Association of Functionally Different <i>RUNX2</i> P2 Promoter Alleles With BMD

Doecke, James D.; Day, Christopher J.; Stephens, Alexandre; Carter, Shea L.; Daal, Angela van; Kotowicz, Mark A.; Nicholson, Geoff; Morrison, Nigel Alexander

doi:10.1359/jbmr.051013

Cited by 50 publications

(44 citation statements)

References 23 publications

(37 reference statements)

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“…A single nucleotide polymorphism (SNP) in exon 2 of RUNX2 was associated with higher BMD in an Australian population (Vaughan et al 2002) and was replicated in a Scottish population (Vaughan et al 2004). Recently, Doecke et al (2006) showed that only SNPs in the RUNX2 P2 promoter were significantly associated with BMD and that greater RUNX2 P2 promoter activity was associated with higher BMD.…”

Section: Resultsmentioning

confidence: 97%

Prediction of osteoporosis candidate genes by computational disease-gene identification strategy

Huang

Cheung

et al. 2008

J Hum Genet

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Osteoporosis is a complex disease with a strong genetic component. To date, more than 20 genome-wide linkage scans across multiple populations have been launched to hunt for osteoporosis susceptibility genes. Some significant or suggestive chromosomal regions of linkage to bone mineral density have been identified and replicated in genome-wide linkage screens. However, identification of key candidate genes within these confirmed regions is challenging. We used five freely available bioinformatics tools (Prioritizer, GeneSeeker, PROSPECTR and SUSPECTS, Disease Gene Prediction, and Endeavor) to analyze the 13 well-replicated osteoporosis susceptibility loci: 1p36, 1q21-25, 2p22-24, 3p14-25, 4q25-34, 6p21, 7p14-21, 11q14-25, 12q23-24, 13q14-34, 20p12, 2q24-32, and 5q12-21. Pathways and regulatory network analyses were performed using the Ingenuity Pathways Analysis (IPA) software. We identified a subset of most likely candidate osteoporosis susceptibility genes that are largely involved in transforming growth factor (TGF)-b signaling, granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, axonal guidance signaling, peroxisome proliferator-activated receptor (PPAR) signaling, and Wnt/b-catenin signaling pathway. Six nonoverlapping networks were generated by IPA 5.0 from 88 out of the 91 candidate genes. The list of most likely candidate genes and the associated pathway identified will assist researchers in prioritizing candidate disease genes for further empirical analysis and understanding the pathogenesis of osteoporosis.

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Section: Resultsmentioning

confidence: 97%

Prediction of osteoporosis candidate genes by computational disease-gene identification strategy

Huang

Cheung

et al. 2008

J Hum Genet

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“…Some of these mutations have been shown to interfere with the DNA-binding activity of CBFA1, whereas others have been found to alter nuclear localization of the protein or to produce a mutant or truncated protein that is biologically inactive. In addition to these rare mutations, various polymorphisms have been identified in CBFA1 and some of these have been associated with bone mass in population-based studies (Vaughan et al 2002(Vaughan et al , 2004Doecke et al 2006). The best functional candidates lie within the Runx2 promoter (Doecke et al 2006) or within polyalanine and polyglutamine repeats in exon 1.…”

Section: Cbfa1mentioning

confidence: 99%

“…In addition to these rare mutations, various polymorphisms have been identified in CBFA1 and some of these have been associated with bone mass in population-based studies (Vaughan et al 2002(Vaughan et al , 2004Doecke et al 2006). The best functional candidates lie within the Runx2 promoter (Doecke et al 2006) or within polyalanine and polyglutamine repeats in exon 1. The polyalanine and polyglutamine repeats are of interest since they lie within one of the transactivation domains of Runx2.…”

Section: Cbfa1mentioning

confidence: 99%

“…Various rare length variants within the polyglutamine repeat have also been identified, resulting in stretches of between 15 and 30 repeats. The strongest association with BMD has been observed with an anonymous polymorphism in the Ala repeat region (Vaughan et al 2002(Vaughan et al , 2004, although it is thought that this might be due to linkage disequilibrium with polymorphisms in the promoter that have been shown to affect Runx2 transcription in reporter assays (Doecke et al 2006). It is currently unclear whether the length variants in the polyalanine and polyglutamine tracts have functional importance, but this is an area of ongoing investigation.…”

Section: Cbfa1mentioning

confidence: 99%

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Genetic regulation of bone mass and susceptibility to osteoporosis

Ralston¹,

Crombrugghe²

2006

Genes Dev.

