Polymorphisms in genes in the RANKL/RANK/OPG pathway are associated with bone mineral density at different skeletal sites in post-menopausal women

Tu, Ping; Duan, Peng; Zhang, R.-S.; Xu, Dan; Wang, Y.; He-ping, WU; Liu, Y.-H.; Long, Si

doi:10.1007/s00198-014-2854-7

Cited by 35 publications

(31 citation statements)

References 22 publications

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“…RANK polymorphisms rs1805034, rs35211496 and RANKL rs2277438 were found to be significantly associated with bone density [16,17]. All of these polymorphisms were analyzed in our study.…”

Section: Discussionmentioning

confidence: 80%

Bone Mineral Density in Prader Willi Syndrome: A Search for Genetic Markers

Altarescu¹,

Gross-Tsur²,

Hirsch³

et al. 2017

J Osteopor Phys Act

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decreased BMD and bone mineral content (BMC) in PWS. Recently it has been shown that PW Snord 116 knockout mice show reduced bone formation indicating a possible link between the PW critical region and osteoporosis [10]. Since bone density and mineral content are highly variable among PWS individuals, other factors may contribute to the development of osteopenia and/or osteoporosis. Identifying risk factors for developing osteopenia or osteoporosis may allow early intervention prior to severe bone loss. The purpose of our study was to investigate polymorphisms of candidate genes previously shown to correlate with osteoporosis and/or bone disease and determine if similar associations are present in a PWS population. Materials and MethodsDNA samples were collected from 96 of 103 individuals above the age of 3 years with PWS followed at the Israeli national multidisciplinary PWS clinic at Shaare Zedek Medical Center, Jerusalem, Israel. There were Keywords: Prader-Willi syndrome; Osteoporosis; Osteopenia; Genetic markers of osteoporosis; Bone mineral density; DXA IntroductionPrader-Willi syndrome (PWS) is a complex genetic disorder caused by lack of expression of genes on the paternally inherited chromosome 15q11.2-q13 region. The estimated prevalence is 1/10,000-1/30,000 [1]. Infants with PWS suffer from severe hypotonia, feeding difficulties, and failure to thrive (FTT) followed in later infancy or early childhood by excessive appetite with gradual development of obesity, short stature, hypogonadism, intellectual disabilities and behavioral problems [2].There are three main genetic subtypes in PWS: paternal 15q11-q13 deletion in 65-75%, maternal uniparental disomy (UPD) in 20-30% and imprinting center defect in 1-3% of all cases [3,4]. PWS is the most common syndromic cause of life-threatening obesity and the first recognized disorder related to genomic imprinting. Muscle mass is decreased by 25-37%, which might partly explain the hypotonia [5]. Diabetes and scoliosis are common features of PWS [6]. Hypothalamic dysfunction has been implicated in many manifestations of this syndrome including hyperphagia, high pain threshold, sleepdisordered breathing, and multiple endocrine abnormalities including hypogonadism [7,8]. The etiology of hypogonadism in PWS (primary gonadal or hypothalamic) is heterogeneous [5].Increased fat mass and decreased lean body mass are characteristics of PWS. Several studies have demonstrated that individuals with PWS have lower bone mineral density (BMD) compared to normal controls [9]. Hypotonia, hypogonadism, growth hormone deficiency, and limited mineral and vitamin intake due to diet restrictions may contribute to the Abstract Introduction: Prader-Willi syndrome (PWS (is caused by lack of paternally expressed imprinted genes at chromosome 15q11.2-q13. Diminished (BMD) and osteoporosis are common in PWS. The purpose of this study was to determine whether polymorphisms in genes previously shown to correlate with bone mineral density (BMD), might explain the variable expression of abnormal...

