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The Genetics of Low-Density Lipoprotein Receptor-Related Protein 5 in Bone: A Story of Extremes

Department of Medical Genetics, University and University Hospital of Antwerp, B-2610 Antwerp, Belgium

Address all correspondence and requests for reprints to: Wim Van Hul, Department of Medical Genetics, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium. E-mail: wim.vanhul{at}ua.ac.be.

	Abstract

Top Abstract Introduction LRP5 and Monogenic Bone... LRP5 and Osteoporosis Functional Aspects of LRP5... Conclusions References

 
A few years ago, human genetic studies provided compelling evidence that the low-density lipoprotein receptor-related protein 5 (LRP5) is involved in the regulation of bone homeostasis because pathogenic LRP5 mutations were found in monogenic conditions with abnormal bone density. On the one hand, the osteoporosis pseudoglioma syndrome results from loss of function of LRP5, whereas on the other hand, gain-of-function mutations in LRP5 cause conditions with an increased bone density. On the molecular level, these types of mutations result in disturbed (respectively, decreased and increased) canonical Wnt signaling, an important metabolic pathway in osteoblasts during embryonic and postnatal osteogenesis. This signaling cascade is activated by binding of Wnt ligand to the Frizzled/LRP5 receptor complex. In addition to the involvement of LRP5 in conditions with extreme bone phenotypes, the genetic profile of this gene has also been shown to contribute to the determination of bone density in the general population. Quite a number of studies already demonstrated that common polymorphic variants in LRP5 are associated with bone mineral density and consequently osteoporosis, a multifactorial trait with low bone mass and porous bone structure. These genetic studies together with results obtained from in vitro and in vivo studies emphasize the importance of LRP5 and canonical Wnt signaling in the regulation of bone homeostasis. Therefore, unraveling the exact mechanisms of this signaling cascade has become an important area in bone research. This review focuses on the genetics of LRP5 and summarizes the findings on monogenic bone conditions as well as the current knowledge of its involvement in the pathogenesis of osteoporosis.

	Introduction

Top Abstract Introduction LRP5 and Monogenic Bone... LRP5 and Osteoporosis Functional Aspects of LRP5... Conclusions References

 
DURING THE LAST 20 yr, positional cloning efforts have resulted in major contributions toward the identification of disease-associated genes in hereditary bone conditions. Some of the initial successes indicated the involvement of collagen genes COL1A1 and COL1A2 in different forms of osteogenesis imperfecta, characterized by increased bone fragility and low bone mass (1, 2). Conditions at the opposite side of the spectrum, with an increase in bone mass, also proved to be a successful starting point in the search for novel genes that play a role in the regulation of bone density in the general population. In this way, a variety of genes that are involved in bone resorption, bone formation, or the coupling between these two processes have been identified (3).

Interestingly, this approach also resulted in the unexpected evidence for a pivotal role of the canonical Wnt signaling pathway in bone metabolism. From 1996 onward, a number of linkage studies suggested the presence of at least one important genetic locus for the regulation of bone mass on chromosome 11q12–13 because different types of monogenic bone conditions were assigned to this chromosomal region. Gong et al. (4) localized the gene causing the autosomal recessive osteoporosis pseudoglioma (OPPG) syndrome to chromosome 11q12–13, and two conditions characterized by increased bone density were linked to the same chromosomal region: the autosomal dominant high bone mass phenotype (5) and autosomal dominant osteopetrosis type I (6). Follow-up genetic studies revealed that mutations in the gene encoding low-density lipoprotein receptor-related protein 5 (LRP5), a coreceptor for Wnt molecules, are at the basis of all the above mentioned conditions.

Besides studies on the simple Mendelian conditions described above, linkage screens in Caucasian populations provided evidence for the presence of at least one quantitative trait locus (QTL) for bone mineral density (BMD) on chromosome 11q12–13 (7, 8, 9). These linkage data were next corroborated by positive association findings between natural variants in the LRP5 gene and BMD (10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22).

