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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.
Aging Dis ; 2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38377021

RESUMO

Recent studies have provided links between glutamine metabolism and bone remodeling, but little is known about its role in primary osteoporosis progression. We aimed to determine the effects of inhibiting glutaminase (GLS) on two types of primary osteoporosis and elucidate the related metabolism. To address this issue, age-related and ovariectomy (OVX)-induced bone loss mouse models were used to study the in vivo effects of CB-839, a potent and selective GLS inhibitor, on bone mass and bone turnover. We also studied the metabolic profile changes related with aging and GLS inhibition in primary bone marrow stromal cells (BMSC) and that related with OVX and GLS inhibition in primary bone marrow-derived monocytes (BMM). Besides, we studied the possible metabolic processes mediating GLS blockade effects during aging-impaired osteogenic differentiation and RANKL-induced osteoclast differentiation respectively via in vitro rescue experiments. We found that inhibiting GLS via CB-839 prevented OVX-induced bone loss while aggravated age-related bone loss. Further investigations showed that effects of CB-839 treatment on bone mass were associated with alterations of bone turnover. Moreover, CB-839 treatment altered metabolic profile in different orientations between BMSC of aged mice and BMM of ovariectomized mice. In addition, rescue experiments revealed that different metabolic processes mediated glutaminase blockade effects between aging-impaired osteogenic differentiation and RANKL-induced osteoclast differentiation. Taken together, our data demonstrated the different outcomes caused by CB-839 treatment between two types of osteoporosis in mice, which were tightly connected to the suppressive effects on both aging-impaired osteoblastogenesis and OVX-enhanced osteoclastogenesis mediated by different metabolic processes downstream of glutaminolysis.

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.
J Ethnopharmacol ; 321: 117560, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38081396

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Dauricine (DA) is a natural plant-derived alkaloid extracted from Menispermum dauricum. Menispermum dauricum has been used in traditional Chinese medicine as a classic remedy for rheumatoid arthropathy and is believed to be effective in alleviating swelling and pain in the limbs. AIM OF THE STUDY: Osteoarthritis (OA) is a classic degenerative disease involving chondrocyte death, and there is still a lack of effective therapeutic agents that can reverse the progression of the disease. Here we explored the therapeutic effects of DA against OA and further explored the mechanism. MATERIALS AND METHODS: The effect of DA on cell viability was assessed by CCK-8. IL-1ß-treated mouse chondrocytes were used as an in vitro model of OA, and apoptosis was detected by flow cytometry. QRT-PCR, western blotting, cell staining, and immunofluorescence were used to detect relevant inflammatory factors and cartilage-specific expression. RNA sequencing was used to identify pertinent signaling pathways. The therapeutic effect of DA was verified by micro-CT, histological analysis and immunohistochemical analysis in a mouse OA model. RESULTS: DA demonstrated a high safety profile on chondrocytes, significantly reversing the inflammatory response induced by IL-1ß, and promoting factors associated with cartilage regeneration. Moreover, DA exhibited a significant protective effect on the knee joints of mice undergoing ACLT-DMM, effectively preventing cartilage degeneration and subchondral bone tissue destruction. These positive therapeutic effects were achieved through the modulation of the NF-κB pathway and the Ca2+ signaling pathway by DA. CONCLUSION: Being derived from a traditional herb, DA exhibits remarkable therapeutic potential and safety in OA treatment, presenting a promising option for patients dealing with osteoarthritis.


Assuntos
Benzilisoquinolinas , Menispermum , Osteoartrite , Humanos , Camundongos , Animais , NF-kappa B/metabolismo , Condrócitos , Menispermum/metabolismo , Células Cultivadas , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Benzilisoquinolinas/farmacologia , Osteoartrite/induzido quimicamente , Osteoartrite/tratamento farmacológico , Interleucina-1beta/metabolismo
5.
Acta Orthop Belg ; 89(2): 354-361, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37924554

RESUMO

The posterolateral tibial plateau fracture is an uncommon intra-articular injury and mostly needed surgery. However, its surgical approach remains controversial. This manuscript describes an anterolateral approach to treat posterolateral tibial plateau fractures and evaluates the patient's functional outcomes. From June 2018 to July 2021 seventeen patients with posterolateral tibial plateau fractures were surgically treated through an anterolateral approach. The intraoperative and postoperative follow-up indicators were recorded. The reduction quality of fractures was assessed using Rasmussen radiological score, and postsurgical functional recovery was estimated using Rasmussen clinical score and Lysholm score. The mean follow-up interval was 28.71 ± 9.61 months (range 18-44). The surgery time and blood loss were 111.06 ± 15.62 min (range 85-140) and 118.12 ± 38.45 mL (range 80-250) separately. Postoperatively, the Rasmussen radiological score was 16.24 ± 2.33 (range 12-18). The average time of bone union was 14.29 ± 1.53 weeks (range 12-18). At the final follow-up, the average PTS and MPTA were 9.71 ± 2.76° (range 5-14°) and 86.82 ± 2.04° (range 84-90°) separately. A satisfactory articular reduction was achieved in 16 patients (94.1%). The final ROM was 123.29 ± 19.70° (range 60-142°). The Rasmussen clinical score and Lysholm score were 25.71 ± 5.74 (range 10-30) and 91.47 ± 6.50 (range 75-98) separately. Anterolateral approach has minimal risk of intraoperative neurovascular injuries in the popliteal fossa with satisfactory results. The hardware removal was also facilitated. This approach is feasible, safe and efficient.


