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1.
Cell Metab ; 2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38569557

RESUMO

Activating Nrf2 by small molecules is a promising strategy to treat postmenopausal osteoporosis. However, there is currently no Nrf2 activator approved for treating chronic diseases, and the downstream mechanism underlying the regulation of Nrf2 on osteoclast differentiation remains unclear. Here, we found that bitopertin, a clinical-stage glycine uptake inhibitor, suppresses osteoclast differentiation and ameliorates ovariectomy-induced bone loss by activating Nrf2. Mechanistically, bitopertin interacts with the Keap1 Kelch domain and decreases Keap1-Nrf2 binding, leading to reduced Nrf2 ubiquitination and degradation. Bitopertin is associated with less adverse events than clinically approved Nrf2 activators in both mice and human subjects. Furthermore, Nrf2 transcriptionally activates ferroportin-coding gene Slc40a1 to reduce intracellular iron levels in osteoclasts. Loss of Nrf2 or iron supplementation upregulates ornithine-metabolizing enzyme Odc1, which decreases ornithine levels and thereby promotes osteoclast differentiation. Collectively, our findings identify a novel clinical-stage Nrf2 activator and propose a novel Nrf2-iron-ornithine metabolic axis in osteoclasts.

2.
Pharmacol Res ; 202: 107121, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38431091

RESUMO

Bone homeostasis is maintained by osteoclast-mediated bone resorption and osteoblast-mediated bone formation. A dramatic decrease in estrogen levels in postmenopausal women leads to osteoclast overactivation, impaired bone homeostasis, and subsequent bone loss. Changes in the gut microbiome affect bone mineral density. However, the role of the gut microbiome in estrogen deficiency-induced bone loss and its underlying mechanism remain unknown. In this study, we found that the abundance of Clostridium sporogenes (C. spor.) and its derived metabolite, indole propionic acid (IPA), were decreased in ovariectomized (OVX) mice. In vitro assays suggested that IPA suppressed osteoclast differentiation and function. At the molecular level, IPA suppressed receptor activator of nuclear factor kappa-Β ligand (RANKL)-induced pregnane X receptor (PXR) ubiquitination and degradation, leading to increased binding of remaining PXR with P65. In vivo daily IPA administration or repeated C. spor. colonization protected against OVX-induced bone loss. To protect live bacteria from the harsh gastric environment and delay the emptying of orally administered C. spor. from the intestine, a C. spor.-encapsulated silk fibroin (SF) hydrogel system was developed, which achieved bone protection in OVX mice comparable to that achieved with repeated germ transplantation or daily IPA administration. Overall, we found that gut C. spor.-derived IPA was involved in estrogen deficiency-induced osteoclast overactivation by regulating the PXR/P65 complex. The C. spor.-encapsulated SF hydrogel system is a promising tool for combating postmenopausal osteoporosis without the disadvantages of repeated germ transplantation.


Assuntos
Reabsorção Óssea , Clostridium , Osteoclastos , Propionatos , Humanos , Feminino , Camundongos , Animais , Osteoclastos/metabolismo , Receptor de Pregnano X/metabolismo , Reabsorção Óssea/metabolismo , Osteogênese , Estrogênios/metabolismo , Indóis/metabolismo , Hidrogéis , Ligante RANK/metabolismo , Diferenciação Celular
3.
Cell Death Dis ; 15(2): 111, 2024 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-38316760

RESUMO

Osteoclasts consume an amount of adenosine triphosphate (ATP) to perform their bone resorption function in the development of osteoporosis. However, the mechanism underlying osteoclast energy metabolism has not been fully elucidated. In addition to glucose, glutamine (Glu) is another major energy carrier to produce ATP. However, the role of Glu metabolism in osteoclasts and the related molecular mechanisms has been poorly elucidated. Here we show that Glu is required for osteoclast differentiation and function, and that Glu deprivation or pharmacological inhibition of Glu transporter ASCT2 by V9302 suppresses osteoclast differentiation and their bone resorptive function. In vivo treatment with V9302 improved OVX-induced bone loss. Mechanistically, RNA-seq combined with in vitro and in vivo experiments suggested that Glu mediates the role of IL-17 in promoting osteoclast differentiation and in regulating energy metabolism. In vivo IL-17 treatment exacerbated OVX-induced bone loss, and this effect requires the participation of Glu or its downstream metabolite α-KG. Taken together, this study revealed a previously unappreciated regulation of IL-17 on energy metabolism, and this regulation is Glu-dependent. Targeting the IL-17-Glu-energy metabolism axis may be a potential therapeutic strategy for the treatment of osteoporosis and other IL-17 related diseases.


