RESUMO
In lactating mothers, the high calcium (Ca2+) demand for milk production triggers significant bone loss1. Although oestrogen normally counteracts excessive bone resorption by promoting bone formation, this sex steroid drops precipitously during this postpartum period. Here we report that brain-derived cellular communication network factor 3 (CCN3) secreted from KISS1 neurons of the arcuate nucleus (ARCKISS1) fills this void and functions as a potent osteoanabolic factor to build bone in lactating females. We began by showing that our previously reported female-specific, dense bone phenotype2 originates from a humoral factor that promotes bone mass and acts on skeletal stem cells to increase their frequency and osteochondrogenic potential. This circulatory factor was then identified as CCN3, a brain-derived hormone from ARCKISS1 neurons that is able to stimulate mouse and human skeletal stem cell activity, increase bone remodelling and accelerate fracture repair in young and old mice of both sexes. The role of CCN3 in normal female physiology was revealed after detecting a burst of CCN3 expression in ARCKISS1 neurons coincident with lactation. After reducing CCN3 in ARCKISS1 neurons, lactating mothers lost bone and failed to sustain their progeny when challenged with a low-calcium diet. Our findings establish CCN3 as a potentially new therapeutic osteoanabolic hormone for both sexes and define a new maternal brain hormone for ensuring species survival in mammals.
Assuntos
Densidade Óssea , Osso e Ossos , Encéfalo , Hormônios , Mães , Proteína Sobre-Expressa em Nefroblastoma , Osteogênese , Adolescente , Animais , Feminino , Humanos , Masculino , Camundongos , Envelhecimento , Núcleo Arqueado do Hipotálamo/citologia , Núcleo Arqueado do Hipotálamo/metabolismo , Osso e Ossos/citologia , Osso e Ossos/metabolismo , Remodelação Óssea , Reabsorção Óssea/metabolismo , Encéfalo/citologia , Encéfalo/metabolismo , Cálcio/administração & dosagem , Cálcio/metabolismo , Lactação/metabolismo , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Células-Tronco/metabolismo , Células-Tronco/citologia , Proteína Sobre-Expressa em Nefroblastoma/metabolismo , Hormônios/metabolismoRESUMO
Alzheimer's disease has a higher incidence in older women, with a spike in cognitive decline that tracks with visceral adiposity, dysregulated energy homeostasis and bone loss during the menopausal transition1,2. Inhibiting the action of follicle-stimulating hormone (FSH) reduces body fat, enhances thermogenesis, increases bone mass and lowers serum cholesterol in mice3-7. Here we show that FSH acts directly on hippocampal and cortical neurons to accelerate amyloid-ß and Tau deposition and impair cognition in mice displaying features of Alzheimer's disease. Blocking FSH action in these mice abrogates the Alzheimer's disease-like phenotype by inhibiting the neuronal C/EBPß-δ-secretase pathway. These data not only suggest a causal role for rising serum FSH levels in the exaggerated Alzheimer's disease pathophysiology during menopause, but also reveal an opportunity for treating Alzheimer's disease, obesity, osteoporosis and dyslipidaemia with a single FSH-blocking agent.
Assuntos
Doença de Alzheimer , Hormônio Foliculoestimulante , Idoso , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Densidade Óssea , Cognição , Feminino , Hormônio Foliculoestimulante/metabolismo , Humanos , Camundongos , TermogêneseRESUMO
BACKGROUND: Testosterone treatment in men with hypogonadism improves bone density and quality, but trials with a sufficiently large sample and a sufficiently long duration to determine the effect of testosterone on the incidence of fractures are needed. METHODS: In a subtrial of a double-blind, randomized, placebo-controlled trial that assessed the cardiovascular safety of testosterone treatment in middle-aged and older men with hypogonadism, we examined the risk of clinical fracture in a time-to-event analysis. Eligible men were 45 to 80 years of age with preexisting, or high risk of, cardiovascular disease; one or more symptoms of hypogonadism; and two morning testosterone concentrations of less than 300 ng per deciliter (10.4 nmol per liter), in fasting plasma samples obtained at least 48 hours apart. Participants were randomly assigned to apply a testosterone or placebo gel daily. At every visit, participants were asked if they had had a fracture since the previous visit. If they had, medical records were obtained and adjudicated. RESULTS: The full-analysis population included 5204 participants (2601 in the testosterone group and 2603 in the placebo group). After a median follow-up of 3.19 years, a clinical fracture had occurred in 91 participants (3.50%) in the testosterone group and 64 participants (2.46%) in the placebo group (hazard ratio, 1.43; 95% confidence interval, 1.04 to 1.97). The fracture incidence also appeared to be higher in the testosterone group for all other fracture end points. CONCLUSIONS: Among middle-aged and older men with hypogonadism, testosterone treatment did not result in a lower incidence of clinical fracture than placebo. The fracture incidence was numerically higher among men who received testosterone than among those who received placebo. (Funded by AbbVie and others; TRAVERSE ClinicalTrials.gov number, NCT03518034.).
