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1.
Medicina (Kaunas) ; 57(3)2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33800136

RESUMO

Background and Objectives: Previous studies have demonstrated that risk of hip fracture is at least partly heritable. The aim of this study was to determine the magnitude of the genetic component of bone mineral density (BMD), using both X-ray and ultrasound assessment at multiple sites. Materials and Methods: 216 adult, healthy Hungarian twins (124 monozygotic, MZ, 92 dizygotic, DZ; mean age 54.2 ± 14.3 years), recruited from the Hungarian Twin Registry with no history of oncologic disease underwent cross-sectional BMD studies. We measured BMD, T- and Z-scores with dual energy X-ray absorptiometry (DEXA) at multiple sites (lumbar spine, femoral neck, total hip and radius). Quantitative bone ultrasound (QUS) was also performed, resulting in a calculated value of estimated bone mineral density (eBMD) in the heel bone. Heritability was calculated using the univariate ACE model. Results: Bone density had a strong genetic component at all sites with estimates of heritability ranging from 0.613 to 0.838 in the total sample. Lumbar BMD and calcaneus eBMD had major genetic components with estimates of 0.828 and 0.838 respectively, and least heritable (0.653) at the total hip. BMD of the radius had also a strong genetic component with an estimate of 0.806. No common environmental effect was found. The remaining variance was influenced by unique environment (0.162 to 0.387). In females only, slightly higher additive genetic estimates were found, especially in the case of the femoral neck and total hip. Conclusion: Bone mineral density is strongly heritable, especially in females at all locations using both DEXA and QUS, which may explain the importance of family history as a risk factor for bone fractures. Unshared environmental effects account for the rest of the variance with slight differences in magnitude across various bone regions, supporting the role of lifestyle in preventing osteoporotic fractures with various efficacy in different bone regions.


Assuntos
Densidade Óssea , Calcâneo , Absorciometria de Fóton , Adulto , Idoso , Densidade Óssea/genética , Calcâneo/diagnóstico por imagem , Estudos Transversais , Feminino , Colo do Fêmur/diagnóstico por imagem , Humanos , Pessoa de Meia-Idade , Ultrassonografia
2.
Nutrients ; 13(3)2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33806559

RESUMO

Vitamin D plays an important role in bone metabolism and is important for the prevention of multifactorial pathologies, including osteoporosis (OP). The biological action of vitamin is realized through its receptor, which is coded by the VDR gene. VDR gene polymorphism can influence individual predisposition to OP and response to vitamin D supplementation. The aim of this work was to reveal the effects of VDR gene ApaI rs7975232, BsmI rs1544410, TaqI rs731236, FokI rs2228570, and Cdx2 rs11568820 variants on bone mineral density (BMD), 25-hydroxyvitamin D level, and OP risk in Belarusian women. METHODS: The case group included 355 women with postmenopausal OP, and the control group comprised 247 women who met the inclusion criteria. TaqMan genotyping assay was used to determine VDR gene variants. RESULTS: Rs7975232 A/A, rs1544410 T/T, and rs731236 G/G single variants and their A-T-G haplotype showed a significant association with increased OP risk (for A-T-G, OR = 1.8, p = 0.0001) and decreased BMD (A-T-G, -0.09 g/cm2, p = 0.0001). The rs11568820 A-allele showed a protective effect on BMD (+0.22 g/cm2, p = 0.027). A significant dose effect with 25(OH)D was found for rs1544410, rs731236, and rs11568820 genotypes. Rs731236 A/A was associated with the 25(OH)D deficiency state. CONCLUSION: Our novel data on the relationship between VDR gene variants and BMD, 25(OH)D level, and OP risk highlights the importance of genetic markers for personalized medicine strategy.


Assuntos
Densidade Óssea/genética , Grupo com Ancestrais do Continente Europeu/genética , Estado Nutricional/genética , Pós-Menopausa/genética , Receptores de Calcitriol/genética , Vitamina D/análogos & derivados , Alelos , Estudos de Casos e Controles , Estudos Transversais , Grupo com Ancestrais do Continente Europeu/etnologia , Feminino , Marcadores Genéticos , Predisposição Genética para Doença/etnologia , Predisposição Genética para Doença/genética , Genótipo , Haplótipos , Humanos , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/etnologia , Osteoporose Pós-Menopausa/genética , Polimorfismo de Nucleotídeo Único , Pós-Menopausa/etnologia , República de Belarus , Vitamina D/sangue
3.
Osteoporos Int ; 32(6): 1239-1244, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33624138