Assuntos
Reabsorção Óssea , Glutamina , Interleucina-17 , Osteoclastos , Osteoporose , Humanos , Trifosfato de Adenosina/metabolismo , Reabsorção Óssea/metabolismo , Diferenciação Celular , Metabolismo Energético , Glutamina/metabolismo , Interleucina-17/genética , Interleucina-17/metabolismo , Osteoclastos/metabolismo , Osteogênese , Osteoporose/metabolismo , Ligante RANK/metabolismo
4.
Am J Rhinol Allergy ; 38(2): 82-91, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38225197

RESUMO

BACKGROUND: Previous studies have shown that respiratory diseases are associated with an increased risk of rheumatoid arthritis (RA). However, whether there is a correlation between chronic rhinosinusitis (CRS) and RA is not known. Due to the high incidence of CRS, it remains to be clarified whether we should pay additional attention to RA risk in the huge population of CRS. METHODS: We used a 2-sample Mendelian randomization (MR) analysis to explore the causal effects of CRS on the incidence of RA. The inverse variance weighted (IVW) approach was used as the main analysis in the MR randomization study. Then, we used the data from the U.K. Biobank to examine the association between RA and CRS at the individual level in a prospective cohort. We identified patients with CRS at the time of recruitment and further followed the incidence of RA until 2021. The risk of developing RA in patients with CRS was determined by a multivariate Cox regression model. We used 3 multivariate Cox models to adjust for individual characteristics, lifestyle factors and concomitant diseases, respectively. RESULTS: The MR analysis by the IVW model suggested that the odds ratio of RA associated with genetically predicted CRS was 2.39 (95% CI [1.08-5.30]; p = .032). In the first multivariate model adjusting for individual characteristics, CRS was associated with a 47% increase of risk of developing RA (hazard ratio [HR] = 1.47; 95% CI [1.12-1.90]). In the second multivariate model adjusting for lifestyle factors, the HR of RA associated with CRS was 1.48 (95% CI [1.15-1.90]). In the third multivariate model, chronic sinusitis was associated with a 32% increase in RA risk (HR = 1.32; 95% CI [1.03-1.70]). CONCLUSION: CRS has a genetically causal effect on the incidence of RA, and the risk of RA is greatly higher in CRS at the individual level. This is the first study to reveal an association between CRS and RA. Due to the high incidence of CRS, it is recommended that additional attention should be paid to the increased RA risk in patients with CRS compared to that in common people.


Assuntos
Artrite Reumatoide , Rinossinusite , Sinusite , Humanos , Bancos de Espécimes Biológicos , Análise da Randomização Mendeliana , Doença Crônica , Polimorfismo de Nucleotídeo Único
5.
Osteoporos Int ; 35(4): 659-668, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38141141

RESUMO

Both COA and AOA have a genetically causal effect on osteoporosis. COA and AOA were independently associated with incident osteoporosis, and the risk was greatly higher in AOA. Besides corticosteroids, the increased risk of osteoporosis among asthma patients should be attributed to genetic susceptibility and other asthma medications. PURPOSE/INTRODUCTION: Childhood-onset asthma (COA) differs with adult-onset asthma (AOA) on genetic susceptibility, severity, and co-morbidities. Whether COA or AOA is independently associated with osteoporosis is unexplored. We aimed to determine the effects of COA and AOA on osteoporosis at genetic and individual level. METHODS: We used two-sample Mendelian randomization analysis to explore the causal effects of COA and AOA on osteoporosis. In the UK Biobank cohort, we included 478,289 osteoporosis-free participants at baseline (2006-2010). Participants were classified as non-asthma, COA, and AOA at recruitment. Multivariate Cox regression analysis was used to evaluate the effects of COA, AOA, and multiple asthma medications on incident osteoporosis risk. RESULTS: COA and AOA were causally related to osteoporosis, with odds ratio of 1.007 (95% confidence interval (CI), 1.0003-1.0132) and 1.012 (95% CI, 1.002-1.023), respectively. Multivariate Cox regression analysis suggested that COA (hazard ratio (HR), 1.46; 95% CI, 1.32-1.61) and AOA (HR, 1.70; 95% CI, 1.61-1.80) were independently associated with incident osteoporosis, and the risk was greatly higher in AOA (HR, 1.51; 95% CI, 1.34-1.70). In addition to corticosteroids, monotherapy with leukotriene modifiers (HR, 1.70; 95% CI, 1.20-2.42), long-acting beta agonists (HR, 1.49; 95% CI, 1.18-1.87), and short-acting beta agonists (HR, 1.72; 95% CI1.01-2.93) were independently associated with a higher risk of osteoporosis. CONCLUSIONS: Both COA and AOA have a genetically causal effect on osteoporosis, and the risk of osteoporosis is greatly higher in AOA. Besides corticosteroids, the increased risk of osteoporosis among asthma patients should be attributed to genetic susceptibility and other asthma medications.