Assuntos
Fraturas Ósseas , Hipogonadismo , Testosterona , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Densidade Óssea/efeitos dos fármacos , Doenças Cardiovasculares/etiologia , Método Duplo-Cego , Fraturas Ósseas/epidemiologia , Fraturas Ósseas/etiologia , Fraturas Ósseas/prevenção & controle , Hipogonadismo/sangue , Hipogonadismo/complicações , Hipogonadismo/tratamento farmacológico , Testosterona/administração & dosagem , Testosterona/efeitos adversos , Testosterona/sangue , Testosterona/farmacologia , Géis , Administração TópicaRESUMO
Postmenopausal osteoporosis arises from imbalanced osteoclast and osteoblast activity, and mounting evidence suggests a role for the osteoimmune system in bone homeostasis. Bisphosphonate (BP) is an antiresorptive agent, but its treatment failure rate can be as high as 40%. Here, we performed single-cell RNA sequencing on peripheral immune cells from carefully selected postmenopausal women: non-osteoporotic, osteoporosis improved after BP treatment, and BP-failed cases. We found an increase in myeloid cells in patients with osteoporosis (specifically, T cell receptor+ macrophages). Furthermore, lymphoid lineage cells varied significantly, notably elevated natural killer cells (NKs) in the BP-failed group. Moreover, we provide fruitful lists of biomarkers within the immune cells that exhibit condition-dependent differences. The existence of osteoporotic- and BP-failure-specific cellular information flows was revealed by cell-cell interaction analysis. These findings deepen our insight of the osteoporosis pathology enhancing comprehension of the role of immune heterogeneity in postmenopausal osteoporosis and BP treatment failure.
Assuntos
Conservadores da Densidade Óssea , Osteoporose Pós-Menopausa , Osteoporose , Humanos , Feminino , Difosfonatos/farmacologia , Difosfonatos/uso terapêutico , Osteoporose Pós-Menopausa/tratamento farmacológico , Osteoporose Pós-Menopausa/genética , Densidade Óssea , Conservadores da Densidade Óssea/farmacologia , Conservadores da Densidade Óssea/uso terapêutico , Osteoporose/tratamento farmacológico , Osteoporose/genética , Perfilação da Expressão GênicaRESUMO
The UK Biobank is a prospective study of 502,543 individuals, combining extensive phenotypic and genotypic data with streamlined access for researchers around the world1. Here we describe the release of exome-sequence data for the first 49,960 study participants, revealing approximately 4 million coding variants (of which around 98.6% have a frequency of less than 1%). The data include 198,269 autosomal predicted loss-of-function (LOF) variants, a more than 14-fold increase compared to the imputed sequence. Nearly all genes (more than 97%) had at least one carrier with a LOF variant, and most genes (more than 69%) had at least ten carriers with a LOF variant. We illustrate the power of characterizing LOF variants in this population through association analyses across 1,730 phenotypes. In addition to replicating established associations, we found novel LOF variants with large effects on disease traits, including PIEZO1 on varicose veins, COL6A1 on corneal resistance, MEPE on bone density, and IQGAP2 and GMPR on blood cell traits. We further demonstrate the value of exome sequencing by surveying the prevalence of pathogenic variants of clinical importance, and show that 2% of this population has a medically actionable variant. Furthermore, we characterize the penetrance of cancer in carriers of pathogenic BRCA1 and BRCA2 variants. Exome sequences from the first 49,960 participants highlight the promise of genome sequencing in large population-based studies and are now accessible to the scientific community.
