A common LRP4 haplotype is associated with bone mineral density and hip geometry in men—Data from the Odense Androgen Study (OAS)

Boudin, Eveline; Steenackers, Ellen; Freitas, Fenna de; Nielsen, Troels Halfeld; Andersen, Marianne; Brixen, Kim; Hul, Wim Van; Piters, Elke

doi:10.1016/j.bone.2013.01.014

Cited by 19 publications

(10 citation statements)

References 34 publications

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“…Pathway analysis of these genes revealed that they are primarily involved in cell development, morphology, survival and death, cell-to-cell signalling and interaction, humoral immune response, inflammatory response, nervous system development and function, and tissue development. In support of this notion, analysis of the chromosomal location of the sequence variants found in the present study as putatively associated with SF pathogenesis (n = 146) showed that none co-localized with any of the SNPs or genes previously associated with metacarpal bone geometry (Karasik et al, 2008), trabecular and cortical volumetric bone mineral densities (Paternoster et al, 2010(Paternoster et al, , 2013, osteoporosis-related phenotype (Karasik et al, 2012), bone mass, hip geometry and fractures (Boudin et al, 2013;Garcia-Ibarbia et al, 2013), bone mineral density, cortical bone thickness and bone strength , bone mineral density loci and osteoporotic fracture (Duncan et al, 2011;Estrada et al, 2012), and femoral neck bone geometry (Zhao et al, 2010) (Supplemental Table 6), including the ones that were reviewed by Ralston & Uitterlinden (2010) (Supplemental Table 7). Noteworthy, some of these genes and pathways have not been considered 'classical SF candidate genes' and have never been reported to be analysed as candidate SF genes.…”

Section: Discussionsupporting

confidence: 78%

Novel candidate genes putatively involved in stress fracture predisposition detected by whole-exome sequencing

et al. 2014

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While genetic factors in all likelihood contribute to stress fracture (SF) pathogenesis, a few studies focusing on candidate genes have previously been reported. The objective of this study is to gain better understanding on the genetic basis of SF in a gene-naive manner. Exome sequence capture followed by massive parallel sequencing of two pooled DNA samples from Israeli combat soldiers was employed: cases with high grade SF and ethnically matched healthy controls. The resulting sequence variants were individually verified using the Sequenom™ platform and the contribution of the genetic alterations was validated in a second cohort of cases and controls. In the discovery set that included DNA pool of cases (n = 34) and controls (n = 60), a total of 1174 variants with >600 reads/variant/DNA pool were identified, and 146 (in 127 genes) of these exhibited statistically significant (P < 0·05) different rates between SF cases and controls after multiple comparisons correction. Subsequent validation of these 146 sequence variants individually in a total of 136 SF cases and 127 controls using the Sequenom™ platform validated 20/146 variants. Of these, three missense mutations (rs7426114, rs4073918, rs3752135 in the NEB, SLC6A18 and SIGLEC12 genes, respectively) and three synonymous mutations (rs2071856, rs2515941, rs716745 in the ELFN2, GRK4, LRRC55 genes) displayed significant different rates in SF cases compared with controls. Exome sequencing seemingly unravelled novel candidate genes as involved in SF pathogenesis and predisposition.

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Section: Discussionsupporting

confidence: 78%

Novel candidate genes putatively involved in stress fracture predisposition detected by whole-exome sequencing

et al. 2014

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“…Furthermore, variations in LRP4 have been reported recently to be associated with bone-mineral density and hip geometry in a genome-wide association study (28)(29)(30). These combined findings suggest a previously underappreciated function of LRP4 in regulating bone homeostasis.…”

Section: Significancementioning

confidence: 77%

“…Our previous structural prediction located LRP4 human mutations, which lead to sclerosing bone overgrowth phenotypes, to the third β-propeller domain, therefore affecting the binding of sclerostin (16). The same region was identified by a genome-wide association study (GWAS) (28). Moreover, a recent report proposed the central cavity of the third β-propeller domain of LRP4 to regulate WNT signaling whereas the edge of the domain is required for MusK signaling (47).…”

Section: Discussionmentioning

confidence: 90%

Disruption of Lrp4 function by genetic deletion or pharmacological blockade increases bone mass and serum sclerostin levels