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“…RANK polymorphisms rs1805034, rs35211496 and RANKL rs2277438 were found to be significantly associated with bone density [16,17]. All of these polymorphisms were analyzed in our study.…”

Section: Discussionmentioning

confidence: 80%

Bone Mineral Density in Prader Willi Syndrome: A Search for Genetic Markers

Altarescu¹,

Gross-Tsur²,

Hirsch³

et al. 2017

J Osteopor Phys Act

View full text Add to dashboard Cite

show abstract

“…Over the past decades, extensive genetic and genomic studies have conducted to discover genes/SNPs associated with BMD variation in human populations . However, our understanding about the underlying association mechanism is very limited.…”

Section: Discussionmentioning

confidence: 99%

“…Over the past decades, extensive genetic and genomic studies have conducted to discover genes/SNPs associated with BMD variation in human populations. [29][30][31][32][33][34] However, our understanding about the underlying association mechanism is very limited. Besides, a majority of phosSNPs in the GPS 2.0 database were predicted, and their potential effects on protein phosphorylation have not been validated by experiments.…”

Section: Discussionmentioning

confidence: 99%

Why SNP rs227584 is associated with human BMD and fracture risk? A molecular and cellular study in bone cells

Zhou

Qiu

et al. 2018

J Cellular Molecular Medi

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A large number of SNPs significant for osteoporosis (OP) had been identified by genome‐wide association studies. However, the underlying association mechanisms were largely unknown. From the perspective of protein phosphorylation, gene expression regulation, and bone cell activity, this study aims to illustrate association mechanisms for representative SNPs of interest.We utilized public databases and bioinformatics tool to identify OP‐associated SNPs which potentially influence protein phosphorylation (phosSNPs). Associations with hip/spine BMD, as well as fracture risk, in human populations for one significant phosSNP, that is, rs227584 (major/minor allele: C/A, EAS population) located in C17orf53 gene, were suggested in prior meta‐analyses. Specifically, carriers of allele C had significant higher BMD and lower risk of low‐trauma fractures than carriers of A. We pursued to test the molecular and cellular functions of rs227584 in bone through osteoblastic cell culture and multiple assays.We identified five phosSNPs significant for OP (P < 0.01). The osteoblastic cells, which was transfected with wild‐type C17orf53 (allele C at rs227584, P126), demonstrated specific interaction with NEK2 kinase, increased expression levels of osteoblastic genes significantly (OPN, OCN, COL1A1, P < 0.05), and promoted osteoblast growth and ALP activity, in contrast to those transfected with mutant C17orf53 (allele A at rs227584, T126).In the light of the consistent evidences between the present functional study in human bone cells and the prior association studies in human populations, we conclude that the SNP rs227584, via altering protein‐kinase interaction, regulates osteoblastic gene expression, influences osteoblast growth and activity, hence to affect BMD and fracture risk in humans.

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“…Genetic variety on population regulates bone mass density, especially on post-menopausal women (Giroux and Rousseau, 2009;Wang et al, 2014;Tu et al, 2015). Decrease of bone mass density caused by osteoclastogenesis increase is influenced by the activity of RANKL/RANK/OPG.…”

Section: Introductionmentioning

confidence: 99%

The Role of Receptor Activator of Nuclear Factor Kappa B (RANK) and Receptor Activator of Nuclear Factor Kappa B Ligand (RANKL) in Osteoporosis Risk: Gene Polymorphism and Soluble RANKL Level in Indonesia Post-Menopausal Women

Yunaini¹,

Suryandari²,

Kusdhany³

et al. 2018

OnLine Journal of Biological Sciences

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Polymorphisms in genes in the RANKL/RANK/OPG pathway are associated with bone mineral density at different skeletal sites in post-menopausal women

Abstract: Our findings suggest that TNFSF11 and TNFRSF11A, but not TNFRSF11B, genetic polymorphisms influence BMD mainly in the femoral neck in post-menopausal Chinese women. This contributes to the understanding of the role of genetic variation in this pathway in determining bone health.

Cited by 35 publications

References 22 publications

Bone Mineral Density in Prader Willi Syndrome: A Search for Genetic Markers

Bone Mineral Density in Prader Willi Syndrome: A Search for Genetic Markers

Why SNP rs227584 is associated with human BMD and fracture risk? A molecular and cellular study in bone cells

The Role of Receptor Activator of Nuclear Factor Kappa B (RANK) and Receptor Activator of Nuclear Factor Kappa B Ligand (RANKL) in Osteoporosis Risk: Gene Polymorphism and Soluble RANKL Level in Indonesia Post-Menopausal Women

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