Assuntos
Bases de Dados Genéticas , Sequenciamento do Exoma , Exoma/genética , Mutação com Perda de Função/genética , Fenótipo , Idoso , Densidade Óssea/genética , Colágeno Tipo VI/genética , Demografia , Feminino , Genes BRCA1 , Genes BRCA2 , Genótipo , Humanos , Canais Iônicos/genética , Masculino , Pessoa de Meia-Idade , Neoplasias/genética , Penetrância , Fragmentos de Peptídeos/genética , Reino Unido , Varizes/genética , Proteínas Ativadoras de ras GTPase/genéticaRESUMO
Genetic factors and estrogen deficiency contribute to the development of osteoporosis. The single-nucleotide polymorphism (SNP) rs2887571 is predicted from genome-wide association studies (GWASs) to associate with osteoporosis but has had an unknown mechanism. Analysis of osteoblasts from 110 different individuals who underwent joint replacement revealed that the genotype of rs2887571 correlates with WNT5B expression. Analysis of our ChIP-sequencing data revealed that SNP rs2887571 overlaps with an estrogen receptor alpha (ERα) binding site. Here we show that 17ß-estradiol (E2) suppresses WNT5B expression and further demonstrate the mechanism of ERα binding at the enhancer containing rs2887571 to suppress WNT5B expression differentially in each genotype. ERα interacts with NFATc1, which is predicted to bind directly at rs2887571. CRISPR-Cas9 and ChIP-qPCR experiments confirm differential regulation of WNT5B between each allele. Homozygous GG has a higher binding affinity for ERα than homozygous AA and results in greater suppression of WNT5B expression. Functionally, WNT5B represses alkaline phosphatase expression and activity, decreasing osteoblast differentiation and mineralization. Furthermore, WNT5B increases interleukin-6 expression and suppresses E2-induced expression of alkaline phosphatase during osteoblast differentiation. We show that WNT5B suppresses the differentiation of osteoblasts via receptor tyrosine kinase-like orphan receptor 1/2 (ROR1/2), which activates DVL2/3/RAC1/CDC42/JNK/SIN3A signaling and inhibits ß-catenin activity. Together, our data provide mechanistic insight into how ERα and NFATc1 regulate the non-coding SNP rs2887571, as well as the function of WNT5B on osteoblasts, which could provide alternative therapeutic targets for osteoporosis.
Assuntos
Densidade Óssea , Receptor alfa de Estrogênio/metabolismo , Fatores de Transcrição NFATC/metabolismo , Osteoblastos/metabolismo , Polimorfismo de Nucleotídeo Único , Proteínas Wnt/genética , Adipogenia , Alelos , Animais , Sítios de Ligação , Densidade Óssea/genética , Diferenciação Celular/genética , Células Cultivadas , Bases de Dados Genéticas , Receptor alfa de Estrogênio/genética , Feminino , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Estudo de Associação Genômica Ampla , Histonas/metabolismo , Humanos , Imuno-Histoquímica , Camundongos , Osteogênese/genética , Ligação Proteica , Transdução de Sinais , Proteínas Wnt/metabolismoRESUMO
MOTIVATION: Colocalization analysis is commonly used to assess whether two or more traits share the same genetic signals identified in genome-wide association studies (GWAS), and is important for prioritizing targets for functional follow-up of GWAS results. Existing colocalization methods can have suboptimal performance when there are multiple causal variants in one genomic locus. RESULTS: We propose SharePro to extend the COLOC framework for colocalization analysis. SharePro integrates linkage disequilibrium (LD) modeling and colocalization assessment by grouping correlated variants into effect groups. With an efficient variational inference algorithm, posterior colocalization probabilities can be accurately estimated. In simulation studies, SharePro demonstrated increased power with a well-controlled false positive rate at a low computational cost. Compared to existing methods, SharePro provided stronger and more consistent colocalization evidence for known lipid-lowering drug target proteins and their corresponding lipid traits. Through an additional challenging case of the colocalization analysis of the circulating abundance of R-spondin 3 GWAS and estimated bone mineral density GWAS, we demonstrated the utility of SharePro in identifying biologically plausible colocalized signals. AVAILABILITY AND IMPLEMENTATION: SharePro for colocalization analysis is written in Python and openly available at https://github.com/zhwm/SharePro_coloc.
Assuntos
Algoritmos , Estudo de Associação Genômica Ampla , Desequilíbrio de Ligação , Estudo de Associação Genômica Ampla/métodos , Humanos , Software , Polimorfismo de Nucleotídeo Único , Densidade Óssea/genéticaRESUMO
BACKGROUND: The human lineage has undergone a postcranial skeleton gracilization (i.e. lower bone mass and strength relative to body size) compared to other primates and archaic populations such as the Neanderthals. This gracilization has been traditionally explained by differences in the mechanical load that our ancestors exercised. However, there is growing evidence that gracilization could also be genetically influenced. RESULTS: We have analyzed the LRP5 gene, which is known to be associated with high bone mineral density conditions, from an evolutionary and functional point of view. Taking advantage of the published genomes of archaic Homo populations, our results suggest that this gene has a complex evolutionary history both between archaic and living humans and within living human populations. In particular, we identified the presence of different selective pressures in archaics and extant modern humans, as well as evidence of positive selection in the African and South East Asian populations from the 1000 Genomes Project. Furthermore, we observed a very limited evidence of archaic introgression in this gene (only at three haplotypes of East Asian ancestry out of the 1000 Genomes), compatible with a general erasing of the fingerprint of archaic introgression due to functional differences in archaics compared to extant modern humans. In agreement with this hypothesis, we observed private mutations in the archaic genomes that we experimentally validated as putatively increasing bone mineral density. In particular, four of five archaic missense mutations affecting the first ß-propeller of LRP5 displayed enhanced Wnt pathway activation, of which two also displayed reduced negative regulation. CONCLUSIONS: In summary, these data suggest a genetic component contributing to the understanding of skeletal differences between extant modern humans and archaic Homo populations.