289

226

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Osteoporosis is a common disease with a strong genetic component characterized by reduced bone mass and increased risk of fragility fractures. Twin and family studies have shown that the heritability of bone mineral density (BMD) and other determinants of fracture risksuch as ultrasound properties of bone, skeletal geometry, and bone turnover-is high, although heritability of fracture is modest. Many different genetic variants of modest effect size are likely to contribute to the regulation of these phenotypes by interacting with environmental factors such as diet and exercise. Linkage studies in rare Mendelian bone diseases have identified several previously unknown genes that play key roles in regulating bone mass and bone turnover. In many instances, subtle polymorphisms in these genes have also been found to regulate BMD in the general population. Although there has been extensive progress in identifying the genetic variants that regulate susceptibility to osteoporosis, most of the genes and genetic variants that regulate bone mass and susceptibility to osteoporosis remain to be discovered.Osteoporosis is characterized by reduced bone mass, alterations in the microarchitecture of bone tissue, reduced bone strength, and an increased risk of fracture (Kanis et al. 1994). Osteoporosis is a common condition that affects up to 30% of women and 12% of men at some point in life. The prevalence of osteoporosis increases with age due to an imbalance in the rate at which bone is removed and replaced during the bone remodeling cycle, which is an important physiological process that is essential for maintenance of a healthy skeleton. Many factors influence the risk of osteoporosis-including diet, physical activity, medication use, and coexisting diseases-but one of the most important clinical risk factors is a positive family history, emphasizing the importance of genetics in the pathogenesis of osteoporosis. In this article, we first review the evidence for a genetic contribution to osteoporosis and related phenotypes, and discuss the mechanisms by which mutations and polymorphisms in genes that regulate susceptibility to osteoporosis affect major signaling pathways in bone. Genetic influences on osteoporosisGenetic factors have long been recognized as playing an important role in the pathogenesis of osteoporosis. Evidence from twin and family studies suggests that between 50% and 85% of the variance in peak bone mass is genetically determined, depending on skeletal site and the age of the subjects studied (Smith et al. 1973;Pocock et al. 1987;Krall and Dawson-Hughes 1993;Gueguen et al. 1995). Heritability studies have also shown evidence of significant genetic effects on other key determinants of osteoporotic fracture risk, including quantitative ultrasound properties of bone (Arden et al. 1996), femoral neck geometry (Arden et al. 1996), muscle strength (Arden and Spector 1997), bone turnover markers (Hunter et al. 2001), and body mass index (Kaprio et al. 1995). The role of genetic factors in the pathogenesis of bon...

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“…The Runx2 gene spans ~210 kb with its two predominant transcripts, governed by P1 and P2 promoters (29,30). Runx2 RNA, driven by the P1 promoter, is extensively stimulated and highly expressed in osteoblastic lineages during skeletal development (31).…”

Section: Discussionmentioning

confidence: 99%

Increased Runx2 expression associated with enhanced Wnt signaling in PDLLA internal fixation for fracture treatment

Ling

Wu²,

Shi

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. Poly-D-L lactide (PDLLA) biodegradable implants to heal fractures are widely applied in orthopedic surgeries. However, whether the process of fracture healing is regulated differently when PDLLA is used compared with traditional metal materials remains unclear. Runt-related transcription factor 2 (Runx2) and canonical Wnt signaling are essential and may interact reciprocally in the regulation of osteogenesis during bone repair. In the present study, a rat femoral open osteotomy model was used to compare the curative efficacy of a PDLLA rod and Kirschner wire under intramedullary fixation for fracture treatment. The dynamic expression of Runx2 and key components of the canonical Wnt signaling in callus tissue during fracture healing was also investigated. The results of the current study indicate that at weeks 4 and 6 following fixation, the callus bone structural parameters of microCT were significantly improved by PDLLA rod compared to that of Kirschner wire. In addition, at weeks 4 and 6 after fixation, the protein and mRNA expression of Runx2 and the positive regulators of canonical Wnt signaling, such as Wnts and β-catenin, were significantly increased. However, the protein and mRNA expression levels of the negative regulators of canonical Wnt signaling, such as glycogen synthase kinase-3β, were significantly decreased in callus tissue when treated with PDLLA rod compared with Kirschner wire. Collectively, these data indicate that compared to the traditional metal material, using PDLLA internal fixation for fracture treatment may further improve bone formation, which is associated with the increased expression of Runx2 and the enhancement of canonical Wnt signaling. IntroductionSince the use of biodegradable implants to heal fractures by Rokkanen et al in 1985, the method of using biodegradable materials has been widely applied in orthopedic surgeries (1-3). Biodegradable materials exhibit various advantages in the treatment of fractures compared with the use of traditional metal implants, including the elimination of implant removal, reduction of the 'stress shielding' effect, improvement of biocompatibility, reduction of radiological artifacts and utilization of magnetic resonance imaging assessment following surgery (4,5). Poly-D-L lactide (PDLLA) is a material with an intermediate degradation time (PDLLA begins to degrade at ~12 weeks) and may be completely replaced by bone tissue following surgery, thus, it is considered to be one of the most effective biodegradable materials for the treatment of fractures (6-8). However, with the exception of clinical outcomes, the differences in the biological processes following the use of PDLLA and metal fixation to treat a fracture remain unknown.The fracture healing process has been widely accepted to comprise a series of overlapping phases; these include inflammation, repair and remodeling events (9). This multistage repair process involves a variety of complex and well-orchestrated cellular and molecular processes, and should be considered as a special...

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Association of Functionally Different RUNX2 P2 Promoter Alleles With BMD

Cited by 50 publications

References 23 publications

Prediction of osteoporosis candidate genes by computational disease-gene identification strategy

Prediction of osteoporosis candidate genes by computational disease-gene identification strategy

Genetic regulation of bone mass and susceptibility to osteoporosis

Increased Runx2 expression associated with enhanced Wnt signaling in PDLLA internal fixation for fracture treatment

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