The Structure and Function of LRP5: History
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Jake Littman
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Wentian Yang
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Jon Olansen
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Chanika Phornphutkul
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Roy K. Aaron

The LRP5 protein plays a significant role in the highly conserved canonical WNT signaling pathway, also known as the WNT–β-catenin pathway, which is involved in multiple processes, including cell fate determination, organogenesis, limb pattern formation, injury repair, and the pathogenesis of a variety of diseases.

  • LRP5
  • low-density lipoprotein receptor-related protein 5
  • skeletal dysmorphogenesis

1. Introduction

Numerous processes take place within the skeletal system to maintain homeostasis and conserve its role as a protective, supportive, and structural scaffold of the human body. Integral to this goal is the maintenance of adequate bone mineral density (BMD), which is mostly dependent on a finely tuned balance between bone formation by osteoblasts and bone degradation by osteoclasts. Also of utmost importance is the establishment and maintenance of the shape and structure of bone which relies on a myriad of physical and chemical stimuli promoting pattern formation in development, the growth of the juvenile skeleton, and remodeling in response to stress in the adult skeleton. Given the complexity and sheer number of factors that affect skeletal growth, formation, and maintenance, it is not surprising that there is a myriad of pathologies in which aberrations in one or a combination of these processes result in malformations and dysplasias.
The low-density lipoprotein receptor-related protein 5 (LRP5; OMIM 603506 [1]) was first implicated in skeletal pathology in 2001 when it was determined that autosomal recessive loss-of-function pathogenic variants in LRP5, the gene encoding for the LRP5 receptor, leads to osteoporosis-pseudoglioma syndrome (OPPG; OMIM 259770 [2]), a disorder characterized by congenital or infancy-onset vision loss and severe osteoporosis [3]. One year later in 2002, it was determined that an autosomal dominant gain-of-function point variant in LRP5 was the cause of one family’s abnormally high bone mass phenotype without other abnormalities, such as dysmorphogenesis or an increased incidence of fracture [4]. From these studies, and from the growing body of work examining patients with a range of LRP5 variants and bone mass polymorphisms that has emerged since, a seemingly simple conclusion can be drawn. Gain-of-function and other variants that lead to the increased functional capability of the LRP5 receptor are associated with increased bone mass, and loss-of-function and other variants (including nonsense variants [5][6]) that lead to the decreased functional capability of the LRP5 receptor are associated with decreased bone mass. However, this direct correlation is only part of the clinical picture. Variants in LRP5 often lead to phenotypic variability aside from changes in bone mineral density, ranging from grossly observed morphogenetic alterations in the axial, appendicular, and craniomaxillofacial skeleton to cellular-level disturbances in the function of osteoblasts, osteocytes, and osteoclasts, which are both discussed in further detail within this report.

2. The Structure and Function of LRP5

The LRP5 gene contains 23 exons, encodes 1615 amino acids, and is located on chromosome 11q13 [7]. The LRP5 protein is largely extracellular, containing a single transmembrane domain and four extracellular β-propeller motifs [8]. There is some evidence that variants in the first propeller are primarily associated with high bone mass phenotypes, while variants in the second and third propellers are mainly associated with low bone mass phenotypes [9]. However, these patterns are being continuously challenged by the discovery of more variants that do not follow these conventions [10][11][12]. The LRP5 protein plays a significant role in the highly conserved canonical WNT signaling pathway, also known as the WNT–β-catenin pathway, which is involved in multiple processes, including cell fate determination, organogenesis, limb pattern formation, injury repair, and the pathogenesis of a variety of diseases [13][14]. In this pathway, WNT proteins bind to a seven-transmembrane-spanning protein called Frizzled using LRP5 or LRP6 as a co-receptor, leading to a variety of downstream effects that ultimately result in the dissociation of the β-catenin destruction complex and the expression of WNT target genes [14][15]. The structures of LRP5 and LRP6 share over 70% homology, and both are single transmembrane receptors with a large extracellular domain and four tandem β-propeller repeats [16]. There is also considerable crossover in the function of LRP5 and LRP6 [16][17], with some data supporting the notion that certain variants in their associated genes can lead to similar pathophysiological phenotypes [18]. However, there are also distinct differences between the two [14][19], and this review will describe abnormalities arising specifically from LRP5 variants.
A review of WNT signaling and bone homeostasis published in Nature Medicine reported that in every mouse model study examined, increased bone mass was observed as a result of increased pathway activation, and decreased bone mass was observed as a result of increased pathway inhibition [20]. It was also reported in the study that WNT–β-catenin signaling plays essential roles in the synthesis and homeostatic-ratio determination of osteoblasts, osteoclasts, and osteocytes in bone. The study further noted, “WNT signaling represses mesenchymal stem cell (MSC) commitment to the chondrogenic and adipogenic lineages and enhances commitment to, and differentiation along, the osteoblastic lineage. Osteoblast and osteocyte WNT–β-catenin signaling also indirectly represses osteoclast differentiation and bone resorption through the increased secretion of osteoprotegerin” [20]. Furthermore, osteocyte-secreted sclerostin acts as an inhibitor of LRP5 and promotes osteoclast differentiation and resorptive activity [21][22], stimulates the apoptosis of osteoblasts [23], and has been called a “master negative regulator of the canonical WNT signaling in bone tissue” [22]. From this collection of evidence, it becomes clear that alterations in the functionality of the LRP5 receptor and subsequent perturbances in the WNT–β-catenin pathway could feasibly alter the ratio of osteoblasts to osteoclasts and thus influence BMD homeostasis in bone. This hypothesis seems to have been validated in at least one mouse model based on the LRP5 variants discovered in human patients with altered BMD phenotypes [4][8][24].
In addition to the aforementioned roles of the LRP5 receptor and the WNT–β-catenin pathway in bone, a growing body of research has shown that both play a key role in mechanotransduction [25], elucidating another mechanism by which they might affect the formation and remodeling of the skeleton. In multiple studies, LRP5 knockout mice consistently showed diminished responsiveness to mechanical stimulation [26][27], while mice with knock-in genes for commonly found LRP5 variants associated with high bone mass phenotypes showed greater osteogenic response to mechanical stimuli [28]. Recently, further mouse studies have suggested that osteocytes are the principal cell types mediating WNT/LRP5-related bone mass modulations and mechanotransduction [29]. This observation, combined with the assertions that osteocyte density is significantly higher in the craniomaxillofacial skeleton compared to the appendicular skeleton and that skeletal remodeling is more prominent in the facial skeleton than elsewhere [30], provides a plausible mechanism for the emphasis on craniomaxillofacial BMD changes and gross morphogenic alterations observed in patients with LRP5 variant-related high bone mass phenotypes, as discussed later in this report in the section entitled “High Bone Mass Phenotypes Related to LRP5”.
While there is a large body of data supporting the hypothesis that the LRP5 receptor affects bone formation and homeostasis through the canonical WNT–β-catenin signaling pathway, a discussion on LRP5 and bone would not be complete without shedding light on other studies that have pointed to an entirely different mechanism of the LRP5 receptor’s effect on bone. Since 2008, a body of evidence has emerged supporting the hypothesis that LRP5 affects bone mass in a WNT pathway-independent endocrine axis involving duodenum-derived serotonin [31][32][33]. This conclusion has been contested, however [34][35], and it is not yet clear how some of these seemingly incongruous results can be reconciled to create a comprehensive picture of how LRP5 affects the skeletal system.

This entry is adapted from the peer-reviewed paper 10.3390/genes14101846

References

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  2. Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 259770. Available online: https://www.omim.org/entry/259770 (accessed on 30 May 2023).
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