Assuntos
Evolução Molecular , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Homem de Neandertal , Humanos , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Animais , Homem de Neandertal/genética , Seleção Genética/genética , Hominidae/genética , Haplótipos/genética , Densidade Óssea/genética , Genoma Humano/genéticaRESUMO
This study examines the interplay between ambient temperature, brown adipose tissue (BAT) function, and bone metabolism, emphasizing the effects of cold exposure and BAT mitochondrial activity on bone health. Utilizing ovariectomized (OVX) mice to model primary osteoporosis and BAT-specific mitochondrial dysfunction (BKO) mice, we evaluated the impact of housing temperature on bone density, immune modulation in bone marrow, and the protective role of BAT against bone loss. Cold exposure was found to universally reduce bone mass, enhance osteoclastogenesis, and alter bone marrow T-cell populations, implicating the immune system in bone remodeling under cold stress. The thermogenic function of BAT, driven by mitochondrial oxidative phosphorylation, was crucial in protecting against bone loss. Impaired BAT function, through surgical removal or mitochondrial dysfunction, exacerbated bone loss in cold environments, highlighting BAT's metabolic role in maintaining bone health. Furthermore, cold-induced changes in BAT function led to systemic metabolic shifts, including elevated long-chain fatty acids, which influenced osteoclast differentiation and activity. These findings suggest a systemic mechanism connecting environmental temperature and BAT metabolism with bone physiology, providing new insights into the metabolic and environmental determinants of bone health. Future research could lead to novel bone disease therapies targeting these pathways.
Assuntos
Tecido Adiposo Marrom , Temperatura Baixa , Mitocôndrias , Osteoporose , Animais , Tecido Adiposo Marrom/metabolismo , Feminino , Camundongos , Mitocôndrias/metabolismo , Osteoporose/metabolismo , Osteoporose/patologia , Osteoclastos/metabolismo , Camundongos Endogâmicos C57BL , Densidade Óssea , Termogênese , Ovariectomia/efeitos adversos , Osso e Ossos/metabolismo , Osso e Ossos/patologia , OsteogêneseRESUMO
BACKGROUND: The relationship between accelerated epigenetic aging and musculoskeletal outcomes in women with HIV (WWH) has not been studied. METHODS: We measured DNA methylation age using the Infinium MethylationEPIC BeadChip in a cohort from the Women's Interagency HIV Study (n = 190) with measures of bone mineral density (BMD) and physical function. We estimated 6 biomarkers of epigenetic aging-epigenetic age acceleration (EAA), extrinsic EAA, intrinsic EAA, GrimAge, PhenoAge, and DNA methylation-estimated telomere length-and evaluated associations of epigenetic aging measures with BMD and physical function. We also performed epigenome-wide association studies to examine associations of DNA methylation signatures with BMD and physical function. RESULTS: This study included 118 WWH (mean age, 49.7 years; 69% Black) and 72 without HIV (mean age, 48.9 years; 69% Black). WWH had higher EAA (mean ± SD, 1.44 ± 5.36 vs -1.88 ± 5.07; P < .001) and lower DNA methylation-estimated telomere length (7.13 ± 0.31 vs 7.34 ± 0.23, P < .001) than women without HIV. There were no significant associations between accelerated epigenetic aging and BMD. Rather, measures of accelerated epigenetic aging were associated with lower physical function. CONCLUSIONS: Accelerated epigenetic aging was observed in WWH as compared with women without HIV and was associated with lower physical function in both groups.
