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1.
Life Sci Space Res (Amst) ; 36: 59-69, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36682830

RESUMO

Microgravity can inhibit osteoblast proliferation and promote apoptosis, which is related to a reduction in mechanical stress on the bones and results in disuse osteoporosis, but the detailed mechanism is still unclear. In this study, we first demonstrated that miR-138-5p was upregulated, inhibited osteoblast proliferation and induced osteoblast apoptosis under simulated microgravity. Moreover, miR-138-5p silencing partially mitigated the effects of proliferation and apoptosis of MC3T3-E1 cells. Our study further showed that sirtuin 1 (SIRT1) was downregulated and negatively correlated with the expression of miR-138-5p under simulated microgravity, which indicated that miR-138-5p inhibited osteoblast proliferation and promoted osteoblast apoptosis by targeting SIRT1. Thus, the miR-138-5p/SIRT1 pathway should be considered for preventative treatment of disuse osteoporosis.


Assuntos
MicroRNAs , Osteoporose , Ausência de Peso , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Sirtuína 1/metabolismo , Proliferação de Células , Apoptose , Osteoblastos/metabolismo , Osteoporose/metabolismo
2.
J Med Food ; 26(1): 49-58, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36594993

RESUMO

Osteoporosis is characterized by low bone mass and elevated structural deterioration of the bone tissue, resulting in bone weakness with an increased risk of fracture. Considering biological activities of various phytochemicals extracted from apples, we herein demonstrated the potential antiosteoporotic effects of apple-derived nanovesicles (apple NVs) using osteoblastic MC3T3-E1 cells. Apple NVs significantly stimulated the growth of MC3T3-E1 cells. The cellular alkaline phosphatase (ALP) activity was significantly upregulated in the 5 µg/mL apple NVs-treated group. In addition, the concentrarion of mineralized nodules was significantly increased in the apple NVs-treated groups. Furthermore, apple NVs increased the expression of the genes and proteins associated with osteoblast growth and differentiation, such as Runx2, ALP, OPN, and BMP2/4, which further activated ERK- and JNK-related mitogen-activated protein kinase signaling. These results demonstrate that apple NVs have a potential to prevent osteoporosis by promoting osteoblastogenesis in osteoblastic MC3T3-E1 cells through regulating the BMP2/Smad1 pathways.


Assuntos
Malus , Osteoporose , Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 2/metabolismo , Diferenciação Celular , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Malus/metabolismo , Osteoblastos , Osteoporose/tratamento farmacológico , Osteoporose/metabolismo , Transdução de Sinais , Animais , Camundongos
3.
In Vivo ; 37(1): 204-217, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36593033

RESUMO

BACKGROUND/AIM: 25-hydroxycholesterol (25-HC) plays important roles in lipid metabolism, inflammatory responses, and apoptosis, but its pathophysiological association with osteoporosis (OP) has not been verified in osteoblasts. Hence, we studied the pathophysiological linkage and underlying cellular mechanisms of 25-HC in human osteoblast-like MG-63 cells and an ovariectomy-induced osteoporotic mouse model. MATERIALS AND METHODS: To investigate the pathophysiological linkage between 25-HC-induced osteoblast oxiapoptophagy and OP, 25-HC ELISA assay, MTT assay, cell live/dead staining, hematoxylin and eosin staining, DAPI staining, flow cytometry analysis, western blot, caspase-3 staining, reactive oxygen species (ROS) assay, autophagy staining, immunocytochemistry, Micro-CT image analysis and immunocytochemistry were performed in MG-63 cells and ovariectomy-induced OP animals. RESULTS: The expression of cholesterol-25-hydroxylase (CH25H), an enzyme catalyzing the conversion of cholesterol to 25-HC, and the production of 25-HC were increased by lipopolysaccharide in MG-63 cells. Cytotoxicity was increased by 25-HC in MG-63 cells. Apoptosis with condensed chromatin and altered morphology was induced by 25-HC through cleavage of caspases-8, -9, and -3 in MG-63 cells. 25-HC induced oxidative stress in MG-63 cells via elevation of ROS production, cyclooxygenase-2, and inducible nitric oxide synthase. Furthermore, the expression of autophagy biomarkers, including beclin-1 and microtubule-associated protein 1A/1B-light chain 3, was elevated by 25-HC in MG-63 cells. In addition, p53 expression was increased, whereas Akt phosphorylation was suppressed in 25-HC-incubated MG-63 cells. The expression of CH25H, cleaved caspase-3, and beclin-1 were up-regulated in the femoral bone of ovariectomy-induced mouse osteoporotic animals. CONCLUSION: 25-HC plays a role in OP via the induction of oxiapoptophagic osteoblast death.