	LRP5 and Monogenic Bone Conditions

Top Abstract Introduction LRP5 and Monogenic Bone... LRP5 and Osteoporosis Functional Aspects of LRP5... Conclusions References

 
OPPG syndrome
OPPG is a rare genetic disorder inherited as an autosomal recessive trait. It is characterized by severe juvenile-onset osteoporosis leading to bone deformity and recurrent fractures and congenital or infancy-onset blindness with a severity ranging from phthisis bulbi to vitreoretinal dysplasia (23). Variable expression of mental retardation, muscular hypotonia, and ligamentous laxity is observed. Biochemical evaluation revealed no defects related to collagen synthesis, calcium homeostasis, anabolic and catabolic hormones, endochondral growth, or bone turnover (23, 24, 25). Although heterozygous carriers of this syndrome have been considered phenotypically normal, several studies reported reduced bone mass, compared with age and gender-matched controls, and increased risk for osteoporotic fractures. However, eye anomalies have never been reported in OPPG carriers (26, 27, 28).

In 2001 the genetic defect causing the OPPG syndrome was unraveled with the identification of homozygous and compound heterozygous loss-of-function mutations in the LRP5 gene (27). Thus far, 48 OPPG-related LRP5 mutations have been reported in the literature (Table 1) (27, 29, 30). About 54% of them are deleterious mutations (nonsense, frameshift, and splice site mutations), whereas the remaining 46% consist of missense variants. OPPG mutations are spread throughout the transmembrane protein; however, more than 90% are located in the extracellular domain, which encompasses the largest part of the protein. Within this extracellular portion, there seems, especially for the amino acid substitutions, a clustering of mutations in the second of four ß-propeller domains present in this protein (Table 1 and Fig. 1).

View larger version (10K): [in this window] [in a new window]   FIG. 1. Protein structure of the LRP5 with a large extracellular domain, a transmembrane segment, and a cytoplasmic tail. The extracellular domain consists of a signal peptide, four ß-propeller domains (containing YWTD motifs separated by an EGF-like repeat), and LDL-repeats. The different proteins binding to the extracellular and cytoplasmic domains are indicated. Pathogenic missense mutations resulting in conditions with increased bone density and OPPG syndrome are clustered, respectively, in ß-propeller domains 1 and 2. Q89R, V667M, and A1330V are naturally occurring LRP5 variants found to be associated with BMD and fracture risk. Frat-1, Frequently rearranged in T-cell lymphomas.

	LRP5 and Osteoporosis

Top Abstract Introduction LRP5 and Monogenic Bone... LRP5 and Osteoporosis Functional Aspects of LRP5... Conclusions References

LRP5 in primary or idiopathic osteoporosis
In the majority of cases, osteoporosis is related to a variety of risk factors such as age, menopause, chronic illness, and medication. Conversely, primary or idiopathic osteoporosis, in which none of these factors is present, is less commonly recognized (46, 47). The mechanism of primary osteoporosis is largely unknown and genes involved remain to be identified. Several authors suggest a major role for a genetic defect in this condition because the prevalence of low bone mass in first-degree relatives of patients is significantly higher, compared with controls (48, 49, 50).

Two genetic studies have been reported describing the role of LRP5 mutations in primary osteoporosis. Hartikka et al. (51) screened 20 pediatric patients with primary osteoporosis for mutations in LRP5 and identified three heterozygous variants: A29T and R1036Q, located, respectively, in the first and fourth ß-propeller domains, and C913fs in the third epidermal growth factor (EGF)-like repeat of LRP5. The three affected children have a history of at least one peripheral fracture, and two of them suffered from severe compression fractures. Two had low lumbar spine (LS) BMD Z-scores. No ocular manifestations were observed. A similar study was carried out in a cohort of 66 male patients, aged 20–65 yr, with idiopathic osteoporosis having a BMD Z-score of –2.0 or less at the LS or proximal femur, and revealed heterozygous S356L (ß-propeller 2), S455L (ß-propeller 2), and A1537T (cytoplasmic tail) missense variants in three men with idiopathic osteoporosis (52). Interestingly, S356L and C913fs were previously reported in compound heterozygous OPPG patients (29), indicating that these variants lead to loss of function. This again strengthens the finding that individuals heterozygous for a OPPG mutation can present with reduced bone mass and/or increased fracture risk without any eye involvement. However, due to their low frequency in the cohorts, LRP5 mutations cannot be considered an important cause of idiopathic osteoporosis.

