scholarly journals Effects of Estrogen on Bone mRNA Levels of Sclerostin and Other Genes Relevant to Bone Metabolism in Postmenopausal Women

2014 ◽  
Vol 99 (1) ◽  
pp. E81-E88 ◽  
Author(s):  
Koji Fujita ◽  
Matthew M. Roforth ◽  
Susan Demaray ◽  
Ulrike McGregor ◽  
Salman Kirmani ◽  
...  
Keyword(s):  
Bone Metabolism ◽  
Postmenopausal Women ◽  
Bone Morphogenetic Protein ◽  
Estrogen Treatment ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Mrna Levels ◽  
Morphogenetic Protein ◽  
Genome Wide ◽  
Bone Biopsies

Context: Studies in postmenopausal women have shown that estrogen reduces circulating sclerostin levels, but effects of estrogen on skeletal sclerostin mRNA levels are unknown. Objective: The objective of the study was to evaluate the effects of short-term estrogen treatment on bone mRNA levels of sclerostin and other genes relevant to bone metabolism. Design, Setting, and Patients: Needle bone biopsies were obtained from 20 postmenopausal women treated with transdermal estrogen for 3 weeks and 20 untreated controls. Quantitative PCR analyses were used to examine the expression of sclerostin and other genes related to bone metabolism, including 71 additional genes linked to bone density/fracture from genome-wide association studies. Results: Estrogen treatment was associated with lower bone sclerostin mRNA levels (by 48%, P < .05) and with lower (by 54%, P < .01) mRNA levels of the sclerostin-related protein, sclerostin domain-containing protein 1 (SOSTDC1), which is also a Wnt/bone morphogenetic protein inhibitor. Consistent with studies in mice showing that ovariectomy increased nuclear factor-κB (NF-κB) activation, we found that estrogen treatment was associated with a significant reduction in inflammatory genes as a group (P = .028), with bone mRNA levels of NFKB2 and RELB (both encoding proteins in the NF-κB transcription factor complex) being significantly reduced individual genes. Eight of the 71 genome-wide association study-related genes examined were modulated by estrogen (P < .05, false discovery rate < 0.10). Conclusion: In humans, estrogen-induced decreases in two key inhibitors of Wnt/bone morphogenetic protein signaling, sclerostin and SOSTDC1, along with reductions in NF-κB signaling, may be responsible for at least part of the protective effects of estrogen on bone.

Abstract 43: Mice With Cardiac-Specific Inactivation Of Ppap2b (Lipid Phosphate Phosphatase 3) Validates Genome-Wide Association Studies.

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Manikandan Panchatcharam ◽  
Sumitra Miriyala ◽  
Natalie D Hendrix ◽  
Diana Escalante-Alcalde
Keyword(s):  
Heart Rate ◽  
Cell Function ◽  
Association Studies ◽  
Myocardial Infarct ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Mrna Levels ◽  
Bioactive Lipids ◽  
Genome Wide ◽  
Lipid Phosphate

A recent meta-analysis of Genome-Wide Association Studies (GWAS) of coronary artery disease (CAD) involving over 86,000 individuals identified PPAP2B (encodes lipid phosphate phosphatase-3; LPP3) as a new loci (SNP rs17114036; P= 3.81 X 10 −19 ) that independently predicts CAD. LPP3 is an integral membrane enzyme that dephosphorylates lysophosphatidic acid, sphingosine-1-phosphate and related bioactive lipids. Strikingly, we found that targeted inactivation of LPP3 in endothelial cells results in early embryonic lethality, in part to due to vascular patterning defects. In addition, we found that constitutive inactivation of LPP3 in the myocardium results in cardiac dysfunction, indicating that dysregulation of LPP3-dependent cardiomyocyte cell function. Heart rate was significantly higher in conditional Ppap2b Δ mice (P<0.001), which may indicate a role for LPP3 in regulating heart rate and/or function. Further, we found that myocardial LPP3 levels are altered following myocardial infarction in mice and these results are in accord with our myocardial infarct data from patient that had down-regulated myocardial LPP3 levels. The major rs17114036A allele was associated with a 1.17 odds ratio for CAD. This SNP is located in the final intron of the six exon PPAP2B gene. At least seven SNPs are in robust linkage disequilbrium (r2>0.9) with rs17114036. The sequence surrounding the SNP rs17114036 matches a U1 spliceosome recognition sequence, and the variant base is located at the final position of a sequence with high homology to a U1 spliceosome 5’ spice site recognition motif. Binding of the U1 spliceosome may alter mRNA stability or processing, perhaps by masking cryptic splice sites, thus enabling efficient splicing or promoting polyadenylation of the mature message. To address the polymorphism, we transfected MDA MB 453 cells, which are homozygous for the “T’ allele of rs17114036 SNP, with a short synthetic 2’-O-methyl phosphorothioate RNA. We found a dramatic decrease in both LPP3 protein expression and LPP3 mRNA levels. These results imply that the region containing the rs17114036 SNP may be important for proper processing and/or stability of the LPP3 transcript thereby functionally validating the GWAS study.

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