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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.
Cancers (Basel) ; 16(2)2024 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-38254792

RESUMO

BACKGROUND: The presence of bone invasion in aggressive pituitary adenoma (PA) was found in our previous study, suggesting that PA cells may be involved in the process of osteoclastogenesis. miR-19a (as a key member of the miR-17-92 cluster) has been reported to activate the nuclear factor-кB (NF-кB) pathway and promote inflammation, which could be involved in the process of the bone invasion of pituitary adenoma. METHODS: In this work, FISH was applied to detect miR-19a distribution in tissues from patients with PA. A model of bone invasion in PA was established, GH3 cells were transfected with miR-19a mimic, and the grade of osteoclastosis was detected by HE staining. qPCR was performed to determine the expression of miR-19a throughout the course of RANKL-induced osteoclastogenesis. After transfected with a miR-19a mimic, BMMs were treated with RANKL for the indicated time, and the osteoclast marker genes were detected by qPCR and Western Blot. Pit formation and F-actin ring assay were used to evaluate the function of osteoclast. The TargetScan database and GSEA were used to find the potential downstream of miR-19a, which was verified by Co-IP, Western Blot, and EMSA. RESULTS: Here, we found that miR-19a expression levels were significantly correlated with the bone invasion of PA, both in clinical samples and animal models. The osteoclast formation prior to bone resorption was dramatically enhanced by miR-19, which was mediated by decreased cylindromatosis (CYLD) expression, increasing the K63 ubiquitination of tumor necrosis factor receptor-associated factor 6 (TRAF6). Consequently, miR-19a promotes osteoclastogenesis by the activation of the downstream NF-кB and mitogen-activated protein kinase (MAPK) pathways. CONCLUSIONS: To summarize, the results of this study indicate that PA-derived miR-19a promotes osteoclastogenesis by inhibiting CYLD expression and enhancing the activation of the NF-кB and MAPK pathways.

5.
Adv Healthc Mater ; 13(6): e2302879, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37927129

RESUMO

Bone infection is one of the most devastating orthopedic outcomes, and overuse of antibiotics may cause drug-resistance problems. Photothermal therapy(PTT) is a promising antibiotic-free strategy for treating infected bone defects. Considering the damage to normal tissues and cells caused by high-temperature conditions in PTT, this study combines the antibacterial property of Cu to construct a multi-functional Cu2 O@MXene/alpha-tricalcium phosphate (α-TCP) scaffold support with internal and external sandwiching through 3D printing technology. On the "outside", the excellent photothermal property of Ti3 C2 MXene is used to carry out the programmed temperature control by the active regulation of 808 nm near-infrared (NIR) light. On the "inside", endogenous Cu ions gradually release and the release accumulates within the safe dose range. Specifically, programmed temperature control includes brief PTT to rapidly kill early bacteria and periodic low photothermal stimulation to promote bone tissue growth, which reduces damage to healthy cells and tissues. Meanwhile, Cu ions are gradually released from the scaffold over a long period of time, strengthening the antibacterial effect of early PTT, and promoting angiogenesis to improve the repair effect. PTT combined with Cu can deliver a new idea forinfected bone defects through in vitro and vivo application.


Assuntos
Antibacterianos , Bactérias , Elementos de Transição , Antibacterianos/farmacologia , Nitritos , Impressão Tridimensional
7.
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
8.
Adv Healthc Mater ; 12(15): e2203099, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36780559

RESUMO

Osteoporosis is a degenerative bone disease resulting from bone homeostasis imbalance regulated by osteoblasts and osteoclasts. Treating osteoporotic bone defects tends to be more difficult due to suppressed osteogenic differentiation, hyperactive osteoclastogenesis, and impaired angiogenesis. Hence, a drug carrier system composed of gelatin-coated hollow mesoporous silica nanoparticles (HMSNs/GM) loaded with pro-osteogenic parathyroid (PTH) and anti-osteoclastogenic alendronate (ALN) is constructed and compounded into calcium magnesium phosphate cement (MCPC). The spatial-temporal release of ions and drugs, controllable degradation rate, and abundant pore structure of MCPC composites enhance osteoporotic bone regeneration in ovariectomized rats by accelerating vascularization, promoting osteogenic differentiation and mineralization, and inhibiting osteoclastogenesis and bone resorption. The MCPC/HMSNs@ALN-PTH/GM demonstrates a synergistic threefold effect on osteogenesis, osteoclastogenesis, and angiogenesis. It improves the osteoporotic pathophysiological microenvironment and promotes osteoporotic vascularized bone defect regeneration, holding huge potential for other functional biomaterials design and clinical management.