RESUMO

Osteogenesis imperfecta (OI) is characterized by bone fragility and increased fracture susceptibility. BMP1 variants have been reported in the rare OI type XIII, specifically referred to herein as BMP1-associated autosomal recessive (AR) OI. We report the clinical presentation and diagnostic evaluation of a patient found to have a novel homozygous variant in BMP1. We also provide an overview of reported BMP1 variants to date, with discussion focusing on the use of bisphosphonate therapy in these patients. A 7-year-old male with speech and motor delay sustained five bilateral tibial fractures with minimal trauma since age 2.5 years. At age 6, he developed severe back pain after a fall. Diffuse spinal osteopenia and multiple vertebral compression fractures (VCF) at T9, L1, L3, and L5 were identified. Total hip BMD was generous (adjusted Z-score* = 1.76), and femoral neck BMD was high (adjusted Z-score* = 2.67). VCFs precluded assessment of lumbar spine BMD. Genetic analysis identified a homozygous missense variant in exon 4 of BMP1 (c.C505T; p.Arg169Cys). Unlike most forms of OI, patients with BMP1-associated AR OI may have normal or paradoxically increased BMD, making BMD and fracture risk correlation difficult. While bisphosphonates (BP) may help reduce recurrent fractures and provide symptomatic relief, the broad phenotypic spectrum and underlying bone pathology, often in the setting of increased BMD, complicate management. HR-pQCT assessment of bone microarchitecture and quality may aid in the decision of BP therapy and subsequent monitoring. Evidence is limited with respect to the effectiveness of BP in this rare form of OI. *Z-score was adjusted for height Z-score.


Assuntos
Fraturas Ósseas , Fraturas por Compressão , Osteogênese Imperfeita , Fraturas da Coluna Vertebral , Densidade Óssea/genética , Criança , Pré-Escolar , Difosfonatos/uso terapêutico , Humanos , Masculino , Mutação , Osteogênese Imperfeita/diagnóstico por imagem , Osteogênese Imperfeita/tratamento farmacológico , Osteogênese Imperfeita/genética , Fenótipo , Fraturas da Coluna Vertebral/genética
4.
BMC Womens Health ; 21(1): 76, 2021 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-33607983

RESUMO

BACKGROUND: The high prevalence of low bone mass in young women in Japan has emerged as a serious health issue in recent years. Therefore, the aim of the present study was to reevaluate the relationship between genetic and dietary factors, as well as its influence on bone mass in young Japanese women, with particular emphasis on vitamin D receptor (VDR) gene polymorphisms and calcium intake. METHODS: A total of 499 Japanese women aged 20-24 years were enrolled in the study. The bone mass of the calcaneus was assessed using the quantitative ultrasound method and expressed as the osteo sono-assessment index (OSI). VDR gene polymorphisms (BsmI, TaqI, ApaI, and FokI) were analyzed using DNA extracted from saliva. Calcium intake was assessed using the Food Frequency Questionnaire based on food groups (FFQg) and adjusted with the energy intake. Participants were divided into two groups based on the median calcium intake (250 mg/1000 kcal). RESULTS: Consequently, bone mass was significantly different among the BsmI and TaqI genotypes after adjusting for body mass index (BMI) (p = 0.030 and 0.019, respectively). In addition, the BsmI AA and ApaI GT genotypes showed significant differences in bone mass between the calcium-intake groups, with low OSI in the low-calcium intake group and high OSI in the high-calcium intake group, respectively, even after adjusting for BMI (p = 0.020 and 0.038, respectively). CONCLUSIONS: These findings may prove instrumental in developing a logical approach towards preventing bone loss in young Japanese women.


Assuntos
Cálcio , Receptores de Calcitriol , Densidade Óssea/genética , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Japão , Polimorfismo Genético , Receptores de Calcitriol/genética
5.
BMC Pediatr ; 21(1): 79, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33588791

RESUMO

BACKGROUND: Our aim was to investigate if moderate to vigorous physical activity (MVPA), calcium intake interacts with bone mineral density (BMD)-related single nucleotide polymorphisms (SNPs) to influence BMD in 750 Hispanic children (4-19y) of the cross-sectional Viva La Familia Study. METHODS: Physical activity and dietary intake were measured by accelerometers and multiple-pass 24 h dietary recalls, respectively. Total body and lumbar spine BMD were measured by dual energy X-ray absorptiometry. A polygenic risk score (PRS) was computed based on SNPs identified in published literature. Regression analysis was conducted with PRSs, MVPA and calcium intake with total body and lumbar spine BMD. RESULTS: We found evidence of statistically significant interaction effects between the PRS and MVPA on total body BMD and lumbar spine BMD (p < 0.05). Higher PRS was associated with a lower total body BMD (ß = - 0.040 ± 0.009, p = 1.1 × 10- 5) and lumbar spine BMD (ß = - 0.042 ± 0.013, p = 0.0016) in low MVPA group, as compared to high MVPA group (ß = - 0.015 ± 0.006, p = 0.02; ß = 0.008 ± 0.01, p = 0.4, respectively). DISCUSSION: The study indicated that calcium intake does not modify the relationship between genetic variants and BMD, while it implied physical activity interacts with genetic variants to affect BMD in Hispanic children. Due to limited sample size of our study, future research on gene by environment interaction on bone health and functional studies to provide biological insights are needed. CONCLUSIONS: Bone health in Hispanic children with high genetic risk for low BMD is benefitted more by MVPA than children with low genetic risk. Our results may be useful to predict disease risk and tailor dietary and physical activity advice delivery to people, especially children.


