystic kidney disease, and atherosclerosis through fibrotic and inflammatory pathways. Recent therapeutic interest has focused on modulating LRP5 activity using agents such as anti-Dickkopf-related protein 1 antibody, sclerostin inhibitors, polyclonal antibodies, CRISPR/Cas9 knockout, and some natural products. This review discusses the current understanding of LRP5's physiological and pathological roles across organ systems and highlights its therapeutic potential, emphasizing the need for targeted approaches considering its context-dependent effects.

Alterations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene have been associated with primary osteoporosis, leading to recurrent low-trauma fractures. Heterozygous carriers typically show a milder phenotype, with reduced bone mass starting in early childhood. In this paper, we described the clinical features and therapeutic outcomes of a cohort of 7 children (5 males) harboring different variants in the LPR5 gene. Eight heterozygous variants of the LRP5 gene were identified (6 missense, 2 nonsense), two of which were likely pathogenic. One male patient was compound heterozygous, carrying two different variants, including p.(Arg570Gln), previously reported as pathogenic in homozygous form, and exhibited a more severe phenotype consistent with Osteoporosis-Pseudoglioma Syndrome, including vitreoretinal abnormalities. At initial presentation, most patients had a history of low-trauma long bone fractures, or spontaneous vertebral fractures, and bone/joint pain. Five of them received bisphosphonate therapy and one patient also received denosumab. No new fractures occurred during follow-up (9 months-4 years). Bone mineral density (BMD) increased in all patients (3-103%, mean: 55%), and partial vertebral reshaping was described. No adverse effects were reported. This pediatric case series highlights the phenotypic variability of LRP5 gene variants, and underscores the efficacy of bisphosphonate therapy in improving BMD and reducing fracture risk. However, while bisphosphonates remain the standard of care, further research is needed on precision therapies that target Wnt signaling and other pathways affected by LRP5 gene alterations.

The low-density lipoprotein receptor-related protein 5 (LRP5) plays a pivotal role in bone formation, influencing the proliferation and differentiation of osteoblasts and thereby impacting overall bone mass. Genetic variations stemming from non-synonymous single nucleotide polymorphisms (nsSNPs) within the LRP5 gene can lead to either enhanced or diminished function of the resultant protein, culminating in distinct phenotypic expressions such as osteoporosis-pseudoglioma syndrome (OPPG) and high bone mass (HBM). Through in silico analysis of 17 identified nsSNPs, it was observed that 14 of these variants induced damage at highly conserved sites, resulting in the destabilization of both protein function and structure. Notably, the functional alteration, be it a gain or loss, is primarily dictated by the interaction between the molecule and LRP5, rather than the specific amino acid substitution. This research offers an identification of detrimental nsSNPs within the LRP5 protein and serves as a foundation for population-based investigations into the phenotypic repercussions on a broader scale.

This case report details the diagnosis and management of a preterm infant with aggressive bilateral retinal pathology. A 4-week-old preterm baby girl, born at 28 weeks and 6 days to consanguineous parents, was referred for suspected aggressive posterior retinopathy of prematurity (ROP). She had a family history of bilateral retinal detachments and intellectual disability in an older sister. Clinical assessment included retinal examination, fluorescein angiography, optical coherence tomography, dual-energy x-ray absorptiometry (DEXA), and genetic testing. The genetic testing involved sequence analysis and copy number variation analysis of 25 genes related to vitreoretinopathy. Retinal examination and fluorescein angiography revealed extensive nonperfusion and telangiectatic vessels in both eyes, and a macula-involving tractional retinal detachment in the left eye. Despite treatment with intravitreal bevacizumab and laser photocoagulation, they progressed to total retinal detachment and no light perception in both eyes. Genetic testing revealed a pathogenic homozygous nonsense mutation in the LRP5 gene (c.3259C>T, p. (Gln1087*)), a mutation not previously reported in association with familial exudative vitreoretinopathy (FEVR). At 10 months of age, DEXA demonstrated normal bone density, diverging from the typical presentation of osteoporosis pseudoglioma syndrome associated with LRP5 mutations. This case describes a novel mutation in a complex retinal disease and underscores the necessity of considering preterm FEVR in the differential diagnosis of atypical or aggressive ROP in preterm infants. The overlap in clinical features between ROP and FEVR highlights the complexity of diagnosis and management and the importance of genetic testing in preterm infants with retinal vascular abnormalities.

Wnt signaling is one of the key regulators of bone development and homeostasis. Wnt signaling regulates key biological events, including stem cell fate and osteoblast and osteoclast activity, leading to the maintenance of bone mass and strength. Wnt ligands are secreted glycoproteins that bind to Frizzled (FZD) receptors and their coreceptors, lipoprotein receptor-related proteins-5/6 (LRP5/6). Binding of Wnts to FZD triggers canonical (β-catenin-dependent) and noncanonical (β-catenin-independent) pathways. In canonical Wnt signaling, stabilized β-catenin translocates to the nucleus, where it promotes osteoblast differentiation by activating target genes, including Runx2 and Osterix. The negative regulators of Wnt or so-called Wnt antagonists, including CXXC5, sFRP, sclerostin, DKK1, and Notum, compete for Fzd binding, attenuating Wnt signaling. The critical roles of Wnt signaling in bone homeostasis have been established by various bone diseases caused by mutations in Wnt signaling pathways. Loss-of-function mutations in the LRP5 gene cause osteoporosis-pseudoglioma syndrome, whereas gain-of-function mutations are linked to osteopetrosis characterized by high bone density. Sclerosteosis and Van Buchem disease are caused by mutations affecting the SOST gene, which encodes sclerostin, a natural inhibitor of Wnt signalling. Loss-of-function mutations in SOST result in excessive bone growth, markedly increased bone density, and other skeletal abnormalities due to uncontrolled Wnt activity. Considering the clinical relevance of Wnt signaling, targeting Wnt inhibitors is being intensely pursued using small molecules that act by inhibiting endogenous Wnt agonists. We used a computational biology approach to review current data on pharmacophores of Wnt antagonists, assessing their potential as therapeutic candidates for postmenopausal osteoporosis.