Assuntos
Osteogênese , Osteoporose , Ratos , Animais , Regeneração Óssea/fisiologia , Osteoporose/tratamento farmacológico , Osteoclastos , Materiais Biocompatíveis/farmacologia , Alendronato/química , Alendronato/farmacologia
9.
Int J Bioprint ; 9(1): 641, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36636134

RESUMO

Three-dimensional (3D)-printed scaffolds of biodegradable polymers have been increasingly applied in bone repair and regeneration, which helps avoid the second surgery. PTMC/PCL/TCP composites were made using poly(trimethylene carbonate), poly(ε-caprolactone), and ß-tricalcium phosphate. PTMC/PCL/TCP scaffolds were manufactured using a biological 3D printing technique. Furthermore, the properties of PTMC/PCL/TCP scaffolds, such as biodegradation, mechanic properties, drug release, cell cytotoxicity, cell proliferation, and bone repairing capacity, were evaluated. We showed that PTMC/PCL/TCP scaffolds had low cytotoxicity and good biocompatibility, and they also enhanced the proliferation of osteoblast MC3T3-E1 and rBMSC cell lines, which demonstrated improved adhesion, penetration, and proliferation. Moreover, PTMC/PCL/TCP scaffolds can enhance bone induction and regeneration, indicating that they can be used to repair bone defects in vivo.

10.
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
11.
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
12.
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
13.
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
15.
Spine (Phila Pa 1976) ; 47(21): 1532-1540, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-35857624

RESUMO

STUDY DESIGN: A retrospective cohort study. OBJECTIVE: The authors aimed to estimate the incidence, prevalence and years lived with disability (YLDs) of spinal cord injury (SCI) by location, sex, age, injury site and socio-demographic index (SDI) based on the data of the Global Burden of Disease Study (GBD) 2019. SUMMARY OF BACKGROUND DATA: GBD 2019 estimates the burden of 369 diseases and injuries worldwide in 2019 and the temporal trends in the past 30 years. SCI is estimated as a result of injury from various causes. METHODS: A Bayesian meta-regression tool, DisMod-MR2.1, was used to produce the estimates. Estimated annual percentage change (EAPC) was calculated based on a linear regression mode of the age standardized rates and the calendar year to represent the temporal trends of the age standardized rates. Spearman rank order correlation was used to determine the correlation between SDI and the incidence and burden of SCI. RESULTS: Globally, there were 0.9 [95% uncertainty interval (UI), 0.7 to 1.2] million incident cases, 20.6 (95% UI, 18.9-23.6) million prevalent cases and 6.2 (95% UI, 4.5-8.2) million YLDs of total SCI in 2019. The ASPR increased (EAPC, 0.1; 95% confidence interval, -0.01 to 0.2), while the age standardized incidence rate (ASIR) (EAPC, -0.08; 95% UI, -0.24 to 0.09) and age standardized YLD rate (ASYR) (EAPC, -0.08; 95% confidence interval, -0.24 to 0.09) decreased. Males had higher ASIR and ASYR, and the rate of incidence, prevalence and YLD increased with age. Spinal injuries at neck level caused higher ASYR than injuries below neck level. A positive correlation existed between SDI and ASIR (ρ=0.1626, P <0.05), while a negative correlation was observed between SDI and EAPC of ASYR (ρ=-0.2421, P <0.01). CONCLUSION: Conclusively, the incidence and burden of SCI has increased over the last 30 years. Males and the elderly were affected to a greater degree than females and younger individuals. LEVEL OF EVIDENCE: Level III.


Assuntos
Carga Global da Doença , Traumatismos da Medula Espinal , Idoso , Teorema de Bayes , Feminino , Saúde Global , Humanos , Incidência , Masculino , Prevalência , Anos de Vida Ajustados por Qualidade de Vida , Estudos Retrospectivos , Traumatismos da Medula Espinal/epidemiologia
16.
DNA Cell Biol ; 41(6): 575-589, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35699379