LRP5, BMD, and fracture risk in the general population
The discovery of LRP5 as an important actor in bone metabolism resulted in a major interest in the role of LRP5 as a susceptibility gene in the regulation of BMD and/or fracture risk in the general population. This led to several recent reports on association studies between LRP5 single-nucleotide polymorphisms (SNPs) and different bone phenotypes (Table 3) (10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22). Overall, these association analyses suggest that the distal haplotype block of LRP5, encompassing exons 8–21, is of particular importance for the variance in bone mass (17, 22, 53). Of most interest are two nonsynonymous SNPs, V667M (exon 9; ß-propeller 3) and A1330V [exon 18; low-density lipoprotein (LDL)-repeat] (Fig. 1). In Caucasian populations, the V667M polymorphism was found to be significantly associated with LS parameters (areal BMD, bone mineral content, and bone area), and stature in adults (10) and marginally associated with idiopathic male osteoporosis (16). However, no association was observed with LS and femoral neck (FN) BMD in premenopausal women (17). Thus far, no studies on V667M have been reported in other ethnic groups. This could be due to the low minor-allele-frequency of this SNP in these populations, as illustrated in a Korean cohort of young men (12).

The Q89R polymorphism, located in the proximal part of LRP5 (exon 2; ß-propeller 1) (Fig. 1), has been studied only in Asian populations, most likely because of its low frequency in other ethnic groups (22). Although Q89R was weakly associated with FN BMD in young Korean men (12), strong associations have been reported with FN BMD in premenopausal women from southern China (18, 21) and postmenopausal Chinese women (19). In Korean and Chinese cohorts, strong linkage disequilibrium was observed between Q89R and A1330V, although for the latter SNP, no associations were observed (12, 19).

Haplotype analyses also showed significant association at the LRP5 locus. Interestingly, in all except one of the studies in which A1330V was included, haplotypes containing the 1330Valine allele are associated with lower BMD in Caucasian and Japanese cohorts (10, 13, 16, 17, 22). Q89R, M667V, and A1330V involve amino acid substitutions and might be functionally important. Thus far, no studies have been reported on the functional significance of associated LRP5 polymorphisms. Alternatively, another polymorphism in LD with the associated SNP can be responsible for the observed effects on bone density.

A number of interesting conclusions can be drawn from the association studies with LRP5. First, genetic variation of LRP5 is associated with not only BMD but also fracture risk at higher age, and associations have been found with fracture risk in a large cohort of elderly Australian women (15) and male participants of advanced age from the Rotterdam study (22). Second, the data suggest that LRP5 variants contribute to the variance in BMD in young individuals, therefore most likely influencing the acquisition of peak bone mass (12, 17, 18), but also in elderly people in whom variance in BMD is primarily due to the combined genetic effects on peak bone mass and age-related bone loss (10, 11, 13, 14, 15, 16, 19, 22). Third, the effects of polymorphisms on bone phenotypes, including LS and FN BMD, LS bone mineral content, bone area, stature, and fracture risk, are consistently stronger in men, compared with women (10, 11, 22). Although no clear explanation can be given, it is known that there are differences in sex-specific hormones (such as androgens and estrogens) during puberty, the period during which differences in bone width and stature are established, that might directly or indirectly affect the action of LRP5 on bone phenotypes. Alternatively, this effect might be explained by gender differences in mechanical loading. Recently we could demonstrate that V667M and A1330V are specifically associated with LS peak bone mass in the physically active subgroup of young, Danish men from the Odense Androgen Study, suggesting a role for LRP5 as a mediator of load-induced bone formation (20).