Assuntos
Osteoblastos , Osteoporose , Feminino , Camundongos , Animais , Humanos , Espécies Reativas de Oxigênio/metabolismo , Caspase 3/metabolismo , Proteína Beclina-1/metabolismo , Osteoblastos/metabolismo , Colesterol , Osteoporose/etiologia , Osteoporose/metabolismo , Apoptose
4.
J Tradit Chin Med ; 43(1): 198-204, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36640013

RESUMO

OBJECTIVE: To organize the fragmented information available in the literature to describe and summarize the extracts used by natural medicines in the treatment of bone loss, and to provide evidence and support for the potential use of natural medicines in the treatment of osteoporosis. METHODS: A literature survey for relevant information regarding the osteogenesis of Dongkuiguo (), Machixian (). etc., was conducted using PubMed, ScienceDirect, MEDLINE, Springer LINK and Google Scholar electronic databases from the years 2000-2020. RESULTS: Dongkuiguo (), Machixian (). etc., both inhibit the activity of osteoclasts and reduce bone resorption by regulation of signaling pathways through interacting with signaling molecules. CONCLUSIONS: In this review, the current knowledge of the novel medicines with osteogenesis properties were summarized and their potential in the treatment of bone loss were demonstrated, but the lack of research on the regulation of the signaling pathway's mechanism of action, and the corresponding theoretical basis for the application of natural medicines in clinical osteoporosis, made it difficult to be widely applied and promoted in clinical practice. Further experiments with some of the medicines and the mechanisms is needed to realize their potential as osteoporosis treatments.


Assuntos
Reabsorção Óssea , Osteoporose , Humanos , Osteoporose/tratamento farmacológico , Osteoporose/metabolismo , Osteoclastos/metabolismo , Osteogênese , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/metabolismo , Transdução de Sinais
5.
Int Immunopharmacol ; 114: 109560, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36538848

RESUMO

BACKGROUND: LincGAS5 have been reported to regulate the progression of osteoporosis (OP). However, the relationship between LincGAS5 and reactive oxygen species (ROS) in osteoporosis were still unclear. METHODS: Bilateral ovariectomy (OVX) rat were established as OP model and verified by the Micro-computed tomography. The ROS level of BMSCs derived from OVX and control rat were detected by Immunofluorescence (IF) and flow cytometry. The role of GAS5, miR-23b-3p and SIRT1 on the osteogenic differentiation were dectected by ARS saining and ALP staining, while the The Oil Red O staining and flow cytometry (FCM) were hired to determine adipogenic differentiation of BMSCs under different treatment. The expression of GAS5,miR-23b-3p and SIRT1 in BMSCs was detected by RT-qPCR and the correlation among them was analyzed. In addition, Luciferase activity was used to detect whether miR-23b-3p combined with GAS5 and SIRT1 in OP mice BMSCs. RESULTS: We established the OVX rat model and found higher ROS level in BMSCs isolated from OVX rats. Meanwhile, GAS5 was down-regulated by ROS and remarkably lowly expressed in OVX rat comparing with the negative control. We confirmed GAS5 inhibited adipogenesis and promoted osteoporosis progression. Mechanically, GAS5 bound with miR-23b-3p and suppressed its biological function. We also identified that miR-23b-3p bound with Sirtuin 1 (SIRT1) and decreased its stability. Furthermore, SIRT1 suppressed ROS production in BMSCs, which in turn un-regulated GAS5 expression through ROS-GAS5 axis. CONCLUSION: We identified a negative feedback loop, ROS-GAS5-SIRT1, in osteoporosis progression. Our findings provided potential targets and biomarkers for osteoporosis prevention and treatment.