RESUMO

Osteoporosis is one of the most common metabolic skeletal diseases, which affects more than 200 million people worldwide, especially elderly and postmenopausal women. One of the main processes of osteoporosis is attenuated bone formation. Abundant evidence has confirmed that overactivated osteoclasts are responsible for the attenuated bone formation. This study aims at identifying novel methylation-associated biomarkers and therapeutic targets in osteoclasts by integrally analyzing methylation profiles and gene expression data. DNA methylation profile and gene expression data were obtained from the Gene Expression Omnibus (GEO) database. Subsequently, we integrated the two sets of data to screen for differentially expressed genes with differential methylation level (DM-DEGs) between osteoclasts and CD14+ monocytes from donors. Then, Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed to uncover the enriched functions and pathways of identified DM-DEGs. In addition, by combining protein-protein interaction analysis and receiver-operator characteristic analysis, we finally identified four hub DM-DEGs. Gene Set Enrichment Analysis was utilized to validate and investigate the potential biological functions of the four hub DM-DEGs. Finally, Real-time quantitative PCR (QPCR) was performed to validate the mRNA expression level of the four identified hub DM-DEGs during osteoclast differentiation. CCRL2, CCL18, C1QB, and SELL were highly correlated with osteoclastic differentiation and osteoporosis phenotype. QPCR revealed that the expression of CCRL2, CCL18, and C1QB was increased during osteoclast differentiation, whereas the expression of SELL was decreased. The present study indicated a connection between gene expression and DNA methylation during osteoclast differentiation and that four hub DM-DEGs in osteoclastogenesis and osteoporosis pathogenesis might be potential candidates for intensive research and therapeutic targets for the treatment of osteoporosis.


Assuntos
Perfilação da Expressão Gênica , Osteoporose , Idoso , Biologia Computacional , Metilação de DNA , Feminino , Redes Reguladoras de Genes , Humanos , Osteoclastos , Osteoporose/genética
17.
Front Endocrinol (Lausanne) ; 13: 870905, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35685212

RESUMO

Objective: We aim to explore the global spatial prevalence and temporal trends of the burden of low bone mineral density (LBMD) worldwide, due to a lack of related studies. Design: Cross-sectional study. Methods: We used data from the Global Burden of Disease Study 2019 to conduct this study. LBMD in the GBD study includes both osteopenia and osteoporosis. The estimation for the prevalence, measured by the summary exposure value (SEV), and burden of LBMD was made in DisMod-MR 2.1, a Bayesian meta-regression tool. Correlation analysis was performed using the Spearman rank order correlation methods. The temporal trends were represented by the estimated annual percentage change (EAPC). Results: In 2019, there were 438 thousand deaths and 16.6 million DALYs attributable to LBMD, increasing by 111.1% and 93.8% respectively, compared to that in 1990. From 1990 to 2019, the prevalence of LBMD has decreased worldwide, but has increased in high-income North America. Some countries, such as the United States, Australia, Canada, and China had increased disability and mortality rates of LBMD with time. Countries with low socio-demographic index (SDI) had higher incidence and mortality rate than those with high SDI. The prevalence of LBMD was lower in males, but the attributable disability and mortality were higher in males in all years from 1990 to 2019. Conclusion: With population aging, countries worldwide, especially those with low-SDI, will face increasing challenges in reducing the burden attributable to LBMD and osteoporosis. The treatment of osteoporosis has been overlooked in men for a long time. Effective measures are warranted to control the prevalence and burden of LBMD.


Assuntos
Doenças Ósseas Metabólicas , Osteoporose , Teorema de Bayes , Estudos Transversais , Carga Global da Doença , Saúde Global , Humanos , Masculino , Osteoporose/epidemiologia , Anos de Vida Ajustados por Qualidade de Vida
18.
J Biol Chem ; : 101775, 2022 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-35257748

RESUMO

It's widely accepted that increasing mitochondrial respiration plays a pivotal role during osteoclastogenesis. Mitochondrial pyruvate carrier (MPC) is the key transporter that links glycolysis to mitochondrial respiration but little is known about its role during osteoclastogenesis. Our goal was to determine the effects of its blockade on osteoclastogenesis and bone resorption in vivo and in vitro. To address this issue, we performed gene knockdown or pharmacologically inhibited MPC in primary bone marrow-derived monocytes (BMMs) or in an ovariectomized mouse model. We also studied the metabolic changes in RANKL-induced differentiating BMMs with MPC blockade and performed rescue experiments. We found that MPC blockade resulted in decreased osteoclastogenesis both in vivo and in vitro and inhibiting MPC significantly alleviated ovariectomy-induced trabecular bone loss. Further investigations showed that MPC blockade significantly reversed the metabolic profile related to RANK activation, including decreased intermediates involved in citric acid cycle and glutamine metabolism. Moreover, metabolic flux analysis verified that MPC blockade decreased pyruvate flux into TCA cycle with no significant effect on glycolysis. Besides, MPC blockade resulted in suppressed mitochondrial biogenesis in addition to oxidative phosphorylation. Rescue experiments revealed that inhibiting pyruvate dehydrogenase kinase (PDK) via sodium dichloroacetate (DCA), but not targeting glutamine metabolism, could reverse the effects of MPC blockade on osteoclastogenesis. These implied that the effects of MPC blockade were mediated by reduced pyruvate fuel into citric acid cycle in multiple aspects. Taken together, our data demonstrated the inhibitory effects of MPC blockade on osteoclastogenesis, which was mediated by decreased mitochondrial energy production.

