scholarly journals Functional polymorphisms within the TNFRSF11B (osteoprotegerin) gene increase the risk for low bone mineral density

2011 ◽  
Vol 47 (3) ◽  
pp. 327-333 ◽  
Author(s):  
Christopher Vidal ◽  
Robert Formosa ◽  
Angela Xuereb-Anastasi
Keyword(s):  
Bone Mineral Density ◽  
Cell Lines ◽  
Bone Mineral ◽  
Promoter Region ◽  
Negative Regulator ◽  
Strong Linkage Disequilibrium ◽  
Mineral Density ◽  
Functional Polymorphisms ◽  
Low Bone Mineral Density ◽  
Significant Difference

Polymorphisms within the TNFRSF11B gene have been studied and associated with osteoporosis and fracture risk. Osteoprotegerin (OPG), the product of this gene, is a key negative regulator of osteoclastogenesis and is secreted by osteoblasts/stromal cells. A previous study in Maltese postmenopausal women showed positive association of low bone mineral density (BMD) with a polymorphism found within the promoter region of this gene (C950T). In this study, direct DNA sequencing revealed 12 variants with polymorphisms C950T, G1181C and rs4876869 observed to be in strong linkage disequilibrium. The constructed haplotype T-G-T was found to increase the risk for a low BMD, while C-G-T and C-C-C have a protective role; thus, we investigated the functional role of both C950T and rs4876869 in vitro. The promoter region, including the C950T alleles, was amplified by PCR, cloned into pGL3 enhancer vector and transfected into HeLa, COS-7 and RAW264.7 cell lines. After incubation, luciferase activity was measured. The T/C (rs4876869) change was tested for its possible effect on pre-mRNA splicing, using an exon-trapping vector. A statistical significant difference in gene expression was observed between the alleles for T950C, with the T allele showing a lower luciferase expression in all cell lines (P<0.01). For rs4876869, exon skipping was observed for the C allele, while only one transcript harbouring the whole exon was observed for the T allele. Our findings suggest that the T-G-T haplotype might be increasing the risk for osteoporosis due to lower quantities of the full OPG transcript being expressed resulting in a higher bone resorption.

Management of bone metabolism in epilepsy

2021 ◽  
Vol 74 (7-8) ◽  
pp. 257-265
Author(s):  
Firdevs Ezgi Uçan Tokuç ◽  
Fatma Genç ◽  
Abidin Erdal ◽  
Yasemin Biçer Gömceli
Keyword(s):  
Bone Mineral Density ◽  
Vitamin D ◽  
Bone Metabolism ◽  
Bone Mineral ◽  
Outpatient Clinic ◽  
Bone Mineralization ◽  
Mineral Density ◽  
Low Bone Mineral Density ◽  
Increased Risk ◽  
Significant Difference

Many systemic problems arise due to the side effects of antiepileptic drugs (AEDs) used in epilepsy patients. Among these adverse effects are low bone mineral density and increased fracture risk due to long-term AED use. Although various studies have supported this association with increased risk in recent years, the length of this process has not been precisely defined and there is no clear consensus on bone density scanning, intervals of screening, and the subject of calcium and vitamin D supplementation. In this study, in accordance with the most current recommendations, our applications and data, including the detection of possible bone mineralization disorders, treatment methods, and recommendations to prevent bone mineralization disorders, were evaluated in epilepsy patients who were followed up at our outpatient clinic. It was aimed to draw attention to the significance of management of bone metabolism carried out with appropriate protocols. Epilepsy patients were followed up at the Antalya Training and Research Hospital Department of Neurology, Epilepsy Outpatient Clinic who were at high risk for osteoporosis (use of valproic acid [VPA] and enzyme-inducing drugs, using any AED for over 5 years, and postmenopausal women) and were evaluated using a screening protocol. According to this protocol, a total of 190 patients suspected of osteoporosis risk were retrospectively evaluated. Four patients were excluded from the study due to secondary osteoporosis. Of the 186 patients who were included in the study, 97 (52.2%) were women and 89 (47.8%) were men. Prevalence of low bone mineral density (BMD) was 42%, in which osteoporosis was detected in 11.8% and osteopenia in 30.6% of the patients. Osteoporosis rate was higher at the young age group (18-45) and this difference was statistically significant (p=0.018). There was no significant difference between male and female sexes according to osteoporosis and osteopenia rates. Patients receiving polytherapy had higher osteoporosis rate and lower BMD compared to patients receiving monotherapy. Comparison of separate drug groups according to osteoporosis rate revealed that osteoporosis rate was highest in patient groups using VPA+ carbamazepine (CBZ) (29.4%) and VPA polytherapy (19.4%). Total of osteopenia and osteoporosis, or low BMD, was highest in VPA polytherapy (VPA+ non-enzyme-inducing AED [NEID]) and CBZ polytherapy (CBZ+NEID) groups, with rates of 58.3% and 55.1%, respectively. In addition, there was no significant difference between drug groups according to bone metabolism markers, vitamin D levels, and osteopenia-osteoporosis rates. Assuming bone health will be affected at an early age in epilepsy patients, providing lifestyle and diet recommendations, avoiding polytherapy including VPA and CBZ when possible, and evaluating bone metabolism at regular intervals are actions that should be applied in routine practice.