Assuntos
Densidade Óssea , Exercício Físico , Absorciometria de Fóton , Densidade Óssea/genética , Criança , Estudos Transversais , Hispano-Americanos/genética , Humanos
6.
Aging (Albany NY) ; 13(2): 2015-2030, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33323545

RESUMO

PURPOSE: Some epidemiological studies and animal studies have reported a relationship between leukocyte telomere length (LTL) and bone mineral density (BMD). However, the causality underlying the purported relationship has not been determined. Here we performed a two-sample MR analysis to test the causal link between telomere length and BMD. RESULTS: Our research suggested no causal link of LTL and BMD using IVW method. The weighted median, MR-Egger regression and MR.RAPS method yielded a similar pattern of effects. MR-Egger intercept test demonstrated our results were not influenced by pleiotropy. Heterogeneities among the genetic variants on heel estimated BMD and TB-BMD vanished after excluding rs6028466. "Leave-one-out" sensitivity analysis confirmed the stability of our results. CONCLUSION: Our MR analysis did not support causal effect of telomere length on BMD. METHODS: We utilized 5 independent SNPs robustly associated with LTL as instrument variables. The outcome results were obtained from GWAS summary data of BMD. The two-sample MR analysis was conducted using IVW, weighted median, MR-Egger regression and MR.RAPS method. MR-Egger intercept test, Cochran's Q test and I2 statistics and "leave-one-out" sensitivity analysis were performed to evaluate the horizontal pleiotropy, heterogeneities and stability of these genetic variants on BMD.


Assuntos
Densidade Óssea/genética , Leucócitos/metabolismo , Osteoporose/epidemiologia , Telômero/metabolismo , Causalidade , Humanos , Análise da Randomização Mendeliana , Osteoporose/genética , Polimorfismo de Nucleotídeo Único , Homeostase do Telômero
7.
Sci Rep ; 10(1): 22090, 2020 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-33328494

RESUMO

Pentosidine (PEN) and carboxymethyl-lysine (CML) are well-recognized advanced glycation end products (AGEs). However, how these AGEs affect the pathophysiology of osteoporosis and osteoporotic fractures remains controversial. This cross-sectional study aimed to investigate the associations of PEN and CML with bone markers, bone mineral density (BMD), and osteoporotic fractures in postmenopausal women from the Nagano Cohort Study. A total of 444 Japanese postmenopausal outpatients (mean ± standard deviation age: 69.8 ± 10.2 years) were enrolled after the exclusion of patients with acute or severe illness or secondary osteoporosis. The relationships among urinary PEN and serum CML levels, various bone markers, lumbar and hip BMD, and prevalent vertebral and long-bone fractures were evaluated. PEN associated significantly with prevalent vertebral fracture after adjustment for other confounders (odds ratio [OR] 1.59, 95% confidence interval [CI] 1.22-2.07; P < 0.001), but not with lumbar BMD. In contrast, a significant negative correlation was found between CML and lumbar BMD (r = - 0.180; P < 0.001), and this relationship was significant after adjustment for confounders (OR 0.84, 95% CI 0.76-0.93; P < 0.01). Although patients with prevalent vertebral fracture had significantly higher CML levels, the association between CML and prevalent vertebral fracture did not reach significance in the multivariate regression model. Both PEN and CML may play important roles in bone health for postmenopausal women, possibly via different mechanisms.


Assuntos
Arginina/análogos & derivados , Lisina/análogos & derivados , Osteoporose Pós-Menopausa/sangue , Fraturas por Osteoporose/sangue , Idoso , Idoso de 80 Anos ou mais , Arginina/urina , Densidade Óssea/genética , Estudos de Coortes , Feminino , Produtos Finais de Glicação Avançada/genética , Humanos , Japão/epidemiologia , Vértebras Lombares/fisiopatologia , Lisina/sangue , Lisina/urina , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/patologia , Osteoporose Pós-Menopausa/urina , Fraturas por Osteoporose/patologia , Fraturas por Osteoporose/urina , Pós-Menopausa
8.
Mutat Res ; 786: 108339, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33339581

RESUMO

As a complex disease, osteoporosis is influenced by several genetic markers. Many studies have examined the link between the Sp1 binding site +1245 G > T (rs1800012) and -1997 G > T (rs1107946) variations in the COL1A1 gene with osteoporosis risk. However, the findings of these studies have been contradictory; therefore, we performed a meta-analysis to aggregate additional information and obtain increased statistical power to more efficiently estimate this correlation. A meta-analysis was conducted with studies published between 1991-2020 that were identified by a systematic electronic search of the Scopus and Clarivate Analytics databases. Studies with bone mineral density (BMD) data and complete genotypes of the single-nucleotide variations (SNVs) for the overall and postmenopausal female population were included in this meta-analysis and analyzed using the R metaphor package. A relationship between rs1800012 and significantly decreased BMD values at the lumbar spine and femoral neck was found in individuals carrying the "ss" versus the "SS" genotype in the overall population according to a random effects model (p < 0.0001). Similar results were also found in the postmenopausal female population (p = 0.003 and 0.0002, respectively). Such findings might be an indication of increased osteoporosis risk in both studied groups in individuals with the "ss" genotype. Although no association was identified between the -1997 G > T and low BMD in the overall population, those individuals with the "GT" genotype showed a higher level of BMD than those with "GG" in the subgroup analysis (p = 0.007). To determine which transcription factor (TF) might bind to the -1997 G > T in COL1A1, 45 TFs were identified based on bioinformatics predictions. According to the GSE35958 microarray dataset, 16 of 45 TFs showed differential expression profiles in osteoporotic human mesenchymal stem cells relative to normal samples from elderly donors. By identifying candidate TFs for the -1997 G > T site, our study offers a new perspective for future research.