Assuntos
Envelhecimento , Densidade Óssea , Metilação de DNA , Epigênese Genética , Infecções por HIV , Humanos , Feminino , Pessoa de Meia-Idade , Infecções por HIV/genética , Envelhecimento/genética , Densidade Óssea/genética , Adulto , Estudos de CoortesRESUMO
Epimedium is thought to enhance the integrity of tendons and bones, ease joint discomfort and rigidity and enhance kidney function. Although glucocorticoids are commonly used in clinical practice, the mechanism by which the active compound Epimedin C (EC) alleviates glucocorticoid-induced osteoporosis (GIOP) is not well understood. The therapeutic potential of EC in treating GIOP was evaluated using alizarin red S staining, calcein immersion and fluorescence imaging, and bone mineralization, bone mass accumulation and bone density in zebrafish larvae were determined. Using the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, the key signalling pathways related to bone development were identified. A protein-protein interaction network (PPIN) was constructed to identify osteoclast characteristic genes and the findings were verified using real-time quantitative PCR (RT-qPCR). The bone tissue damage caused by prednisolone was reduced by EC. It also altered physiological processes, improved bone density, boosted mineralization and increased bone mass and activity. Subsequent empirical investigations showed that EC impacted the major signalling pathways involved in bone development, such as osteoclast differentiation, oestrogen, MAPK, insulin resistance, PPAR and AMPK signalling pathways. It also decreased the expression of genes typical of osteoclasts. The results of our study uncover a previously unknown function of EC in controlling bone formation and emphasize the potential of EC as a therapeutic target. The osteoprotective effect of EC indicates its potential as a cost-effective strategy for treating GIOP.
Assuntos
Modelos Animais de Doenças , Flavonoides , Glucocorticoides , Osteoclastos , Osteoporose , Transdução de Sinais , Peixe-Zebra , Animais , Osteoporose/induzido quimicamente , Osteoporose/metabolismo , Osteoporose/genética , Osteoporose/patologia , Osteoporose/tratamento farmacológico , Flavonoides/farmacologia , Glucocorticoides/efeitos adversos , Glucocorticoides/farmacologia , Osteoclastos/metabolismo , Osteoclastos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Mapas de Interação de Proteínas , Osteogênese/efeitos dos fármacos , Osteogênese/genética , Calcificação Fisiológica/efeitos dos fármacosRESUMO
Despite numerous investigations on the influence of fibroblast growth factor 23 (FGF23), α-Klotho and FGF receptor-1 (FGFR1) on osteoporosis (OP), there is no clear consensus. Mendelian randomization (MR) analysis was conducted on genome-wide association studies (GWASs)-based datasets to evaluate the causal relationship between FGF23, α-Klotho, FGFR1 and OP. The primary endpoint was the odds ratio (OR) of the inverse-variance weighted (IVW) approach. Furthermore, we stably transfected FGF23-mimic or siRNA-FGF23 into human bone marrow mesenchymal stem cells (hBMSCs) in culture and determined its cell proliferation and the effects on osteogenic differentiation. Using MR analysis, we demonstrated a strong correlation between serum FGF23 levels and Heel- and femoral neck-BMDs, with subsequent ORs of 0.919 (95% CI: 0.860-0.983, p = 0.014) and 0.751 (95% CI: 0.587-0.962; p = 0.023), respectively. The expression levels of FGF23 were significantly increased in femoral neck of patients with OP than in the control cohort (p < 0.0001). Based on our in vitro investigation, after overexpression of FGF23, compared to the control group, the BMSC's proliferation ability decreased, the expression level of key osteogenic differentiation genes (RUNX2, OCN and OSX) significantly reduced, mineralized nodules and ALP activity significantly decreased. After silencing FGF23, it showed a completely opposite trend. Augmented FGF23 levels are causally associated with increased risk of OP. Similarly, FGF23 overexpression strongly inhibits the osteogenic differentiation of hBMSCs, thereby potentially aggravating the pathological process of OP.
Assuntos
Diferenciação Celular , Proliferação de Células , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Células-Tronco Mesenquimais , Osteogênese , Osteoporose , Humanos , Fator de Crescimento de Fibroblastos 23/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Fatores de Crescimento de Fibroblastos/genética , Osteoporose/genética , Osteoporose/metabolismo , Osteoporose/patologia , Células-Tronco Mesenquimais/metabolismo , Osteogênese/genética , Proliferação de Células/genética , Diferenciação Celular/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Proteínas Klotho/metabolismo , Feminino , Glucuronidase/genética , Glucuronidase/metabolismo , Densidade Óssea/genética , Masculino , Pessoa de Meia-Idade , Colo do Fêmur/metabolismo , Colo do Fêmur/patologiaRESUMO
Alleviating bone loss is an essential way to prevent osteoporotic fractures. Proper exercise improves bone density without the side effects of long-term medications, but the mechanism is unclear. Our study explored the role of Antxr1/LncRNA H19/Wnt/ß-catenin axis in the process of exercise-mediated alleviation of bone loss. Here we discovered that moderate-intensity treadmill exercise alleviates bone loss caused by ovariectomy and ameliorates bone strength accompanied by an increased lncRNA H19 expression. Concomitantly, Antxr1, a mechanosensitive protein was found downregulated by exercise but upregulated by ovariectomy. Interestingly, knockdown expression of Antxr1 increased lncRNA H19 expression and Wnt/ß-catenin signaling pathway in bone marrow mesenchymal stem cells, whereas overexpression of Antxr1 decreased lncRNA H19 expression and Wnt/ß-catenin signaling pathway. Hence, our study demonstrates the regulation of Antxr1/LncRNA H19/Wnt/ß-catenin axis in the process of mechanical strain-induced osteogenic differentiation, which provides further mechanistic insight into the role of mechanical regulation in bone metabolism.