Overexpression of Mig-6 in Cartilage Induces an Osteoarthritis-Like Phenotype in Mice

2020 ◽  
Author(s):  
Melina Bellini ◽  
Michael Andrew Pest ◽  
Manuela Miranda Rodrigues ◽  
Ling Qin ◽  
Jae-Wook Jeong ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Body Composition ◽  
Articular Cartilage ◽  
Bone Mineral ◽  
Cartilage Degeneration ◽  
Negative Regulator ◽  
Control Group ◽  
Multiple Time ◽  
Mineral Density ◽  
Significant Difference

Abstract Background: Osteoarthritis (OA) is the most common form of arthritis and characterized by degeneration of articular cartilage. Mitogen-inducible gene 6 (Mig-6) has been identified as a negative regulator of the Epidermal Growth Factor Receptor (EGFR). Cartilage-specific Mig-6 knockout (KO) mice display increased EGFR signaling, an anabolic buildup of articular cartilage and formation of chondro-osseous nodules. Since our understanding of the EGFR/Mig-6 network in cartilage remains incomplete, we characterized mice with cartilage-specific overexpression of Mig-6 in this study. Methods: Utilizing knee joints from cartilage-specific Mig-6 overexpressing (Mig-6over/over) mice (at multiple time points), we evaluated the articular cartilage using histology, immunohistochemical staining and semi-quantitative histopathological scoring (OARSI) at multiple ages. MicroCT analysis was employed to examine skeletal morphometry, body composition, and bone mineral density.Results: Our data show that cartilage-specific Mig-6 overexpression did not cause any major developmental abnormalities in articular cartilage, although Mig-6over/over mice have slightly shorter long bones compared to the control group. Moreover, there was no significant difference in bone mineral density and body composition in any of the groups. However, our results indicate that Mig-6over/over male mice show accelerated cartilage degeneration at 12 and 18 months of age. Immunohistochemistry for SOX9 demonstrated that the number of positively stained cells in Mig-6over/over mice was decreased relative to controls. Immunostaining for MMP13 appeared increased in areas of cartilage degeneration in Mig-6over/over mice. Moreover, staining for phospho-EGFR (Tyr-1173) and lubricin (PRG4) was decreased in the articular cartilage of Mig-6over/over mice. Conclusion: Overexpression of Mig-6 in articular cartilage causes no major developmental phenotype; however, these mice develop earlier OA during aging. These data demonstrate that Mig-6/EGFR pathways is critical for joint homeostasis and might present a promising therapeutic target for OA.

scholarly journals Overexpression Of Mig-6 In Cartilage Induces An Osteoarthritis-like Phenotype In Mice

2020 ◽  
Author(s):  
Melina Bellini ◽  
Michael Andrew Pest ◽  
Manuela Miranda Rodrigues ◽  
Ling Qin ◽  
Jae-Wook Jeong ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Body Composition ◽  
Articular Cartilage ◽  
Bone Mineral ◽  
Cartilage Degeneration ◽  
Negative Regulator ◽  
Control Group ◽  
Multiple Time ◽  
Mineral Density ◽  
Significant Difference