Assuntos
Colágeno Tipo I/genética , Biologia Computacional , Osteoporose/genética , Regiões Promotoras Genéticas/genética , Fator de Transcrição Sp1/genética , Sítios de Ligação , Densidade Óssea/genética , Feminino , Genótipo , Humanos , Células-Tronco Mesenquimais , Risco , Transcriptoma
9.
PLoS Genet ; 16(12): e1009190, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33370286

RESUMO

The genetic landscape of diseases associated with changes in bone mineral density (BMD), such as osteoporosis, is only partially understood. Here, we explored data from 3,823 mutant mouse strains for BMD, a measure that is frequently altered in a range of bone pathologies, including osteoporosis. A total of 200 genes were found to significantly affect BMD. This pool of BMD genes comprised 141 genes with previously unknown functions in bone biology and was complementary to pools derived from recent human studies. Nineteen of the 141 genes also caused skeletal abnormalities. Examination of the BMD genes in osteoclasts and osteoblasts underscored BMD pathways, including vesicle transport, in these cells and together with in silico bone turnover studies resulted in the prioritization of candidate genes for further investigation. Overall, the results add novel pathophysiological and molecular insight into bone health and disease.


Assuntos
Densidade Óssea/genética , Regulação da Expressão Gênica/genética , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteoporose/genética , Animais , Feminino , Ontologia Genética , Pleiotropia Genética , Estudo de Associação Genômica Ampla , Genótipo , Masculino , Camundongos , Camundongos Transgênicos , Mutação , Osteoblastos/patologia , Osteoclastos/patologia , Osteoporose/metabolismo , Fenótipo , Regiões Promotoras Genéticas , Mapas de Interação de Proteínas , Caracteres Sexuais , Transcriptoma
10.
Nat Commun ; 11(1): 4093, 2020 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-33097703

RESUMO

A major challenge in genetic association studies is that most associated variants fall in the non-coding part of the human genome. We searched for variants associated with bone mineral density (BMD) after enriching the discovery cohort for loss-of-function (LoF) mutations by sequencing a subset of the Nord-Trøndelag Health Study, followed by imputation in the remaining sample (N = 19,705), and identified ten known BMD loci. However, one previously unreported variant, LoF mutation in MEPE, p.(Lys70IlefsTer26, minor allele frequency [MAF] = 0.8%), was associated with decreased ultradistal forearm BMD (P-value = 2.1 × 10-18), and increased osteoporosis (P-value = 4.2 × 10-5) and fracture risk (P-value = 1.6 × 10-5). The MEPE LoF association with BMD and fractures was further evaluated in 279,435 UK (MAF = 0.05%, heel bone estimated BMD P-value = 1.2 × 10-16, any fracture P-value = 0.05) and 375,984 Icelandic samples (MAF = 0.03%, arm BMD P-value = 0.12, forearm fracture P-value = 0.005). Screening for the MEPE LoF mutations before adulthood could potentially prevent osteoporosis and fractures due to the lifelong effect on BMD observed in the study. A key implication for precision medicine is that high-impact functional variants missing from the publicly available cosmopolitan panels could be clinically more relevant than polygenic risk scores.


Assuntos
Densidade Óssea/genética , Proteínas da Matriz Extracelular/genética , Fraturas Ósseas/genética , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Glicoproteínas/genética , Fosfoproteínas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Biologia Computacional , Feminino , Frequência do Gene , Testes Genéticos , Genoma Humano , Humanos , Islândia , Masculino , Pessoa de Meia-Idade , Osteoporose/genética
11.
Ecotoxicol Environ Saf ; 203: 111031, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32888610

RESUMO

Bone mineral density (BMD) changes were reported to be associated with excessive fluoride exposure and abnormal expression of RUNX2. However, whether the alteration of methylation status, a most commonly used marker for the alteration of gene expression in epidemiological investigation, of RUNX2 is associated with low-to-moderate fluoride exposure and BMD changes has not been reported. Our study aims to explore the role of RUNX2 promoter methylation in BMD changes induced by low-to-moderate fluoride exposure. A total of 1124 adults (413 men and 711 women) were recruited from Kaifeng City in 2017. We measured BMD using ultrasound bone densitometer. Concentrations of urinary fluoride (UF) were measured using ion-selective electrode, and the participants were grouped into control group (CG) and excessive fluoride group (EFG) according to the concentration of UF. We extracted DNA from fasting peripheral blood samples and then detected the promoter methylation levels of RUNX2 using quantitative methylation-specific PCR. Relationships between UF concentration, RUNX2 promoter methylation and BMD changes were analyzed using generalized linear model and logistic regression. Results showed in EFG (UF concentration > 1.6 mg/L), BMD was negatively correlated with UF concentration (ß: -0.14; 95%CI: -0.26, -0.01) and RUNX2 promoter methylation (ß: -0.13; 95%CI: -0.22, -0.03) in women. The methylation rate of RUNX2 promoter increased by 2.16% for each 1 mg/L increment in UF concentration of women in EFG (95%CI: 0.37, 3.96). No any significant associations between UF concentration, RUNX2 promoter methylation, and BMD were observed in the individuals in CG. Mediation analysis showed that RUNX2 promoter methylation mediated 18.2% (95% CI: 4.2%, 53.2%) of the association between UF concentration and BMD of women in EFG. In conclusion, excessive fluoride exposure (>1.6 mg/L) is associated with changes of BMD in women, and this association is mediated by RUNX2 promoter methylation.