Assuntos
Proteínas dos Microfilamentos , Osteogênese , RNA Longo não Codificante , Receptores de Superfície Celular , Estresse Mecânico , Via de Sinalização Wnt , beta Catenina , Animais , Feminino , Camundongos , beta Catenina/metabolismo , beta Catenina/genética , Densidade Óssea/genética , Diferenciação Celular , Células-Tronco Mesenquimais/metabolismo , Osteogênese/genética , Osteoporose/genética , Osteoporose/metabolismo , Osteoporose/patologia , Ovariectomia/efeitos adversos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Via de Sinalização Wnt/genética , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos/metabolismo , Receptores de Superfície Celular/metabolismoRESUMO
At present, there have only been a few DNA sequencing-based studies to explore the genetic determinants of bone mineral density (BMD). We carried out the largest whole genome sequencing analysis to date for femoral neck and spine BMD (n = 4981), with one of the highest average sequencing depths implemented thus far at 22×, in a multiethnic sample (58% Caucasian and 42% African American) from the Louisiana Osteoporosis Study (LOS). The LOS samples were combined with summary statistics from the GEFOS consortium and several independent samples of various ethnicities to perform GWAS meta-analysis (n = 44 506). We identified 31 and 30 genomic risk loci for femoral neck and spine BMD, respectively. The findings substantiate many previously reported susceptibility loci (e.g. WNT16 and ESR1) and reveal several others that are either novel or have not been widely replicated in GWAS for BMD, including two for femoral neck (IGF2 and ZNF423) and one for spine (SIPA1). Although we were not able to uncover ethnicity specific differences in the genetic determinants of BMD, we did identify several loci which demonstrated sex-specific associations, including two for women (PDE4D and PIGN) and three for men (TRAF3IP2, NFIB and LYSMD4). Gene-based rare variant association testing detected MAML2, a regulator of the Notch signaling pathway, which has not previously been suggested, for association with spine BMD. The findings provide novel insights into the pathophysiological mechanisms of osteoporosis.
Assuntos
Densidade Óssea , Estudo de Associação Genômica Ampla , Densidade Óssea/genética , Feminino , Colo do Fêmur/fisiologia , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Sequenciamento Completo do GenomaRESUMO
BACKGROUND: Androgen deprivation therapy (ADT) inhibits prostate cancer growth. However, ADT causes loss of bone mineral density (BMD) and an increase in fracture risk; effective interventions for ADT-induced bone loss are limited. METHODS: A phase 2 randomized controlled trial investigated the feasibility, safety, and preliminary efficacy of high-dose weekly vitamin D (HDVD, 50,000 IU/week) versus placebo for 24 weeks in patients with prostate cancer receiving ADT, with all subjects receiving 600 IU/day vitamin D and 1000 mg/day calcium. Participants were ≥60 years (mean years, 67.7), had a serum 25-hydroxyvitamin D level <32 ng/mL, and initiated ADT within the previous 6 months. At baseline and after intervention, dual-energy x-ray absorptiometry was used to assess BMD, and levels of bone cell, bone formation, and resorption were measured. RESULTS: The HDVD group (N = 29) lost 1.5% BMD at the total hip vs. 4.1% for the low-dose group (N = 30; p = .03) and 1.7% BMD at the femoral neck vs. 4.4% in the low-dose group (p = .06). Stratified analyses showed that, for those with baseline 25-hydroxyvitamin D level <27 ng/mL, the HDVD group lost 2.3% BMD at the total hip vs 7.1% for the low-dose group (p < .01). Those in the HDVD arm showed significant changes in parathyroid hormone (p < .01), osteoprotegerin (p < 0.01), N-terminal telopeptide of type 1 collagen (p < 0.01) and C-terminal telopeptide of type 1 collagen (p < 0.01). No difference in adverse events or toxicity was noted between the groups. CONCLUSIONS: HDVD supplementation significantly reduced hip and femoral neck BMD loss, especially for patients with low baseline serum 25-hydroxyvitamin D levels, although demonstrating safety and feasibility in prostate cancer patients on ADT.