Assuntos
Fraturas da Tíbia , Fraturas do Planalto Tibial , Humanos , Resultado do Tratamento , Fixação Interna de Fraturas/métodos , Consolidação da Fratura , Fraturas da Tíbia/diagnóstico por imagem , Fraturas da Tíbia/cirurgia , Estudos Retrospectivos , Placas Ósseas
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.
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
9.
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
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.
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
12.
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
14.
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
15.
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
16.
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.

17.
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
18.
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
19.
Spine J ; 22(5): 857-868, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-34906740

RESUMO

BACKGROUND CONTEXT: In the context of the population growing and aging worldwide, the epidemiology, and burden of vertebral fracture have not been comprehensively analyzed. PURPOSE: To delineate the global number and rate of incidence, prevalence and burden of vertebral fracture in 2019, and the temporal trends from 1990 to 2019 by location, age, sex, and the socio-demographic index (SDI). STUDY DESIGN/SETTING: A cross-sectional study using data from the Global Burden of Disease Study 2019 (GBD study 2019). PATIENT SAMPLE: Patients with vertebral fracture documented in medical records or registrations and included in the GBD study 2019 from different countries worldwide. OUTCOME MEASURES: Age standardized incidence rate (ASIR), age standardized prevalence rate (ASPR), and age standardized years lived with disability (YLDs). METHODS: The GBD study 2019 was used to obtain data for this analysis. The incidence, prevalence and disability were analyzed by location, year, sex, age, and SDI. DisMod-MR 2.1, a Bayesian meta-regression tool, was used to produce the estimates for each value after adjustment for age, sex, and other variables. Estimated annual percentage change (EAPC) was calculated to represent the temporal trends from 1990 to 2019. Spearman's rank order correlation was used to determine the correlation between SDI and the incidence and burden of vertebral fracture. This work was supported by the Key Research and Development Program of Hubei Province of China (No. 2020BCB049), and no conflicts of interest-associated biases existed in this study. RESULTS: Globally, there were 8.6 million (95% uncertainty interval [UI], 6,6-11,3 million) incident cases, 5.3 million (95% UI, 4.6-6.2 million) prevalent cases, and 0.55 million (95% UI, 0.37-0.77 million) YLDs of vertebral fracture. Compared with 1990, the number of incident cases and YLDs in 2019 increased by 38% (95% UI, 23%-48%) and 75% (95% UI, 65%-85%), respectively, while the ASIR (EAPC, -0.28; 95% CI, -0.41 to -0.14), ASPR (EAPC, -0.12; 95% CI, -0.22 to -0.02) and age standardized YLD rate (ASYR) (EAPC, -0.13; 95% CI, -0.23 to -0.04) decreased during this period. High ASIR, ASPR and ASYR were commonly seen in high-SDI countries, such as high-income North America, Australia, Central and Eastern Europe. In the country level, positive correlations were observed between SDI and ASIR (rho, 0.596; p<.001) and ASYR (rho, 0.413; p<.001). Males had higher ASIR and ASYR worldwide in each year from 1990 to 2019. However, the incidence, and YLD rates in females surpassed that in males after 65 years of age. Increasing trends were observed for both incidence and YLD rates with age. Falls were the leading cause for vertebral fracture across all ages. CONCLUSIONS: The past thirty years have seen increasing numbers but decreasing rates of global incidence, prevalence, and disability of vertebral fractures, resulting from the growing population worldwide. With population aging, efforts are still in urgent need to address vertebral fracture related health outcomes.


Assuntos
Carga Global da Doença , Fraturas da Coluna Vertebral , Distribuição por Idade , Teorema de Bayes , Estudos Transversais , Feminino , Saúde Global , Humanos , Incidência , Masculino , Prevalência , Anos de Vida Ajustados por Qualidade de Vida , Distribuição por Sexo , Fraturas da Coluna Vertebral/epidemiologia
20.
Front Cell Dev Biol ; 9: 640867, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33777947

RESUMO

Osteoporosis is a common chronic metabolic bone disease characterized by reduced trabecular bone and increased bone fragility. Monoacylglycerol lipase (MAGL) is a lipolytic enzyme to catalyze the hydrolysis of monoglycerides and specifically degrades the 2-arachidonoyl glycerol (2-AG). Previous studies have identified that 2-AG is the mainly source for arachidonic acid and the most abundant endogenous agonist of cannabinoid receptors. Considering the close relationship between inflammatory mediators/cannabinoid receptors and bone metabolism, we speculated that MAGL may play a role in the osteoclast differentiation. In the present study, we found that MAGL protein expression increased during osteoclast differentiation. MAGL knockdown by adenovirus-mediated shRNA in bone marrow-derived macrophages demonstrated the suppressive effects of MAGL on osteoclast formation and bone resorption. In addition, pharmacological inhibition of MAGL by JZL184 suppressed osteoclast differentiation, bone resorption, and osteoclast-specific gene expression. Activation of the Mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) pathways was inhibited by JZL184 and deletion of MAGL. Our in vivo study indicated that JZL184 ameliorated bone loss in an ovariectomized mouse model. Furthermore, overexpressing H1 calponin partially alleviated the inhibition caused by JZL184 or MAGL deletion on osteoclastogenesis. Therefore, we conclude that targeting MAGL may be a novel therapeutic strategy for osteoporosis.

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