Assuntos
Densidade Óssea/efeitos dos fármacos , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Exposição Ambiental/análise , Fluoretos/toxicidade , Poluentes Químicos da Água/toxicidade , Absorciometria de Fóton , Adulto , Idoso , Densidade Óssea/genética , China , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Estudos Transversais , Metilação de DNA/efeitos dos fármacos , Feminino , Fluoretos/urina , Humanos , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Inquéritos e Questionários , Poluentes Químicos da Água/urina
12.
Zhen Ci Yan Jiu ; 45(9): 702-7, 2020 Sep 25.
Artigo em Chinês | MEDLINE | ID: mdl-32959551

RESUMO

OBJECTIVE: To observe the effect of electroacupuncture (EA) on bone mineral density (BMD) and expression of calcium transport-related receptors in ovariectomized rats, so as to explore its mechanisms underlying improvement of osteoporosis. METHODS: Thirty-two three-month female SD rats were randomly divided into control, sham operation, model and EA groups (n=8 in each group). The ovariectomy model was established by resection of bilateral ovaries. EA (2 Hz/15 Hz, 2 mA) was applied to "Guanyuan"(CV4)+"Sanyinjiao"(SP6) or "Shenshu"(BL23)+"Housanli"(ST36) alternatively for 20 min, once daily (except the weekends) for 12 weeks. BMD of the tibia and femur were detected by using a bone densitometer. The expression levels of transient receptor potential vanillic receptor 5 (TRPV5), transient receptor potential vanillic receptor 6 (TRPV6), sodium calcium exchanger 1 (NCX1), membrane calcium adenosine triphosphate hydrolase (PMCA1b), zonula occludens 1 (ZO-1), occludin and claudin in intestinal mucosa were detected by quantitative real-time PCR and Western blot, respectively. RESULTS: Following modeling, BMD of both tibia and femur, and expression levels of TRPV5, PMCA1b, ZO-1, occludin and claudin mRNAs were significantly decreased in the model group compared with the control and sham operation groups (P<0.05, P<0.01),while the mRNAs levels of TRPV6 and NCX1 in the model group were increased (P<0.01). After the treatment, BMD of both tibia and femur, and expression levels of TRPV5, PMCA1b, ZO-1 and occludin mRNAs were significantly increased(P<0.01,P<0.05),and TRPV6 and NCX1 were significantly decreased(P<0.01,P<0.05) in the EA group than those in the model group. Compared with the control and sham operation groups, protein expression levels of TRPV5, PMCA1b, ZO-1, occludin and claudin in the model group were significantly decreased (P<0.05), while the protein levels of TRPV6 and NCX1 in the model group were increased (P<0.05). After EA intervention, modeling-induced decrease of TRPV5, PMCA1b, ZO-1, occludin and claudin protein levels and increase of TRPV6 and NCX1 protein levels were all completely reversed in the EA group relevant to the model group (P<0.05). CONCLUSION: EA intervention can improve bone mineral density and up-regulate the mRNA and protein expression of TRPV5, PMCA1b, ZO-1 and occludin, which may be one of the mechanisms of acupuncture in the treatment of osteoporosis.


Assuntos
Eletroacupuntura , Osteoporose , Pontos de Acupuntura , Animais , Densidade Óssea/genética , Cálcio , Feminino , Osteoporose/genética , Osteoporose/terapia , Ratos , Ratos Sprague-Dawley
13.
J Bone Miner Metab ; 38(6): 868-877, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32653958

RESUMO

INTRODUCTION: Osteoporosis is a common disorder characterized by decreased bone mineral density (BMD). Interestingly, osteoporosis and obesity have several similar features, including a genetic predisposition and a common bone marrow stem cell. With aging, the composition of bone marrow shifts to adipocytes, osteoclast activity increases, and osteoblast function declines, resulting in osteoporosis. MATERIALS AND METHODS: We performed a genome-wide association study (GWAS) analysis with osteoporosis and body mass index (BMI) and did identify an association in 349 and 384 SNPs by filtering with the significant p values (p < 0.001) of BMI and osteoporosis, respectively. RESULTS: Only three of those SNPs were common (rs2326365, rs7097028, and rs11000205) between the SNPs significantly associated with BMI and/or osteoporosis in Korean Association REsource (KARE) females. Two of the three SNPs belonged to the ASCC1 gene and one to the FAM50B gene. We carried out a minor allele frequency (MAF) analysis of the rs7097028 and rs11000205 SNPs in the ASCC1 gene with a geographic genome variant browser. Both rs7097028 and rs11000205 in the ASCC1 gene were seen mostly in African and Southeast Asian populations. CONCLUSIONS: Our results suggest that the ASCC1 gene is a significant genetic factor for determining the risk for both osteoporosis and obesity in KARE postmenopausal females.