Assuntos
Antagonistas de Androgênios , Densidade Óssea , Neoplasias da Próstata , Vitamina D , Humanos , Masculino , Neoplasias da Próstata/tratamento farmacológico , Vitamina D/sangue , Vitamina D/análogos & derivados , Vitamina D/administração & dosagem , Idoso , Antagonistas de Androgênios/efeitos adversos , Antagonistas de Androgênios/administração & dosagem , Antagonistas de Androgênios/uso terapêutico , Densidade Óssea/efeitos dos fármacos , Pessoa de Meia-Idade , Osteoporose/induzido quimicamente , Osteoporose/prevenção & controleRESUMO
BACKGROUND: The current treatment of osteogenesis imperfecta (OI) is imperfect. Our study thus delves into the potential of using Dickkopf-1 antisense (DKK1-AS) to treat OI. METHODS: We analysed serum DKK1 levels and their correlation with lumbar spine and hip T-scores in OI patients. Comparative analyses were conducted involving bone marrow stromal cells (BMSCs) and bone tissues from wild-type mice, untreated OI mice, and OI mice treated with DKK1-ASor DKK1-sense (DKK1-S). RESULTS: Significant inverse correlations were noted between serum DKK1 levels and lumbar spine (correlation coefficient = - 0.679, p = 0.043) as well as hip T-scores (correlation coefficient = - 0.689, p = 0.042) in OI patients. DKK1-AS improved bone mineral density (p = 0.002), trabecular bone volume/total volume fraction (p < 0.001), trabecular separation (p = 0.010), trabecular thickness (p = 0.001), trabecular number (p < 0.001), and cortical thickness (p < 0.001) in OI mice. DKK1-AS enhanced the transcription of collagen 1α1, osteocalcin, runx2, and osterix in BMSC from OI mice (all p < 0.001), resulting in a higher von Kossa-stained matrix area (p < 0.001) in ex vivo osteogenesis assays. DKK1-AS also reduced osteoclast numbers (p < 0.001), increased ß-catenin and T-cell factor 4 immunostaining reactivity (both p < 0.001), enhanced mineral apposition rate and bone formation rate per bone surface (both p < 0.001), and decreased osteoclast area (p < 0.001) in OI mice. DKK1-AS upregulated osteoprotegerin and downregulated nuclear factor-kappa B ligand transcription (both p < 0.001). Bone tissues from OI mice treated with DKK1-AS exhibited significantly higher breaking force compared to untreated OI mice (p < 0.001). CONCLUSIONS: Our study elucidates that DKK1-AS has the capability to enhance bone mechanical properties, restore the transcription of osteogenic genes, promote osteogenesis, and inhibit osteoclastogenesis in OI mice.
Assuntos
Modelos Animais de Doenças , Peptídeos e Proteínas de Sinalização Intercelular , Osteogênese Imperfeita , Animais , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Osteogênese Imperfeita/metabolismo , Camundongos , Humanos , Feminino , Masculino , Densidade Óssea , Osteogênese , Células-Tronco Mesenquimais/metabolismoRESUMO
Standard CHOP treatment includes a high cumulative dose of prednisone, and studies have shown increased fracture risk following CHOP. It is unclear whether reductions in bone mineral density (BMD) are caused by glucocorticoids or by the combination with chemotherapy. Our objective was to determine the effect of obinutuzumab (G)/rituximab (R)-bendamustine versus G/R-CHOP on BMD in follicular lymphoma patients. Patients in this GALLIUM post hoc study were ≥60 years old and in complete remission at induction treatment completion (ITC), following treatment with G or R in combination with bendamustine or CHOP. To assess BMD, Hounsfield units (HU) were measured in lumbar vertebra L1 on annual computed tomography. Furthermore, vertebral compression fractures were recorded. Of 173 patients included, 59 (34%) received CHOP and 114 (66%) received bendamustine. At baseline, there was no difference in HU between groups. The mean HU decrease from baseline to ITC was 27.8 after CHOP and 17.3 after bendamustine, corresponding to a difference of 10.4 (95% CI: 3.2-17.6). Vertebral fractures were recorded in 5/59 patients receiving CHOP and in 2/114 receiving bendamustine. CHOP was associated with a significant greater decrease in BMD and more frequent fractures. These results suggest that prophylaxis against BMD loss should be considered.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Cloridrato de Bendamustina , Densidade Óssea , Linfoma Folicular , Fraturas da Coluna Vertebral , Humanos , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cloridrato de Bendamustina/efeitos adversos , Fraturas por Compressão/tratamento farmacológico , Linfoma Folicular/tratamento farmacológico , Prednisona/efeitos adversos , Rituximab/efeitos adversos , Fraturas da Coluna Vertebral/tratamento farmacológico , Vincristina/efeitos adversosRESUMO