Assuntos
Asma , Osteoporose , Adulto , Criança , Humanos , Corticosteroides/efeitos adversos , Asma/complicações , Asma/tratamento farmacológico , Asma/genética , Predisposição Genética para Doença , Osteoporose/etiologia , Osteoporose/genética , Estudos Prospectivos , Análise da Randomização Mendeliana
6.
Mater Today Bio ; 23: 100816, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37859997

RESUMO

The refined functional cell subtypes in the immune microenvironment of specific titanium (Ti) surface and their collaborative role in promoting bone marrow mesenchymal stem cells (BMSCs) driven bone integration need to be comprehensively characterized. This study employed a simplified co-culture system to investigate the dynamic, temporal crosstalk between macrophages and BMSCs on the Ti surface. The M2-like sub-phenotype of macrophages, characterized by secretion of CXCL chemokines, emerges as a crucial mediator for promoting BMSC osteogenic differentiation and bone integration in the Ti surface microenvironment. Importantly, these two cells maintain their distinct functional phenotypes through a mutually regulatory interplay. The secretion of CXCL3, CXCL6, and CXCL14 by M2-like macrophages plays a pivotal role. The process activates CXCR2 and CCR1 receptors, triggering downstream regulatory effects on the actin cytoskeleton pathway within BMSCs, ultimately fostering osteogenic differentiation. Reciprocally, BMSCs secrete pleiotrophin (PTN), a key player in regulating macrophage differentiation. This secretion maintains the M2-like phenotype via the Sdc3 receptor-mediated cell adhesion molecules pathway. Our findings provide a novel insight into the intricate communication and mutual regulatory mechanisms operating between BMSCs and macrophages on the Ti surface, highlight specific molecular events governing cell-cell interactions in the osteointegration, inform the surface design of orthopedic implants, and advance our understanding of osteointegration.

8.
Med ; 4(11): 778-796.e3, 2023 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-37683637

RESUMO

BACKGROUND: Unbalanced fatty acids intake is associated with a range of health outcomes; however, the impact on human health remains unclear globally. We aim to provide a comprehensive assessment of the health effect of unbalanced fatty acids intake on a global scale. METHODS: We analyzed the trends of summary exposure value (SEV) and the attributable burden of unbalanced fatty acids intake, including diet low in polyunsaturated fatty acids (low PUFAs), diet low in seafood omega-3 fatty acids (low seafood-(ω-3)-PUFAs), and diet high in trans fatty acids (high TFAs) from 1990 to 2019 using data from Global Burden of Disease Study 2019. FINDINGS: The global fatty acids intake was far from the optimal level. High-income North America had the highest SEV of diet of high TFAs, while less-developed regions located in Saharan Africa had the highest SEVs of low PUFAs and low seafood-(ω-3)-PUFAs. The attributable burden was unequally distributed to less-developed regions. Males had lower SEVs but higher attributable burden than females and this gender gap was particularly pronounced before the age of 59. The young population had a higher SEV of diet of low PUFAs, comparable SEV of low seafood-(ω-3)-PUFAs but lower SEV of high TFAs than the elderly population. CONCLUSIONS: This study underpinned the high prevalence of unbalanced fatty acids intake worldwide and provided evidence-based guidance for identifying at-risk populations and developing effective strategies to improve fatty acids intake in the future. FUNDING: The study was funded by Shanxi Province "136" Revitalization Medical Project Construction Funds and the Fundamental Research Funds for the Central Universities.


