LDL Receptor-Related Protein 5 (LRP5) Affects Bone Accrual and Eye Development

Abstract

In humans, low peak bone mass is a significant risk factor for osteoporosis. We report that LRP5, encoding the low-density lipoprotein receptor-related protein 5, affects bone mass accrual during growth. Mutations in LRP5 cause the autosomal recessive disorder osteoporosis-pseudoglioma syndrome (OPPG). We find that OPPG carriers have reduced bone mass when compared to age- and gender-matched controls. We demonstrate LRP5 expression by osteoblasts in situ and show that LRP5 can transduce Wnt signaling in vitro via the canonical pathway. We further show that a mutant-secreted form of LRP5 can reduce bone thickness in mouse calvarial explant cultures. These data indicate that Wnt-mediated signaling via LRP5 affects bone accrual during growth and is important for the establishment of peak bone mass.

Atherosclerotic Calcification: Wnt Is the Hint

“…During development, canonical ligand Wnt3a maintains apical ectodermal cells of limb buds in a highly proliferative state and is, thus, essential to embryonic skeletal development 110, 111. Loss‐of‐function mutations of Wnt coreceptor LRP5 cause reduced bone mass, skeletal fragility, and osteoporosis 112. LRP5 −/− mice have increased tibial fractures because of an overall decrease in bone mass and reduced osteoblast proliferation and function with no effect on bone resorption, whereas single‐allele knockouts of LRP5 lead to an intermediate phenotype of bone mass.…”

Genetic predisposition for femoral neck stress fractures in military conscripts

“…Because sequence variations in COL1A1 , COL1A2 , LRP5 , OPG , and ESR1 increase the risk of low bone mass or osteoporotic fractures, we first examined their possible role in the pathogenesis of stress fractures by scanning all their exons and exon boundaries in the 72 subjects and the 120 controls for mutations using CSGE [14,15,17,20]. The analysis revealed no putative disease-causing mutations.…”

“…The function of LRP5 in bone development, however, is indisputable [41]; mutations in LRP5 cause various bone disorders [20,42] and polymorphisms are associated with BMD and bone mineral content in general [43], but also with reduced BMD and fractures [44]. Mouse studies demonstrated that mutations in Lrp5 affect bone formation sensitivity in response to normal mechanical loading [45,46], and thus the LRP5 haplotype A-G-G-C might affect bone sensitivity and response to mechanical loading.…”

“…Polymerase chain reaction amplification of 51 exons of COL1A1 , 52 exons of COL1A2 , and 23 exons of LRP5 was performed from 72 cases and 120 controls as previously described [14,20]. Primers were designed to amplify the 8 exons of OPG and the 5 exons of ESR1 (available on request).…”

“…Mutations or allelic variants in the genes leading to a variety of bone pathologies that increase bone fragility, such as collagen I, ( COL1A1 and COL1A2 ) [14,15], vitamin D receptor ( VDR ) [16], osteoprotegerin ( OPG ) [17], calcitonin receptor ( CTR ) [18], estrogen receptor ( ESR ) [19], low density lipoprotein receptor-related protein 5 ( LRP5 ) [20], and interleukin 6 ( IL-6 ) [21] may also increase the risk of stress fractures. Sequence variations in these genes are associated with a low peak bone mass, osteoporosis, osteogenesis imperfecta, osteoporosis-pseudoglioma syndrome, and high bone mass, but their role in predisposing to stress fracture is not clear [14-21].…”