Assuntos
Células-Tronco Mesenquimais , MicroRNAs , Osteoporose , Animais , Feminino , Camundongos , Ratos , Adipogenia , Medula Óssea , Diferenciação Celular/fisiologia , Células Cultivadas , Retroalimentação , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/metabolismo , Osteogênese , Osteoporose/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo , Microtomografia por Raio-X
6.
Exp Gerontol ; 172: 112057, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36513214

RESUMO

Osteoporosis (OP) is a systemic bone degenerative disease characterized by low bone mass and deteriorated microarchitecture of bone tissue, causing high morbidity and mortality rates. Bone resorption by overactivated osteoclasts (OCs) is the main cause of osteoporosis. Glucuronomannan and its oligomers (Gs) and their sulfated derivatives (SGs) were previously prepared. The anti-osteoporosis activities of these glycans were evaluated. Firstly, we determined the viability of RAW264.7 by CCK-8 test. Nextly, we investigated the inhibitory effects of Gs and SGs on the differentiation of RAW264.7 cells into OCs using tartrate-resistant acid phosphatase (TRAP) staining, F-actin ring staining, qualitative reverse-transcription polymerase chain reaction(qRT-PCR) and western blotting. TRAP staining revealed that Gs significantly blocked RANKL-induced OC generation while SGs did not exhibit this ability. F-actin staining assays demonstrated that Gs inhibits RANKL-induced actin ring formation. qRT-PCR analyses indicated that Gs dose-dependently inhibited the expression of OCs marker genes including Trap, NFATc1, c-Fos, DC-Stamp and ATP60 during the differentiation process, while SGs did not suppress. Regarding the mechanism of Gs, it was found that Gs suppressed osteoclastogenesis via inhibiting the degradation of IRF-8 and interfering with NF-κB pathway activation. Together, these results suggest that Gs have the ability to inhibit osteoclastogenesis by modulating IRF-8 signaling.


Assuntos
Osteoporose , Sargassum , Actinas , Diferenciação Celular , NF-kappa B/metabolismo , Fatores de Transcrição NFATC , Oligossacarídeos/farmacologia , Osteoclastos , Osteogênese , Osteoporose/metabolismo , Sargassum/metabolismo , Animais , Camundongos
7.
Pharmacol Res ; 187: 106635, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36581167

RESUMO

Osteoporosis is a common metabolic bone disease that results from the imbalance of homeostasis within the bone. Intra-bone homeostasis is dependent on a precise dynamic balance between bone resorption by osteoclasts and bone formation by mesenchymal lineage osteoblasts, which comprises a series of complex and highly standardized steps. Programmed cell death (PCD) (e.g., apoptosis, autophagy, ferroptosis, pyroptosis, and necroptosis) is a cell death process that involves a cascade of gene expression events with tight structures. These events play a certain role in regulating bone metabolism by determining the fate of bone cells. Moreover, existing research has suggested that natural products derived from a wide variety of dietary components and medicinal plants modulate the PCDs based on different mechanisms, which show great potential for the prevention and treatment of osteoporosis, thus revealing the emergence of more acceptable complementary and alternative drugs with lower costs, fewer side effects and more long-term application. Accordingly, this review summarizes the common types of PCDs in the field of osteoporosis. Moreover, from the perspective of targeting PCDs, this review also discussed the roles of currently reported natural products in the treatment of osteoporosis and the involved mechanisms. Based on this, this review provides more insights into new molecular mechanisms of osteoporosis and provides a reference for developing more natural anti-osteoporosis drugs in the future.