	Functional Aspects of LRP5 and Associated Mutations

Top Abstract Introduction LRP5 and Monogenic Bone... LRP5 and Osteoporosis Functional Aspects of LRP5... Conclusions References

 
The LRP5 protein belongs to the LDL receptor (LDLR) family of cell surface receptors (54, 55). The LRP5 gene spans approximately 136 kb; contains 23 exons; and encodes a 1516 amino acid-protein with a large extracellular domain, a single transmembrane domain, and a cytoplasmic tail. The extracellular fraction consists of a signal peptide followed by a series of four ß-propeller motifs, typically containing six YWTD-motifs that form a six-bladed ß-propeller-like structure. These motifs are each followed by an EGF-like repeat domain. In addition, three LDLR domains flank the 23-amino acid membrane-spanning segment (Fig. 1).

LRP5 plays an important role in canonical Wnt signaling because it acts as a coreceptor together with the seven-transmembrane-spanning Frizzled for Wnt proteins to regulate intracellular signal transduction by ß-catenin (56). Activation of the pathway results in cytoplasmic ß-catenin accumulation. Consequently, ß-catenin translocates to the nucleus, in which it can associate with T-cell transcription factor/lymphoid enhancer binding factor transcription factors and in turn regulates target gene transcription (reviewed in Ref. 57). The canonical Wnt signal transduction cascade regulates a variety of cellular and physiological activities important for development and morphogenesis (58). Furthermore, dysregulation of this pathway has been associated with tumorigenesis (59). As described in this review and confirmed by in vitro and in vivo models, evidence has been provided for a role of canonical Wnt signaling in osteoblast differentiation and/or function and consequently bone anabolism.

To correlate the type and position of LRP5 mutations with the observed bone phenotypes, it is obvious that deleterious LRP5 variants, as seen in most OPPG patients, encoding truncated proteins that might not even be synthesized in vivo due to nonsense-mediated mRNA decay, result in decreased BMD due to reduced canonical Wnt signaling (27). Of more functional interest are OPPG missense mutations because they impair LRP5 functioning. Ai et al. (29) investigated the molecular mechanisms of this type of mutations and showed that some mutants were less efficiently transported to the cell membrane in vitro. The most likely explanation is an impaired binding to mesoderm development (MESD), a chaperone protein important in LRP5 membrane trafficking. Most OPPG missense variants cluster in the second ß-propeller domain, a region that has been suggested to play a role in MESD binding (Table 1 and Fig. 1) (60). Ai et al. (29) additionally illustrated that other mutant LRP5 proteins reached the cell surface at sufficient amounts. Impaired signaling in these cases might be due to decreased ligand (Wnt) binding because the second ß-propeller domain has also been shown to be involved in this process (Fig. 1) (61). Whereas OPPG missense mutations cluster in the second ß-propeller domain of LRP5, all the activating mutations associated with increased bone density cluster in the first ß-propeller domain (Table 1 and Fig. 1). The mechanism that has been suggested for these mutations is impaired extracellular inhibition by Dickkopf (DKK)-1, a member of the DKK family of canonical Wnt signaling modulators (38, 60, 62). However, this is not in line with previous data indicating that binding between DKKs and LRP5 takes place at the third ß-propeller domain (61), although a role for the first ß-propeller domain cannot be excluded at this point. Alternatively, recent evidence has emerged for an antagonistic role for the osteocyte-derived bone formation inhibitor sclerostin on canonical Wnt signaling by binding to the first and/or second ß-propeller domain of LRP5 (Fig. 1) (63). Sclerostin, encoded by the SOST gene, was identified as being absent in sclerosteosis and Van Buchem disease, two clinically and radiologically related sclerosing bone dysplasias (64, 65, 66, 67). Sclerostins antagonistic role was recently corroborated by the evidence that binding between sclerostin and LRP5 is impaired by the G171V mutation, leading to absence of inhibition by sclerostin and therefore increased canonical Wnt signaling (68). We were able to show a similar effect for the other activating LRP5 missense variants (our unpublished data).