Assuntos
Proteínas de Transporte/genética , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Obesidade/genética , Osteoporose/genética , Polimorfismo de Nucleotídeo Único/genética , Pós-Menopausa/genética , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Índice de Massa Corporal , Densidade Óssea/genética , Feminino , Frequência do Gene/genética , Geografia , Humanos , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , República da Coreia
14.
PLoS Genet ; 16(6): e1008805, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32497039

RESUMO

Osteoporosis is a genetic disease characterized by progressive reductions in bone mineral density (BMD) leading to an increased risk of fracture. Over the last decade, genome-wide association studies (GWASs) have identified over 1000 associations for BMD. However, as a phenotype BMD is challenging as bone is a multicellular tissue affected by both local and systemic physiology. Here, we focused on a single component of BMD, osteoblast-mediated bone formation in mice, and identified associations influencing osteoblast activity on mouse Chromosomes (Chrs) 1, 4, and 17. The locus on Chr. 4 was in an intergenic region between Wnt4 and Zbtb40, homologous to a locus for BMD in humans. We tested both Wnt4 and Zbtb40 for a role in osteoblast activity and BMD. Knockdown of Zbtb40, but not Wnt4, in osteoblasts drastically reduced mineralization. Additionally, loss-of-function mouse models for both genes exhibited reduced BMD. Our results highlight that investigating the genetic basis of in vitro osteoblast mineralization can be used to identify genes impacting bone formation and BMD.


Assuntos
Densidade Óssea/genética , Proteínas de Ligação a DNA/fisiologia , Osteoblastos/metabolismo , Animais , Células Cultivadas , Proteínas de Ligação a DNA/genética , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Osteoblastos/citologia , Osteogênese/genética , Proteína Wnt4/genética
15.
Rev. cuba. invest. bioméd ; 39(2): e515, abr.-jun. 2020. tab
Artigo em Espanhol | LILACS, CUMED | ID: biblio-1126605

RESUMO

Los defectos óseos alrededor de los implantes dentales son considerados enfermedades que afectan el soporte y estabilidad del implante dental lo que limita la oseointegración. El tratamiento de estos defectos involucra procedimientos de regeneración ósea guiada que se define como la reproducción o reconstitución de una parte perdida o dañada del tejido óseo periimplantario con el fin de restaurar su arquitectura y función. El plasma rico en plaquetas y el plasma rico en fibrina son concentrados de plaquetas autólogos ampliamente usados en la regeneración periodontal y regeneración ósea guiada; sin embargo, sus resultados clínicos, histológicos y radiográficos son discutidos cuando se tratan defectos óseos alrededor de implantes dentales. En la presente revisión se realizó una búsqueda de la información mediante las bases de datos de diferentes buscadores (PubMed, SciELO, Redalyc y ScienceDirect) para encontrar artículos que traten sobre el uso de los concentrados plaquetarios (plasma rico en plaquetas y plasma rico en fibrina) en la terapia de la regeneración ósea guiada. Clínicamente, los concentrados plaquetarios otorgan resultados favorables en la reducción de la profundidad de sondaje y ganancia de nivel de inserción clínica en el tratamiento de defectos infraóseos periodontales. Histológicamente, los concentrados plaquetarios favorecen la neoformación ósea aumentando la velocidad de regeneración. Radiográficamente, los concentrados plaquetarios favorecen el aumento de densidad ósea, relleno óseo y tejido mineralizado. Con ello, se logra una reducción significativa del tamaño del defecto óseo(AU)


Bone defects around dental implants are considered to be diseases affecting the support and stability of the implant, thus limiting osseointegration. Treatment of these defects involves guided bone regeneration procedures, defined as the reproduction or reconstitution of a part lost or damaged of the peri-implant bone tissue with the purpose of restoring its architecture and function. Platelet-rich plasma and fibrin-rich plasma are autologous platelet concentrates widely used in guided bone regeneration and periodontal regeneration. However, their clinical, histological and radiographic results are debated when bone defects around dental implants are dealt with. The present review included a search for information in the databases of various search engines (PubMed, SciELO, Redalyc and ScienceDirect) to find papers about the use of platelet concentrates (platelet-rich plasma and fibrin-rich plasma) in guided bone regeneration therapy. Clinically, platelet concentrates yield favorable results in reducing probing depth and raising the level of clinical insertion in the treatment of periodontal intraosseous defects. Histologically, platelet concentrates enhance bone neoformation, speeding up regeneration. Radiographically, platelet concentrates lead to an increase in bone density, bone filler and mineralized tissue. A significant reduction is thus achieved in the size of the bone defect(AU)


Assuntos
Humanos , Plasma Rico em Plaquetas/fisiologia , Regeneração Óssea/fisiologia , Densidade Óssea/genética , Fibrina Rica em Plaquetas/fisiologia
16.
J Bone Miner Metab ; 38(5): 658-669, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32399675