Assuntos
Ácidos Graxos Ômega-3 , Ácidos Graxos , Masculino , Feminino , Humanos , Idoso , Dieta , Ácidos Graxos Insaturados , Fatores de Risco
9.
ACS Appl Mater Interfaces ; 15(38): 44689-44710, 2023 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-37699536

RESUMO

Ferroptosis is characterized by iron accumulation and lipid peroxidation. However, a clinical dose of Fe3O4 nanoparticles could not cause effective ferroptosis in tumors, and the mechanism is yet to be completely understood. In this study, using RNA-seq data, we found that tumor cells could feedback-activate the antioxidant system by upregulating Nrf-2 expression, thus avoiding ferroptosis caused by Fe3O4 nanoparticles. We also found that DHJS (a probe for ROS generation) can antagonize Nrf-2 expression when it synergizes with Fe3O4 nanoparticles, thus inducing ferroptosis in tumor cells. Considering these findings, we created a biomimetic hybrid cell membrane camouflaged by PLGA-loaded Fe3O4 and DHJS to treat osteosarcoma. The hybrid cell membrane endowed the core nanoparticle with the extension of blood circulation life and enhanced homologous targeting ability. In addition, DHJS and Fe3O4 in nanoparticles prompted synergistically lethal ferroptosis in cancer cells and induced macrophage M1 polarization as well as the infiltration of CD8(+) T cells and dendritic cells in tumors. In summary, this study provides novel mechanistic insights and practical strategies for ferroptosis induction of Fe3O4 nanoparticles. Meanwhile, the synthesized biomimetic nanoparticles exhibited synergistic ferroptosis/immunotherapy against osteosarcoma.


Assuntos
Neoplasias Ósseas , Ferroptose , Osteossarcoma , Humanos , Membrana Eritrocítica , Linfócitos T CD8-Positivos , Osteossarcoma/tratamento farmacológico , Imunoterapia
10.
BMC Public Health ; 23(1): 991, 2023 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-37248448

RESUMO

Talking about osteoporosis, we tend to focus on post-menopause women who are at increased risk due to estrogen depletion, while less attention has been paid to the disease in men. Currently, there is a lack of understanding about the difference of osteoporosis incidence and burden by sex. In this study, we used data from the Global Burden of Disease Study 2019 (GBD 2019) to compare the difference in the prevalence and burden of low bone mineral density (LBMD) between men and women, by location, year, age and socio-demographic index. We found the prevalence of LBMD was higher in women than in men. However, the age standardized mortality rate was greatly higher in men than in women. Using disability-adjusted life year (DALY) to measure the burden, we also observed higher age standardized DALY rate in men. Using sociodemographic index (SDI) as the measure of social development level, we found that higher mortality and DALY rates were mainly seen in middle and high SDI countries. Falls were the leading cause for of deaths and disabilities in both men and women with LBMD, followed by transport injuries. Fall-related mortality was higher in women, while transport injuries caused more deaths and disabilities in men. Conclusively, more attention should be paid to osteoporosis in men, and related policies, clinical practices, and guidelines are in need to reduce the burden of LBMD and osteoporosis in men.


Assuntos
Pessoas com Deficiência , Osteoporose , Masculino , Humanos , Feminino , Anos de Vida Ajustados por Qualidade de Vida , Carga Global da Doença , Prevalência , Osteoporose/epidemiologia , Incidência , Saúde Global
11.
Antimicrob Agents Chemother ; 67(6): e0009823, 2023 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-37140388

RESUMO

Spinal cystic echinococcosis, a severely neglected, rare disease, is characterized by high morbidity, disability, and mortality in prevalent regions. Due to the high-risk nature of surgical treatment and the ineffectiveness of conventional drugs, there is an unmet need for novel safe and effective drugs for the treatment of this disease. In this study, we examined the therapeutic effects of α-mangostin for spinal cystic echinococcosis, and explored its potential pharmacological mechanism. The repurposed drug exhibited a potent in vitro protoscolicidal effect and significantly inhibited the evolution of larval encystation. Moreover, it demonstrated a remarkable anti-spinal cystic echinococcosis effect in gerbil models. Mechanistically, we found that α-mangostin intervention led to intracellular depolarization of mitochondrial membrane potential and reactive oxygen species generation. In addition, we observed elevated expression of autophagic proteins, aggregation of autophagic lysosomes, activated autophagic flux, and disrupted larval microstructure in protoscoleces. Further metabolite profiling showed that glutamine was imperative for autophagic activation and anti-echinococcal effects mediated by α-mangostin. These results suggest that α-mangostin is a potentially valuable therapeutic option against spinal cystic echinococcosis through its effect on glutamine metabolism.