The mouse femur, particularly the distal femur, is commonly utilized in orthopedic research. Despite its significance, little is known about the key events involved in the postnatal development of the distal femur. Therefore, investigating the development process of the mouse distal femur is of great importance. In this study, distal femurs of CD-1 mice aged 1, 2, 4, 6, and 8 weeks were examined. We found that the width and height of the distal femur continued to increase till the 4th week, followed with stabilization. Notably, the width to height ratio remained relatively consistent with age. Micro computed tomography analysis demonstrated gradual increases in bone volume/tissue volume, trabecular number, and trabecular thickness from 1 to 6 weeks, alongside a gradual decrease in trabecular separation. Histological analysis further indicated the appearance of the secondary ossification center at approximately 2 weeks, with ossification mostly completed by 4 weeks, leading to the formation of a prototype epiphyseal plate. Subsequently, the epiphyseal plate gradually narrowed at 6 and 8 weeks. Moreover, the thickness and maturity of the bone cortex surrounding the epiphyseal plate increased over time, reaching peak cortical bone density at 8 weeks. In conclusion, to enhance model stability and operational ease, we recommend constructing conventional mouse models of the distal femur between 4 and 8 weeks old.
Assuntos
Fêmur , Animais , Fêmur/metabolismo , Fêmur/diagnóstico por imagem , Fêmur/crescimento & desenvolvimento , Camundongos , Microtomografia por Raio-X , Lâmina de Crescimento/metabolismo , Lâmina de Crescimento/crescimento & desenvolvimento , Lâmina de Crescimento/diagnóstico por imagem , Densidade Óssea , Desenvolvimento Ósseo , Osteogênese , MasculinoRESUMO
OBJECTIVE: To investigate the effect of intermittent parathyroid hormone (iPTH) administration on pathological new bone formation during treatment of ankylosing spondylitis-related osteoporosis. METHODS: Animal models with pathological bone formation caused by hypothetical AS pathogenesis received treatment with iPTH. We determined the effects of iPTH on bone loss and the formation of pathological new bone with micro-computed tomography (micro-CT) and histological examination. In addition, the tamoxifen-inducible conditional knockout mice (CAGGCre-ERTM; PTHflox/flox, PTH-/-) was established to delete PTH and investigate the effect of endogenous PTH on pathological new bone formation. RESULTS: iPTH treatment significantly improved trabecular bone mass in the modified collagen-induced arthritis (m-CIA) model and unbalanced mechanical loading models. Meanwhile, iPTH treatment did not enhance pathological new bone formation in all types of animal models. Endogenous PTH deficiency had no effects on pathological new bone formation in unbalanced mechanical loading models. CONCLUSION: Experimental animal models of AS treated with iPTH show improvement in trabecular bone density, but not entheseal pathological bone formationï¼indicating it may be a potential treatment for inflammatory bone loss does in AS.
Assuntos
Osteogênese , Hormônio Paratireóideo , Animais , Hormônio Paratireóideo/administração & dosagem , Hormônio Paratireóideo/farmacologia , Hormônio Paratireóideo/uso terapêutico , Osteogênese/efeitos dos fármacos , Camundongos , Osteoporose/tratamento farmacológico , Osteoporose/patologia , Camundongos Knockout , Masculino , Microtomografia por Raio-X , Espondilite Anquilosante/tratamento farmacológico , Espondilite Anquilosante/patologia , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Densidade Óssea/efeitos dos fármacosRESUMO
INTRODUCTION: Osteoporosis in candidates for liver transplantation (LT) is often underdiagnosed despite the important consequences of morbidity. METHODS: We included 376 patients with cirrhosis evaluated for LT with available computed tomography (CT) scans. Prevalent vertebral fractures (VFs) were identified on CT reconstructions, and bone density was assessed by measuring CT attenuation of the L1 vertebra (L1-CT). RESULTS: We identified 139 VFs in 55 patients (14.6%). Logistic regression models showed that low L1-CT was the only independent determinant of VF. DISCUSSION: In patients with cirrhosis evaluated for LT, CT scans identified persons with severe osteoporosis without additional costs.