RESUMO

INTRODUCTION: Leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) could affect differentiation of osteoblasts and bone mass through potentiating Wnt/ß-catenin signaling. LGR4 is also relevant to glycolipid metabolism. The present study aims to explore the relationship between genetic variations in LGR4 gene and peak bone mineral density (peak BMD) and body composition phenotypes in Chinese nuclear families. MATERIALS AND METHODS: 22 single-nucleotide polymorphisms (SNPs) were selected and five blocks were constructed in LGR4. Body composition (lean mass and fat mass) and peak BMD were measured by dual-energy X-ray absorptiometry (DXA). Quantitative transmission disequilibrium test (QTDT) analysis was used to explore the relationship between LGR4 genotypes and the mentioned phenotypes. RESULTS: For QTDT analysis after 1000 permutations, significant within-family associations were observed between rs11029986 and total fat mass (TFM) and percentage of TFM (PFM) (P = 0.014 and 0.011, respectively), rs12787344, rs4128868, rs4923445, and rs7936621 and body mass index (BMI) (P = 0.008, 0.003, 0.046, and 0.003, respectively), rs11029986 and total hip BMD (P = 0.026), and rs12796247, rs2219783, and lumbar spine BMD (P = 0.013 and 0.027, respectively). Haplotypes GCGT and AAGC (both in block 3) were observed in significant within-family association with BMI (P = 0.003 and 0.002, respectively). CONCLUSION: It is the first family-based association analysis to explore and demonstrate significant associations between LGR4 genotypes and variations of peak BMD and body composition in young Chinese men. The results are consistent with the findings that recent studies revealed, and confirm the critical relationship between LGR4 gene and both BMD and body composition.


Assuntos
Composição Corporal/genética , Densidade Óssea/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Receptores Acoplados a Proteínas-G/genética , Absorciometria de Fóton , Adiposidade , Grupo com Ancestrais do Continente Asiático/genética , Feminino , Haplótipos/genética , Humanos , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade
17.
PLoS Genet ; 16(5): e1008361, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32463812

RESUMO

Osteocalcin (OCN), the most abundant noncollagenous protein in the bone matrix, is reported to be a bone-derived endocrine hormone with wide-ranging effects on many aspects of physiology, including glucose metabolism and male fertility. Many of these observations were made using an OCN-deficient mouse allele (Osc-) in which the 2 OCN-encoding genes in mice, Bglap and Bglap2, were deleted in ES cells by homologous recombination. Here we describe mice with a new Bglap and Bglap2 double-knockout (dko) allele (Bglap/2p.Pro25fs17Ter) that was generated by CRISPR/Cas9-mediated gene editing. Mice homozygous for this new allele do not express full-length Bglap or Bglap2 mRNA and have no immunodetectable OCN in their serum. FTIR imaging of cortical bone in these homozygous knockout animals finds alterations in the collagen maturity and carbonate to phosphate ratio in the cortical bone, compared with wild-type littermates. However, µCT and 3-point bending tests do not find differences from wild-type littermates with respect to bone mass and strength. In contrast to the previously reported OCN-deficient mice with the Osc-allele, serum glucose levels and male fertility in the OCN-deficient mice with the Bglap/2pPro25fs17Ter allele did not have significant differences from wild-type littermates. We cannot explain the absence of endocrine effects in mice with this new knockout allele. Possible explanations include the effects of each mutated allele on the transcription of neighboring genes, or differences in genetic background and environment. So that our findings can be confirmed and extended by other interested investigators, we are donating this new Bglap and Bglap2 double-knockout strain to the Jackson Laboratories for academic distribution.


Assuntos
Sistema Endócrino/fisiologia , Osteocalcina/genética , Animais , Densidade Óssea/genética , Osso e Ossos/metabolismo , Sistema Endócrino/metabolismo , Feminino , Fertilidade/genética , Resistência à Insulina/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteocalcina/deficiência
18.
Nutrients ; 12(1)2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-32284510

RESUMO

Studies investigating the effect of the caudal-type homeobox protein 2 (Cdx2) polymorphism in the vitamin D receptor gene and calcium intake on bone mass have shown inconsistent results. This study investigated whether the effect of calcium intake on peak bone mass is affected by Cdx2 polymorphism in young Japanese women. A cross-sectional study of 500 young women was conducted. Dietary intake was assessed by the Food Frequency Questionnaire. The osteo sono-assessment index (OSI), assessed by the qualitative ultrasound method, was used as a bone mass index. The subjects were divided into two groups by the median calcium intake. The OSI was not different among Cdx2 genotypes and between calcium groups (p = 0.960, p = 0.191, respectively). The interaction between calcium and Cdx2 genotypes on the OSI approached significance (GG versus GA and AA genotypes, p = 0.092). The difference in the OSI between calcium groups was significant in the GG genotype (p = 0.028), but not in the GA or AA genotypes (p = 0.501, p = 0.306, respectively). Adjustment for covariates (body mass index and physical activity) did not change the results. In conclusion, the relationship between dietary calcium intake and peak bone mass may vary according to Cdx2 polymorphism.