Assuntos
Produtos Biológicos , Osteoporose , Plantas Medicinais , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Produtos Biológicos/química , Osteoporose/tratamento farmacológico , Osteoporose/metabolismo , Osteoclastos/metabolismo , Morte Celular
8.
Front Endocrinol (Lausanne) ; 13: 1032262, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36568088

RESUMO

Introduction: Sirtuin 1 (SIRT1) is a key player in aging and metabolism and regulates bone mass and architecture. Sexual dimorphism in skeletal effects of SIRT1 has been reported, with an unfavorable phenotype primarily in female mice. Methods: To investigate the mechanisms of gender differences in SIRT1 skeletal effect, we investigated femoral and vertebral cortical and cancellous bone in global Sirt1 haplo-insufficient 129/Sv mice aged 2,7,12 months lacking Sirt1 exons 5,6,7 (Sirt1+/Δ ) and their wild type (WT) counterparts. Results: In females, femoral bone mineral content, peak cortical thickness, and trabecular bone volume (BV/TV%), number and thickness were significantly lower in Sirt1+/Δ compared to WT mice. Increased femoral cortical porosity was observed in 7-month-old Sirt1+/Δ compared to WT female mice, accompanied by reduced biomechanical strength. No difference in vertebral indices was detected between Sirt1+/Δ and WT female mice. SIRT1 decreased with aging in WT female mice and was lower in vertebrae and femur in 18- and 30- versus 3-month-old 129/Sv and C57BL/6J female mice, respectively. Decreased bone estrogen receptor alpha (ERα) was observed in Sirt1+/Δ compared to WT female mice and was significantly higher in Sirt1 over-expressing C3HT101/2 murine mesenchymal stem cells. In males no difference in femoral indices was detected in Sirt1+/Δ versus WT mice, however vertebral BV/TV%, trabecular number and thickness were higher in Sirt1+/Δ vs. WT mice. No difference in androgen receptor (AR) was detected in bone in Sirt1+/Δ vs. WT male mice. Bone SIRT1 was significantly lower in male compared to female WT mice, suggesting that SIRT1 maybe more significant in female than male skeleton. Discussion: These findings demonstrate that 50% reduction in SIRT1 is sufficient to induce the hallmarks of skeletal aging namely, decreased cortical thickness and increased porosity in female mice, highlighting the role of SIRT1 as a regulator of cortical bone quantity and quality. The effects of SIRT1 in cortical bone are likely mediated in part by its regulation of ERα. The age-associated decline in bone SIRT1 positions SIRT1 as a potential therapeutic target to ameliorate age-related cortical bone deterioration in females. The crosstalk between ERα, AR and SIRT1 in the bone microenvironment remains to be further investigated.


Assuntos
Osso Cortical , Receptor alfa de Estrogênio , Osteoporose , Sirtuína 1 , Animais , Feminino , Masculino , Camundongos , Osso Cortical/metabolismo , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Camundongos Endogâmicos C57BL , Porosidade , Sirtuína 1/genética , Osteoporose/genética , Osteoporose/metabolismo
9.
Front Endocrinol (Lausanne) ; 13: 996244, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36568116

RESUMO

Objective: To explore the genetic causal association between osteoporosis (OP) and iron status through Mendelian randomization (MR). Methods: Publicly available genome-wide association study (GWAS) summary data were used for MR analysis with four iron status-related indicators (ferritin, iron, total iron binding capacity, and transferrin saturation) as exposures and three different types of OP (OP, OP with pathological fracture, and postmenopausal OP with pathological fracture) as outcomes. The inverse-variance weighted (IVW) method was used to analyze the genetic causal association between the four indicators of iron status and OP. The heterogeneity of MR results was determined using IVW and MR-Egger methods. The pleiotropy of MR results was determined using MR-Egger regression. A leave-one-SNP-out test was performed to determine whether the MR results were affected by a single nucleotide polymorphism (SNP). The weighted median method was conducted to further validate our results. Results: Based on IVW, MR-Egger and weighted median models, we found no causal association between iron status (ferritin, iron, total iron binding capacity, or transferrin saturation) and OP (Pbeta > 0.05 in all models). IVW and MR-Egger analysis of OP with pathological fracture and iron status indicators showed no potential genetic causal association (Pbeta> 0.05 in the two analyses). The results of the weighted median were consistent with those of IVW (Pbeta> 0.05 in all analyses). There was no potential genetic causal association between iron status and postmenopausal OP with pathological fracture based on serum iron (Pbeta>0.05 in all models). No heterogeneity or horizontal pleiotropy was found in any of the analyses. None of the leave-one-out tests in the analyses found any SNP that could affect the results of MR. Conclusion: Our results demonstrate that there is no genetic causal association between OP and iron status, but the effects of other factors were not excluded.