Abstract Background: Osteoarthritis (OA) is the most common form of arthritis and characterized by degeneration of articular cartilage. Mitogen-inducible gene 6 (Mig-6) has been identified as a negative regulator of the Epidermal Growth Factor Receptor (EGFR). Cartilage-specific Mig-6 knockout (KO) mice display increased EGFR signaling, an anabolic buildup of articular cartilage and formation of chondro-osseous nodules. Since our understanding of the EGFR/Mig-6 network in cartilage remains incomplete, we characterized mice with cartilage-specific overexpression of Mig-6 in this study. Methods : Utilizing knee joints from cartilage-specific Mig-6 overexpressing ( Mig- 6over/over ) mice (at multiple time points), we evaluated the articular cartilage using histology, immunohistochemical staining and semi-quantitative OARSI scoring at multiple ages. MicroCT analysis was employed to examine skeletal morphometry, body composition, and bone mineral density. Results: Our data show that cartilage-specific Mig-6 overexpression did not cause any major developmental abnormalities in articular cartilage, although Mig-6 over/over mice have slightly shorter long bones compared to the control group. Moreover, there was no significant difference in bone mineral density and body composition in any of the groups. However, our results indicate that Mig-6 over/over male mice show accelerated cartilage degeneration at 12 and 18 months of age. Immunohistochemistry for SOX9 demonstrated that the number of positively stained cells in Mig-6 over/over mice decreased relative to controls. Immunostaining for MMP13 staining is increased in areas of cartilage degeneration in Mig-6 over/over mice. Moreover, staining for phospho-EGFR (Tyr-1173) and lubricin (PRG4) was decreased in the articular cartilage of Mig-6 over/over mice. Conclusion: Overexpression of Mig-6 in articular cartilage causes no major developmental phenotype; however these mice develop earlier OA during aging. These data demonstrate that Mig-6/EGFR pathways is critical for joint homeostasis and might present a promising therapeutic target for OA.

scholarly journals A gene-to-gene interaction between aromatase and estrogen receptors influences bone mineral density

2006 ◽  
Vol 155 (1) ◽  
pp. 53-59 ◽  
Author(s):  
José A Riancho ◽  
María T Zarrabeitia ◽  
Carmen Valero ◽  
Carolina Sañudo ◽  
Verónica Mijares ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Estrogen Receptors ◽  
Postmenopausal Women ◽  
Bone Mineral ◽  
Promoter Region ◽  
Gene Interaction ◽  
Strong Linkage Disequilibrium ◽  
Mineral Density ◽  
Allelic Variants ◽  
Intron 1

Objective: The aromatization of androgenic precursors is the main source of estrogens in postmenopausal women. We tested the hypothesis that allelic variants of the genes coding for aromatase and estrogen receptors (ER) could interact to determine the estrogenic signals on the bone tissue and, consequently, bone mineral density (BMD). Design: Cross-sectional study including 331 postmenopausal women. Methods: BMD was measured by dual energy x-ray absorptiometry. A CG polymorphism of the aromatase gene as well as three polymorphisms of ERα (a TA repeat in the promoter region, a C T single nucleotide polymorphism (SNP) in intron 1 and an AG SNP in exon 8) and a CA repeat polymorphism of ERβ were studied. Results: Age, body weight and the aromatase genotype were associated with BMD. Allelic variants of ERβ and the exon 8 of ERα did not show a significant association with BMD. The polymorphisms located on the promoter and intron 1 of ERα interacted strongly with aromatase. Thus, in women TT homozygous for the ERα gene, there was a marked influence of aromatase genotypes on BMD: spine BMD was 0.724±0.027 g/cm2 in women with CC aromatase alleles and 0.926±0.032 g/cm2 in those with GG alleles (P<0.001). Hip BMD in women with CC and GG aromatase genotypes was 0.722±0.020 and 0.842±0.026 g/cm2 respectively (P=0.002). On the contrary, there were no aromatase-related differences in BMD in women with CT/CC alleles of ERα. Similarly, aromatase-related differences in BMD were found in women with short alleles at the promoter region of ERα, but not in those with long alleles. Both ERα polymorphisms were in strong linkage disequilibrium (P<0.001). Conclusion: These results suggest that the interaction between polymorphisms of genes involved in estrogen synthesis and estrogen signaling exerts an important influence on BMD in postmenopausal women, thus helping to explain, in part, its heritable component. Nevertheless, further studies are warranted to confirm this gene-to-gene interaction in other populations.

scholarly journals Overexpression of mig-6 in cartilage induces an osteoarthritis-like phenotype in mice