Assuntos
Densidade Óssea/genética , Osso e Ossos/efeitos dos fármacos , Fator de Transcrição CDX2/genética , Cálcio na Dieta/farmacologia , Cálcio/farmacologia , Polimorfismo Genético , Receptores de Calcitriol/metabolismo , Adulto , Densidade Óssea/efeitos dos fármacos , Osso e Ossos/metabolismo , Estudos Transversais , Feminino , Genótipo , Humanos , Japão , Adulto Jovem
19.
Gene ; 741: 144543, 2020 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-32165300

RESUMO

INTRODUCTION: Collagen cross-linking, which is regulated by lysyl oxidase (LOX), plays critical roles in bone mechanical strength. LOX can influence bone remodeling by modulating osteoblast and osteoclast activity. This study aimed to explore the effect of LOX gene polymorphisms on osteoporotic fractures susceptibility in postmenopausal Chinese women. METHODS: This was a prospective study of postmenopausal women who visited the outpatient and community clinics of the local Hospital. Five tagging single nucleotide polymorphisms (SNPs) in the LOX gene were determined. Bone mineral density (BMD) was measured at the lumbar spine, femoral neck, and hip using dual-energy X-ray absorptiometry. Fractures were confirmed by X-ray and divided into: vertebral compression fracture (OVCF) and non-OVCF (all other fractures). RESULTS: This study included 602 patients with non-traumatic fractures and 1343 healthy volunteers. The rs1800449 was significantly associated with vertebral compression fracture (OVCF) after adjusting for age and BMI (P = 0.012). Compared with subjects with the GG genotype, the risk of having OVCF was 1.28 and 1.74, respectively for subjects with the GA and AA genotypes (P = 0.043 and P = 0.018). A recessive genetic model showed that carriers of the AA genotype had higher fracture risk compared to G carriers (GA and GG genotypes) (P = 0.015). The rs2288393 SNP exhibited marginally significant association with OVCF (P = 0.051). Haplotype analyses corroborated our single SNP results: both haplotype CGA and CCG contained rs10519694, rs2288393, and rs1800449, and were significant associated with OVCF (P = 0.048 and P = 0.032, respectively). On the other hand, we found no evidence of an association of LOX gene allelic variants with either BMD or non-OVCF (all P > 0.05). CONCLUSION: The results suggest that genetic polymorphisms in LOX may contribute to susceptibility to OVCF in Chinese postmenopausal women.


Assuntos
Fraturas por Compressão/genética , Osteoporose Pós-Menopausa/genética , Fraturas por Osteoporose/genética , Proteína-Lisina 6-Oxidase/genética , Absorciometria de Fóton , Idoso , Densidade Óssea/genética , Feminino , Colo do Fêmur/diagnóstico por imagem , Colo do Fêmur/fisiopatologia , Fraturas por Compressão/diagnóstico por imagem , Fraturas por Compressão/fisiopatologia , Genótipo , Humanos , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/fisiopatologia , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/diagnóstico por imagem , Osteoporose Pós-Menopausa/fisiopatologia , Fraturas por Osteoporose/diagnóstico por imagem , Fraturas por Osteoporose/fisiopatologia , Pós-Menopausa/genética , Pós-Menopausa/fisiologia , Fatores de Risco
20.
J Pharmacol Exp Ther ; 373(3): 337-346, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32213546

RESUMO

Bone loss in response to alcohol intake has previously been hypothesized to be mediated by excessive production of reactive oxygen species via NADPH oxidase (Nox) enzymes. Nox4 is one of several Nox enzymes expressed in bone. We investigated the role of Nox4 in the chondro-osteoblastic lineage of the long bones in mice during normal chow feeding and during chronic ethanol feeding for 90 days. We generated mice with a genotype (PrxCre +/- Nox4 fl/fl) allowing conditional knockout of Nox4 in the limb bud mesenchyme. Adult mice had 95% knockdown of Nox4 expression in the femoral shafts. For mice on regular chow, only whole-body Nox4 knockout mice had clearly increased cortical thickness and bone mineral density in the tibiae. When chronically fed a liquid diet with and without ethanol, conditional Nox4 knockout mice had slightly reduced dimensions of the cortical and trabecular regions of the tibiae (P < 0.1). The ethanol diet caused a significant reduction in cortical bone area and cortical thickness relative to a control diet without ethanol (P < 0.05). The ethanol diet further reduced gene expression of Frizzled related protein (Frzb), myosin heavy chain 3, and several genes encoding collagen and other major structural bone proteins (P < 0.05), whereas the Nox4 genotype had no effects on these genes. In conclusion, Nox4 expression from both mesenchymal and nonmesenchymal cell lineages appears to exert subtle effects on bone. However, chronic ethanol feeding reduces cortical bone mass and cortical gene expression of major structural bone proteins in a Nox4-independent manner. SIGNIFICANCE STATEMENT: Excessive alcohol intake contributes to osteopenia and osteoporosis, with oxidative stress caused by the activity of NADPH oxidases hypothesized to be a mediator. We tested the role of NADPH oxidase (Nox) 4 in osteoblast precursors in the long bones of mice with a conditional Nox4 knockout model. We found that Nox4 exerted effects independent of alcohol intake, and ethanol effects on bone were Nox4-independent.


Assuntos
Osso e Ossos/efeitos dos fármacos , Etanol/administração & dosagem , Expressão Gênica/efeitos dos fármacos , NADPH Oxidase 4/genética , Animais , Densidade Óssea/efeitos dos fármacos , Densidade Óssea/genética , Feminino , Genótipo , Masculino , Camundongos , Camundongos Knockout , NADPH Oxidases/genética , Osteoblastos/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Espécies Reativas de Oxigênio/metabolismo
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