Assuntos
Equinococose , Xantonas , Humanos , Glutamina/uso terapêutico , Equinococose/tratamento farmacológico , Xantonas/farmacologia , Proteínas
13.
Clin J Am Soc Nephrol ; 18(1): 60-71, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36719159

RESUMO

BACKGROUND: CKD is becoming a major human health concern. Limited quantitative assessments of the burden of CKD due to glomerulonephritis have been performed. We performed a comprehensive analysis of the disease burden to update the epidemiology of this disease. METHODS: Incidence, prevalence, deaths, and disability-adjusted life-years (DALYs) data and percent changes in these indicators were extracted from Global Burden of Disease Study 2019 to analyze the burden of CKD due to glomerulonephritis. RESULTS: Globally, there were 606,300 (95% uncertainty interval [UI], 560,100 to 658,100) incident patients, 17,300,000 (95% UI, 16,100,000 to 18,600,000) prevalent patients, 183,700 (95% UI, 146,300 to 228,900) deaths, and 6,900,000 (95% UI, 5,900,000 to 8,100,000) DALYs of CKD due to glomerulonephritis in 2019. Compared with those in 1990, the numbers of incident patients, prevalent patients, deaths, and DALYs increased by 77%, 81%, 100%, and 66%, respectively. Most of the disease burden was concentrated in countries with lower sociodemographic index. In Central Latin America, the disease burden was much higher than expected on the basis of its sociodemographic index. Decomposition analysis showed that population aging and growth were the two major drivers of the increase in DALYs. Frontier analysis revealed considerable opportunities to reduce the age-standardized DALYs in the middle of the sociodemographic-index spectrum. Although middle-aged and elderly individuals accounted for the majority of the disease burden, the highest incidence rate was observed in children aged 1-4 years. CONCLUSIONS: The disease burden of CKD due to glomerulonephritis has increased worldwide, especially in regions and countries with lower sociodemographic indexes.


Assuntos
Pessoas com Deficiência , Insuficiência Renal Crônica , Idoso , Pessoa de Meia-Idade , Criança , Humanos , Carga Global da Doença , Anos de Vida Ajustados por Qualidade de Vida , Efeitos Psicossociais da Doença , Incidência , Prevalência , Insuficiência Renal Crônica/epidemiologia , Saúde Global
14.
Injury ; 54(2): 589-597, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36528424

RESUMO

INTRODUCTION: Pelvic fracture is a severe injury resulting in high mortality and disability rate, and brought heavy health burden. However, existing research conclusions only restricted to the national level while global estimation of pelvic fracture was lack. We aimed to estimate the global incidence, prevalence, and years lived with disability (YLDs) of pelvic fracture by region, age, gender, cause and sociodemographic index (SDI). MATERIALS AND METHODS: Publicly available data was gained based on the Global Burden of Disease Study (GBD) 2019. We calculated the estimated annual percent change (EAPC) to analyze the temporal trends of pelvic fractures from 1990 to 2019. Incidence, prevalence and YLDs were analyzed by region, age, gender, cause and SDI. Spearman's rank order correlation was used to determine the correlation between SDI and incidence, prevalence and YLDs. RESULTS: Globally, there were about 6 million incident cases, 18.8 million prevalent cases and 3.2 million YLDs cases of pelvic fractures for both sexes in 2019. The incidence number increased over 40% compared to 1990. However, the age standardized rate of incidence (ASIR) (EAPC = -0.22; 95% CI, -0.38 to -0.05), prevalence (ASPR) (EAPC = -0.42; 95% CI, -0.51 to -0.32) and YLDs (ASYR) (EAPC = -0.41; 95% CI, -0.50 to -0.32) all presented downward trends. Males had higher ASIR, ASPR and ASYR than females in each year from 1990 to 2019. The incidence, prevalence and YLDs rates were higher in males in early adulthood but exceeded in females at older age. A positive correlation was observed between ASIR and SDI (rho = 0.3732, p < 0.01). Regions with higher SDI tended to have higher ASIR, ASPR and ASYR than lower SDI regions. Falls and road injuries were the major causes of pelvic fracture at all ages and during the whole period. CONCLUSION: The global health burden of pelvic fracture still remained high during the past thirty years. More policies and strategies are needed to face the challenge brought by population growth and aging.