Chang

Krämer

Huber

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

113

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We identified previously in vitro LRP4 (low-density lipoprotein receptor-related protein 4) as a facilitator of the WNT (Winglesstype) antagonist sclerostin and found mutations disrupting this function to be associated with high bone mass in humans similar to patients lacking sclerostin. To further delineate the role of LRP4 in bone in vivo, we generated mice lacking Lrp4 in osteoblasts/osteocytes or osteocytes only. Lrp4 deficiency promoted progressive cancellous and cortical bone gain in both mutants, although more pronouncedly in mice deficient in osteoblast/osteocyte Lrp4, consistent with our observation in human bone that LRP4 is most strongly expressed by osteoblasts and early osteocytes. Bone gain was related primarily to increased bone formation. Interestingly, Lrp4 deficiency in bone dramatically elevated serum sclerostin levels whereas bone expression of Sost encoding for sclerostin was unaltered, indicating that osteoblastic Lrp4 retains sclerostin within bone. Moreover, we generated anti-LRP4 antibodies selectively blocking sclerostin facilitator function while leaving unperturbed LRP4-agrin interaction, which is essential for neuromuscular junction function. These antibodies increased bone formation and thus cancellous and cortical bone mass in skeletally mature rodents. Together, we demonstrate a pivotal role of LRP4 in bone homeostasis by retaining and facilitating sclerostin action locally and provide a novel avenue to bone anabolic therapy by antagonizing LRP4 sclerostin facilitator function.LRP4 | SOST | sclerostin | WNT | bone anabolism

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“…While the involvement of LRP5 and LRP6 in bone homeostasis has been established for the past dozen years, more recently MEGF4/LRP4 and LRP8 have been shown to play a role [50, 19, 20, 18, 21, 51] Global deletion of Lrp5 (Lrp5 -/- ) in mice resembles the phenotypes observed in patients with OPPG. These mice present low bone mass phenotype and a persistent embryonic eye vascularization through their adult life [52].…”

Section: The Lrp Family Of Proteinsmentioning

confidence: 99%

“…Recently Boudin and colleagues reported that mutation in the LRP4 was associated with osteoporosis. They found an association between rs2306029 and rs6485702 and BMD at all sites except in the lumbar spine [50]. …”

Section: Lrp Mutations In Bone Related Diseasesmentioning

confidence: 99%

LRP receptor family member associated bone disease

Lara-Castillo

Johnson

2015

Rev Endocr Metab Disord

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A dozen years ago the identification of causal mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene involved in two rare bone disorders propelled research in the bone field in totally new directions. Since then, there have been an explosion in the number of reports that highlight the role of the Wnt/β-catenin pathway in the regulation of bone homeostasis. In this review we discuss some of the most recent reports (in the past 2 years) highlighting the involvement of the members of the LRP family (LRP5, LRP6, LRP4, and more recently LRP8) in the maintenance of bone and their implications in bone diseases. These reports include records of new single nucleotides polymorphisms (SNPs) and haplotypes that suggest variants in these genes can contribute to subtle variation in bone traits to mutations that give rise to extreme bone phenotypes. All of these serve to further support and reinforce the importance of this tightly regulated pathway in bone. Furthermore, we discuss provocative reports suggesting novel approaches through inhibitors of this pathway to treat rarer diseases such as Osteoporosis-Pseudoglioma Syndrome (OPPG), Osteogenesis Imperfecta (OI), and Sclerosteosis/Van Buchem disease. It is hoped that by understanding the role of each component of the pathway and their involvement in bone diseases that this knowledge will allow us to develop new, more effective therapeutic approaches for more common diseases such as post-menopausal osteoporosis, osteoarthritis, and rheumatoid arthritis as well as these rarer bone diseases.

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A common LRP4 haplotype is associated with bone mineral density and hip geometry in men—Data from the Odense Androgen Study (OAS)

Cited by 19 publications

References 34 publications

Novel candidate genes putatively involved in stress fracture predisposition detected by whole-exome sequencing

Novel candidate genes putatively involved in stress fracture predisposition detected by whole-exome sequencing

Disruption of Lrp4 function by genetic deletion or pharmacological blockade increases bone mass and serum sclerostin levels

LRP receptor family member associated bone disease

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