	Conclusions

Top Abstract Introduction LRP5 and Monogenic Bone... LRP5 and Osteoporosis Functional Aspects of LRP5... Conclusions References

 
Plenty of evidence has accumulated in recent years that the genetic profile of the LRP5 gene in an individual has a significant effect on BMD. As shown in Fig. 2, BMD Z-scores are highly influenced by, most significantly, pathogenic mutations or, more mildly, polymorphisms in the LRP5 gene. At the lower end of the spectrum, loss-of-function mutations in homozygous or heterozygous stage are found, but LRP5 polymorphisms can also contribute to an osteoporotic phenotype. At the opposite end, activating missense mutations in the first ß-propeller domain of LRP5 lead to increased BMD. These mutations were detected in cases initially diagnosed with different bone conditions including high bone mass phenotype, Worth disease, autosomal dominant osteopetrosis type I, autosomal dominant osteosclerosis, etc. However, detailed review of both clinical and radiological data from all these conditions suggests that there are no strong indications to differentiate them. Supported now by molecular evidence, we would suggest to unify these conditions as craniotubular hyperostoses because of major involvement of skull and long tubular bones. Interestingly, we also reported an activating LRP5 mutation in a case diagnosed with Van Buchem disease (33). This is not unexpected because differential diagnosis between Van Buchem disease and the related phenotype of sclerosteosis, both inherited as autosomal recessive traits, on the one hand, and conditions associated with LRP5 mutations with increased BMD, on the other hand, is often difficult to make, and all of them could fit under the craniotubular hyperostoses. At the molecular level, however, there is a clear difference because the former two are due to loss-of-function mutations in the SOST gene encoding sclerostin (Fig. 2) (64, 65, 66, 67). Recent functional data strongly suggest that LRP5 missense mutants might have a reduced inhibition of Wnt signaling (60, 62, 38), whereas the somewhat more severe phenotype in Van Buchem disease/sclerosteosis, illustrated by even higher BMDs (Fig. 2), is due to the complete absence of sclerostin being a key inhibitor of Wnt signaling (63, 69, 70).

View larger version (15K): [in this window] [in a new window]   FIG. 2. Spectrum of conditions with variability in BMD due to variation in canonical Wnt signaling. VBCH, Van Buchem disease; SCL, sclerosteosis.

Finally, the role of natural variants in LRP5 in determining BMD and fracture risk has already been replicated in different populations, corroborating the conclusion that LRP5 is to some extent to be considered a susceptibility gene for osteoporosis and subsequent fracture risk in the general population. However, analysis of large cohorts and metaanalysis of performed studies in combination with functional studies to identify the true functional variant can be of further support.

	Footnotes

 
This work was supported by the Flemish Fund for Scientific Research (F.W.O. Vlaanderen) (Grant 0117.06) and the European Union FP6 project ANABONOS (LSHM-CT-2003-503020, to W.V.H.) and the Special Research Fund (B.O.F.) of the University of Antwerp (to W.B.). W.B. holds a postdoctoral fellowship obtained from the F.W.O. Vlaanderen.

Disclosure Statement: The authors have nothing to disclose.

First Published Online March 29, 2007

Abbreviations: BMD, Bone mineral density; DKK, Dickkopf; EGF, epidermal growth factor; FN, femoral neck; LDL, low-density lipoprotein; LDLR, LDL receptor; LRP5, low-density lipoprotein receptor-related protein 5; LS, lumbar spine; MESD, mesoderm development; OPPG, osteoporosis pseudoglioma; QTL, quantitative trait locus; SNP, single-nucleotide polymorphism.

Received October 4, 2006.

Accepted for publication November 6, 2006.

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Top Abstract Introduction LRP5 and Monogenic Bone... LRP5 and Osteoporosis Functional Aspects of LRP5... Conclusions References

 

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