Assuntos
Pessoas com Deficiência , Fraturas Ósseas , Masculino , Feminino , Humanos , Adulto , Carga Global da Doença , Incidência , Prevalência , Fraturas Ósseas/epidemiologia , Saúde Global , Anos de Vida Ajustados por Qualidade de Vida
15.
Eur Spine J ; 32(2): 590-600, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36350373

RESUMO

PURPOSE: We aimed to estimate the incidence, prevalence and years lived with disability (YLDs) of spinal cord injury (SCI) in China in 2019 and temporal trends from 1990 to 2019. METHODS: The Global Burden of Disease Study 2019 was used to obtain data. Outcome measures included age-standardized incidence rate (ASIR), prevalence rate (ASPR) and YLDs rate (ASYR). A Bayesian meta-regression tool, DisMod-MR 2.1, was used to produce the estimates of each value after adjustments. RESULTS: In 2019, there were 234.19 [95% uncertainty interval (UI) 171.84-312.87] thousand incident cases of SCI in China, with an ASIR of 13.87 (95% UI 10.15-18.66) per 100,000. ASIR and ASYR increased by 40.81% (95% UI 32.92-49.14%) and 11.44% (95% UI 5.16-17.29%) compared with 1990, individually. Males had higher ASIR and ASYR in each year from 1990 to 2019, but the incidence and YLDs rates of females exceeded males after 70 years old. Incidence and YLDs rates both ascended with age. SCI at neck level had slightly higher incidence rate but much higher YLDs rate than that below neck level. The average incidence age increased from 38.97 in 1990 to 54.59 in 2019. Falls were the leading cause of SCI. CONCLUSION: The incidence and burden of SCI in China increased significantly during the past three decades. The age structure of SCI patients showed a shift from the young to the elderly as population aging. Urgent efforts are needed to relieve the health pressure from SCI.


Assuntos
Carga Global da Doença , Traumatismos da Medula Espinal , Masculino , Feminino , Humanos , Idoso , Incidência , Prevalência , Teorema de Bayes , Saúde Global , Traumatismos da Medula Espinal/epidemiologia , China/epidemiologia , Anos de Vida Ajustados por Qualidade de Vida
16.
FASEB J ; 37(1): e22690, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36468880

RESUMO

Fatty amide hydrolase (FAAH) is a key degradation enzyme of the endocannabinoid system, mainly responsible for the hydrolysis of arachidonic acid ethanolamine (AEA). Previous investigations have shown that FAAH is involved in a series of biological processes, such as inflammation, immune regulation, and transmembrane signal transduction of neurons. Endogenous cannabinoids and cannabinoid receptors have been reported to participate in the regulation of bone homeostasis by regulating the differentiation of osteoblasts and osteoclasts. We hypothesized that FAAH may play an important role in osteoclastogenesis based on the above evidence. The present study found that the FAAH expression was increased at both mRNA and protein levels during RANKL-induced osteoclastogenesis. Pharmacological and genetic inhibition of FAAH in bone marrow-derived macrophages (BMMs) inhibited osteoclastogenesis, F-actin ring formation, bone resorption, and osteoclast-specific gene expression in vitro. Moreover, intragastric administration of the FAAH inhibitor PF-04457845(PF) ameliorated ovariectomy (OVX)-induced bone loss in mice. Further investigation revealed that nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways were inhibited by PF treatment and FAAH knockdown. RNAseq indicated that the IL17 pathway was blocked by PF, and administration of recombinant murine IL17 protein could partially restore osteoclastogenesis and activate NF-κB and MAPK pathways. To sum up, our findings demonstrate that targeting FAAH could be a promising candidate strategy for treating osteoclast-related diseases, especially osteoporosis.