2019 ◽  
Author(s):  
Melina Bellini ◽  
Michael A. Pest ◽  
M. Miranda-Rodrigues ◽  
JW Jeong ◽  
Frank Beier
Keyword(s):  
Bone Mineral Density ◽  
Body Composition ◽  
Articular Cartilage ◽  
Bone Mineral ◽  
Cartilage Degeneration ◽  
Negative Regulator ◽  
Control Group ◽  
Multiple Time ◽  
Mineral Density ◽  
Significant Difference

ABSTRACTBackgroundOsteoarthritis (OA) is the most common form of arthritis and characterized by degeneration of articular cartilage. Mitogen-inducible gene 6 (Mig-6) has been identified as a negative regulator of the Epidermal Growth Factor Receptor (EGFR). Cartilage-specific Mig-6 knockout (KO) mice display increased EGFR signaling, an anabolic buildup of articular cartilage and formation of chondro-osseous nodules. Since our understanding of the EGFR/Mig-6 network in cartilage remains incomplete, we characterized mice with cartilage-specific overexpression of Mig-6 in this study.MethodsUtilizing knee joints from cartilage-specific Mig-6 overexpressing (Mig-6over/over) mice (at multiple time points), we evaluated the articular cartilage using histology, immunohistochemical staining and semi-quantitative OARSI scoring at multiple ages. MicroCT analysis was employed to examine skeletal morphometry, body composition, and bone mineral density.ResultsOur data show that cartilage-specific Mig-6 overexpression did not cause any major developmental abnormalities in articular cartilage, although Mig-6over/over mice have slightly shorter long bones compared to the control group. Moreover, there was no significant difference in bone mineral density and body composition in any of the groups. However, our results indicate that Mig-6over/over male mice show accelerated cartilage degeneration at 12 and 18 months of age. Immunohistochemistry for SOX9 demonstrated that the number of positively stained cells in Mig-6over/over mice decreased relative to controls. Immunostaining for MMP13 staining is increased in areas of cartilage degeneration in Mig-6over/over mice. Moreover, staining for phospho-EGFR (Tyr-1173) and lubricin (PRG4) was decreased in the articular cartilage of Mig-6over/over mice.ConclusionOverexpression of Mig-6 in articular cartilage causes no major developmental phenotype; however these mice develop earlier OA during aging. These data demonstrate that Mig-6/EGFR pathways is critical for joint homeostasis and might present a promising therapeutic target for OA.

Low Bone Mineral Density Is Not Associated with Subclinical Atherosclerosis: A Population-Based Study in Rural China

Cardiology ◽  
2018 ◽  
Vol 141 (2) ◽  
pp. 78-87 ◽  
Author(s):  
Yanfeng Jiang ◽  
Zehan Fan ◽  
Yingzhe Wang ◽  
Chen Suo ◽  
Mei Cui ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Femoral Neck ◽  
Postmenopausal Women ◽  
Bone Mineral ◽  
Rural China ◽  
Subclinical Atherosclerosis ◽  
Ankle Brachial Index ◽  
Mineral Density ◽  
Low Bone Mineral Density ◽  
Significant Difference

Objectives: Loss of bone mass may affect the progression of atherosclerosis. We investigated the relationship between low bone mineral density (BMD) and subclinical atherosclerosis in rural China. Methods: In total, 333 men and 421 postmenopausal women aged 55–65 years were enrolled. BMD was measured in the lumbar spine, femoral neck, and total hip using dual-energy X-ray absorptiometry. Subclinical atherosclerosis was defined as increased carotid artery intima-media thickness (CIMT ≥0.9 mm), the presence of carotid plaques, high brachial-ankle pulse wave velocity (baPWV ≥1,400 cm/s), and low ankle-brachial index (ABI ≤1). Binary logistic regression analyses were used to estimate the association between low BMD and subclinical atherosclerosis. Results: There was no significant difference in BMD between the normal group and the subclinical atherosclerosis group. After full adjustment for the relevant covariates, a boundary significant association was found between low BMD in the femoral neck and baPWV in postmenopausal women (odds ratio = 1.77, p = 0.049). After full adjustment, neither BMD nor low BMD were significantly associated with subclinical atherosclerosis in men or postmenopausal women. Conclusions: Low BMD is not associated with subclinical atherosclerosis in Chinese individuals aged 55–65 years resident in rural China.

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