19.
FASEB J ; 36(2): e22167, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35064691

RESUMO

Methionine adenosyltransferase II alpha (MAT2A) is the key enzyme to transform methionine and adenosine-triphosphate (ATP) to S-adenosylmethionine (SAM), a general methyl-group donor in vitro. MAT2A has been reported to participate in the NF-κB pathway and maintain the methylated modification, which also affects osteoclastogenesis. In this study, we found the expression of MAT2A was increased upon RANKL stimulation. Pharmacological inhibition of MAT2A by its selective inhibitor AG-270 or genetic silencing by MAT2A-shRNA suppressed osteoclast formation and function in vitro. In vivo treatment with the inhibitor AG-270 also prevented OVX-induced bone loss. Further study revealed that the inhibition of MAT2A affected osteoclast differentiation mainly by suppressing crucial transcription factors and reactive oxygen species induced by RANKL. A quasi-targeted metabolomics assay performed by LC-MS/MS indicated that SAM was reduced by MAT2A knockdown, and the administration of SAM partly rescued the effects of MAT2A inhibition on osteoclastogenesis. These findings revealed that MAT2A is crucial for osteoclastogenesis and might be a potential target for the treatment of osteoporosis attributed to osteoclast dysfunction.


Assuntos
Reabsorção Óssea/metabolismo , Metionina Adenosiltransferase/metabolismo , Osteogênese/fisiologia , Animais , Diferenciação Celular/fisiologia , Cromatografia Líquida/métodos , Feminino , Metaboloma/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Osteoclastos/metabolismo , Ovariectomia/métodos , Ligante RANK/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/fisiologia , Espectrometria de Massas em Tandem/métodos
20.
Biochem Pharmacol ; 197: 114932, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35085541

RESUMO

Neck pain and low back pain are two of the major diseases, which causes patients a low quantify of life and a heavy economic burden, intervertebral disc degeneration (IDD) contributes to them, and the mechanism is not totally clear. The increased inflammatory cytokines including interleukin (IL)-1ß and tumor necrosis factor (TNF)α and downstream signaling pathways are involved. Inositol requiring enzyme 1 (IRE1) is a crucial enzyme that regulates endoplasmic reticulum (ER) stress. It is reported that IRE1 plays an important role in the activation of NF-κB, PI3K/Akt and MAPK signaling pathways. Considering this, we performed a series of experiments in vitro and in vivo to evaluate the role of IRE1 in the progress of IDD. We demonstrated that IRE1 pathway was induced by IL-1ß, inhibition of IRE1 suppressed the matrix degeneration of NP cells and ameliorated IDD grade in the punctured rat model. Further results indicated that inhibition of IRE1 suppressed H2O2 induced cell senescence, IL-1ß-induced cellular reactive oxygen species (ROS) level and the activation of NF-κB, PI3K/Akt and MAPK signaling pathways. It also played a crucial role in the apoptosis of NP cells and the progress of macrophage polarization. Our findings demonstrated that inhibition of IRE1 could suppress the degeneration of NP cells and prevent IDD in vivo. IRE1 may be a potential target for IDD treatment.


Assuntos
Endorribonucleases/metabolismo , Interleucina-1beta/metabolismo , Degeneração do Disco Intervertebral/metabolismo , Degeneração do Disco Intervertebral/prevenção & controle , Complexos Multienzimáticos/metabolismo , Núcleo Pulposo/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Endorribonucleases/antagonistas & inibidores , Interleucina-1beta/antagonistas & inibidores , Degeneração do Disco Intervertebral/patologia , Masculino , Complexos Multienzimáticos/antagonistas & inibidores , Núcleo Pulposo/patologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , RNA Interferente Pequeno/administração & dosagem , Ratos , Ratos Sprague-Dawley
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