Assuntos
Amidoidrolases , Reabsorção Óssea , Interleucina-17 , Osteogênese , Animais , Feminino , Camundongos , Reabsorção Óssea/etiologia , Reabsorção Óssea/prevenção & controle , Diferenciação Celular , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Osteoclastos/metabolismo , Ovariectomia/efeitos adversos , Ligante RANK/metabolismo , Amidoidrolases/antagonistas & inibidores , Interleucina-17/metabolismo
17.
Clin Orthop Relat Res ; 481(6): 1209-1220, 2023 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-36374576

RESUMO

BACKGROUND: Hip fractures are associated with a high risk of death; among those who survive a hip fracture, many experience substantial decreases in quality of life. A comprehensive understanding of the epidemiology and burden of hip fractures by country, age, gender, and sociodemographic factors would provide valuable information for healthcare policymaking and clinical practice. The Global Burden of Disease (GBD) study 2019 was a global-level study estimating the burden of 369 diseases and injuries in 204 countries and territories. An exploration and additional analysis of the GBD 2019 would provide a clearer picture of the incidence and burden of hip fractures. QUESTIONS/PURPOSES: Using data from the GBD 2019, we asked, (1) What are the global, regional, and national incidences of hip fractures, and how did they change over a recent 30-year span? (2) What is the global, regional, and national burden of hip fractures in terms of years lived with disability, and how did it change over that same period? (3) What is the leading cause of hip fractures? (4) How did the incidence and years lived with disability of patients with hip fractures change with age, gender, and sociodemographic factors? METHODS: This was a cross-sectional study. Participant data were obtained from the GBD 2019 ( http://ghdx.healthdata.org/gbd-results-tool ). The GBD study is managed by the WHO, coordinated by the Institute of Health Metrics and Evaluation, and funded by the Bill and Melinda Gates Foundation. It estimates the burden of disease and injury for 204 countries by age, gender, and sociodemographic factors, and can serve as a valuable reference for health policymaking. All estimates and their 95% uncertainty interval (UI) were produced using DisMod-MR 2.1, a Bayesian meta-regression tool in the GBD 2019. In this study, we directly pulled the age-standardized incidence rate and years lived with disability rate of hip fractures by location, age, gender, and cause from the GBD 2019. Based on these data, we analyzed the association between the incidence rate and latitude of each country. Then, we calculated the estimated annual percentage change to represent trends from 1990 to 2019. We also used the Spearman rank-order correlation analysis to determine the correlation between the incidence or burden of hip fractures and the sociodemographic index, a composite index of the income per capita, average years of educational attainment, and fertility rates in a country. RESULTS: Globally, hip fracture incidences were estimated to be 14.2 million (95% UI 11.1 to 18.1), and the associated years lived with disability were 2.9 million (95% UI 2.0 to 4.0) in 2019, with an incidence of 182 (95% UI 142 to 231) and 37 (95% UI 25 to 50) per 100,000, respectively. A strong, positive correlation was observed between the incidence rate and the latitude of each country (rho = 0.65; p < 0.001). From 1990 to 2019, the global incidence rate for both genders remained unchanged (estimated annual percentage change 0.01 [95% confidence interval -0.08 to 0.11]), but was slightly increased in men (estimated annual percentage change 0.11 [95% CI 0.01 to 0.2]). The years lived with disability rate decreased slightly (estimated annual percentage change 0.66 [95% CI -0.73 to -0.6]). These rates were standardized by age. Falls were the leading cause of hip fractures, accounting for 66% of all patients and 55% of the total years lived with disability. The incidence of hip fractures was tightly and positively correlated with the sociodemographic index (rho 0.624; p < 0.001), while the years lived with disability rate was slightly negatively correlated (rho -0.247; p < 0.001). Most hip fractures occurred in people older than 70 years, and women had higher incidence rate (189.7 [95% UI 144.2 to 247.2] versus 166.2 [95% UI 133.2 to 205.8] per 100,000) and years lived with disability (38.4 [95% UI 26.9 to 51.6] versus 33.7 [95% UI 23.1 to 45.5] per 100,000) than men. CONCLUSION: Hip fractures are common, devastating to patients, and economically burdensome to healthcare systems globally, with falls being the leading cause. The age-standardized incidence rate has slightly increased in men. Many low-latitude countries have lower incidences, possibly because of prolonged sunlight exposure. Policies should be directed to promoting public health education about maintaining bone-protective lifestyles, enhancing the knowledge of osteoporosis management in young resident physicians and those in practice, increasing the awareness of osteoporosis screening and treatment in men, and developing more effective antiosteoporosis drugs for clinical use. LEVEL OF EVIDENCE: Level III, prognostic study.