Assuntos
Fraturas Espontâneas , Ferro , Osteoporose , Humanos , Ferritinas , Fraturas Espontâneas/genética , Fraturas Espontâneas/metabolismo , Estudo de Associação Genômica Ampla , Ferro/efeitos adversos , Ferro/metabolismo , Análise da Randomização Mendeliana , Osteoporose/genética , Osteoporose/metabolismo , Transferrinas , Feminino , Osteoporose Pós-Menopausa/genética , Osteoporose Pós-Menopausa/metabolismo
10.
Cell Death Dis ; 13(11): 919, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36319624

RESUMO

Osteoporosis (OP) tends to occur in postmenopausal women, making them prone to fractures. N6-methyladenosine (m6A) methylation plays a crucial role in OP. Herein, we aimed to explore the effects of METTL14 on osteogenesis and the underlying mechanism. Osteogenic differentiation was assessed through osteoblast markers expression, cell proliferation, ALP activity, and mineralization, which were detected by qRT-PCR, CCK-8, EdU assay, ALP staining assay, and ARS staining assay, respectively. Osteoporosis was evaluated in OVX mice using qRT-PCR, microcomputed tomography, and H&E staining assay. The levels of METTL14 and SMAD1 were measured using qRT-PCR and western blot, and their interaction was assessed using RIP and luciferase reporter assay. M6A methylation was analyzed using the Me-RIP assay. The results indicated that m6A, METTL14, and SMAD1 levels were downregulated in patients with OP and OVX mice, and upregulated in osteogenic BMSCs. Knockdown of METTL14 suppressed osteogenesis of BMSCs and reduced bone mass of OVX mice. Moreover, silencing of METTL14 positively related to SMAD1 and inhibited m6A modification of SMAD1 by suppressing its stability. IGF2BP1 was identified as the methylation reader, and which knockdown reversed the upregulation induced by SMAD1. Overexpression of SMAD1 reversed the suppression of osteogenic differentiation induced by METTL14 knockdown. In conclusion, interference with METTL14 inhibited osteogenic differentiation of BSMCs by m6A modification of SMAD1 in an IGFBP1 manner, suggesting that METTL14 might be a novel approach for improving osteoporosis.


Assuntos
Células-Tronco Mesenquimais , MicroRNAs , Osteoporose Pós-Menopausa , Osteoporose , Animais , Feminino , Humanos , Camundongos , Diferenciação Celular , Células Cultivadas , Regulação para Baixo , Células-Tronco Mesenquimais/metabolismo , Metiltransferases/metabolismo , MicroRNAs/metabolismo , Osteogênese , Osteoporose/metabolismo , Proteína Smad1/metabolismo , Microtomografia por Raio-X
11.
Front Endocrinol (Lausanne) ; 13: 1012508, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36387862

RESUMO

Osteoarthritis (OA) is the most prevalent joint disease characterized by degradation of articular cartilage, inflammation, and changes in periarticular and subchondral bone of joints. Osteoporosis (OP) is another systemic skeletal disease characterized by low bone mass and bone mineral density (BMD) accompanied by microarchitectural deterioration in bone tissue and increased bone fragility and fracture risk. Both OA and OP are mainly affected on the elderly people. Recent studies have shown that osteopontin (OPN) plays a vital role in bone metabolism and homeostasis. OPN involves these biological activities through participating in the proliferation, migration, differentiation, and adhesion of several bone-related cells, including chondrocytes, synoviocytes, osteoclasts, osteoblasts, and marrow mesenchymal stem cells (MSCs). OPN has been demonstrated to be closely related to the occurrence and development of many bone-related diseases, such as OA and OP. This review summarizes the role of OPN in regulating inflammation activity and bone metabolism in OA and OP. Furthermore, some drugs that targeted OPN to treat OA and OP are also summarized in the review. However, the complex mechanism of OPN in regulating OA and OP is not fully elucidated, which drives us to explore the depth effect of OPN on these two bone diseases.