Assuntos
Fraturas do Quadril , Osteoporose , Humanos , Masculino , Feminino , Carga Global da Doença , Qualidade de Vida , Teorema de Bayes , Estudos Transversais , Distribuição por Idade , Incidência , Fraturas do Quadril/epidemiologia , Saúde Global , Prevalência , Anos de Vida Ajustados por Qualidade de Vida
18.
ACS Appl Bio Mater ; 5(12): 5832-5843, 2022 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-36442520

RESUMO

The balance of bone turnover mediated by osteoclastogenesis and osteogenesis implants that could suppress osteoclastogenesis and promote osteogenesis is an appropriate treatment strategy for osteoporosis patients. Titanium is one of the most applied materials in implants. In this study, titania nanotubes (Ti-NTs) were produced by anodization at 10, 40, and 60 V. We found that Ti-NTs were nontoxic to bone marrow mesenchymal stem cells (BMSCs). Ti-NTs suppressed osteoclast formation and function in a diameter dependent manner in vitro. Furthermore, Ti-NTs enhanced the activity of osteogenesis, expressions of osteogenesis-related marker genes were increased and ß-Catenin pathway was active. Alkaline phosphatase (ALP) activity and matrix mineralization were also promoted in vitro. To explore the possible mechanisms, we performed a series of experiments to indicate the effects of Ti-NTs on cytoskeletal organization and integrin ανß3 expression of osteoclasts and osteoblasts. The results demonstrated that 90-nm-diameter Ti-NTs could suppress the expression of integrin ανß3 in osteoclast precursor cells. Interestingly, it revealed an opposite effect on BMSCs. Moreover, 90 nm-diameter Ti-NTs prevented ovariectomy (OVX)-induced bone loss. These findings indicated that Ti-NTs could inhibit osteoclastogenesis and enhance osteogenesis; it was mediated via regulation of integrin ανß3─90 nm-diameter Ti-NT revealed a good biological ability especially suited for osteoporosis treatment.


Assuntos
Nanotubos , Osteoporose , Feminino , Humanos , Osteogênese/genética , Titânio/farmacologia , Integrinas , Diferenciação Celular
19.
Pharmacol Res ; 185: 106513, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36252772

RESUMO

cytohesin-2 is a guanine nucleotide exchange factor to activate ARF1 and ARF6, which are involved in various biological processes, including signal transduction, cell differentiation, cell structure organization, and survival. Nevertheless, there is a lack of evidence revealing the role of cytohesin-2 in osteoclast differentiation and in the development of osteoporosis. In this study, we find cytohesin-2 and ARF1 positively regulate osteoclast differentiation and function. Blocking the cytohesin-2 /ARF1 axis with SecinH3 or by genetic silencing of cytohesin-2 inhibits osteoclast formation and function in vitro. In vivo treatment with SecinH3 ameliorates ovariectomy-induced osteoporosis. Mechanistically, RNA-sequencing combined with molecular biological methodologies reveal that the regulatory function of cythohesin-2/ARF1 axis in osteoclast differentiation is mainly dependent on activating the JNK pathway. Further, in addition to the common viewpoint that JNK is activated by IRE1 via its kinase activity, we found that JNK can act upstream and regulate the endoribonuclease activity of IRE1 to promote XBP1 splicing. Both SecinH3 and silencing of cytohesin-2 inhibit JNK activation and IRE1 endoribonuclease activity, leading to the suppression of osteoclast differentiation. Taken together, our findings add new insights into the regulation between JNK and IRE1, and reveal that inhibiting the cytohesin-2/ARF1/JNK/IRE1 axis might represent a potential new strategy for the treatment of post-menopause osteoporosis.


Assuntos
Fatores de Ribosilação do ADP , Osteoporose , Humanos , Fatores de Ribosilação do ADP/fisiologia , Osteoclastos/metabolismo , Fator 6 de Ribosilação do ADP , Osteoporose/tratamento farmacológico , Endorribonucleases/metabolismo , Proteínas Serina-Treonina Quinases
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