Assuntos
Cartilagem Articular , Osteoartrite , Osteoporose , Humanos , Idoso , Osteopontina/metabolismo , Osteoporose/etiologia , Osteoporose/metabolismo , Osteoartrite/complicações , Osteoartrite/metabolismo , Inflamação/metabolismo
12.
Oxid Med Cell Longev ; 2022: 5982014, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36388169

RESUMO

Dysregulation of osteoclast-osteoblast balance, resulting in abnormal bone remodeling, is responsible for postmenopausal osteoporosis (PMOP) or other secondary forms of osteoporosis. We demonstrated that dictamnine (DIC), a novel RANKL-targeted furoquinoline alkaloid, inhibits osteoclastogenesis by facilitating the activities of reactive oxygen species (ROS), NF-κB, and NFATc1 in vitro and prevents the development of OVX-induced osteoporosis mouse models in vivo. Methods. The docking mechanism of DIC and RANKL was initially identified by protein-ligand molecular docking. RNA sequencing was performed and analyzed to reveal the potential mechanism and signaling pathway of the antiosteoporosis effects of DIC. To verify the sequencing results, we examined the impact of DIC on RANKL-induced osteoclast differentiation, bone resorption, F-actin ring production, ROS generation, and NF-κB activation in osteoclasts in vitro. Moreover, a luciferase assay was performed to determine the binding and transcriptional activity of Nrf2 and NF-κB. The in vivo efficacy of DIC was assessed with an ovariectomy- (OVX-) induced osteoporosis model, which was analyzed using micro-CT and bone histomorphometry. Results. The molecular docking results indicated that DIC could bind particularly to RANKL. RNA-seq confirmed that DIC could regulate the osteoclast-related pathway. DIC suppressed osteoclastogenesis, bone resorption, F-actin belt formation, osteoclast-specific gene expression, and ROS activity by preventing NFATc1 expression and affecting NF-κB signaling pathways in vitro. The luciferase assay showed that DIC not only suppressed the activity of Nrf2 but also contributed to the combination of Nrf2 and NF-κB. Our in vivo study indicated that DIC protects against OVX-induced osteoporosis and preserves bone volume by inhibiting osteoclast activity and function. Conclusions. DIC can ameliorate osteoclast formation and OVX-induced osteoporosis and therefore is a potential therapeutic treatment for osteoporosis.


Assuntos
Alcaloides , Reabsorção Óssea , Osteoporose , Camundongos , Humanos , Animais , Feminino , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Actinas/metabolismo , Simulação de Acoplamento Molecular , Osteoporose/tratamento farmacológico , Osteoporose/metabolismo , Transdução de Sinais , Alcaloides/farmacologia , Dacarbazina/farmacologia , Dacarbazina/uso terapêutico
13.
Pharm Biol ; 60(1): 2219-2228, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36382865

RESUMO

CONTEXT: Isoorientin has many biological activities, including antioxidant, anti-inflammatory, antitumor. However, the effect of isoorientin on postmenopausal osteoporosis remains unclear. OBJECTIVE: To evaluate the effect of isoorientin on postmenopausal osteoporosis. MATERIALS AND METHODS: Sprague-Dawley rats were divided into five groups (n = 5): sham, model, 17-ß-oestradiol (E2, 10 µg/kg/day), low-dose isoorientin (L-Iso, 50 mg/kg), and high-dose isoorientin (H-Iso, 100 mg/kg). The rats were ovariectomized, treated by gavage daily for 12 weeks, and serum and femur samples were collected. Bone mineral density, bone metabolism, and oxidative stress were assessed. H&E staining, immunohistochemistry, and western blotting were employed. RESULTS: Isoorientin improved the bone mineral density of the lumbar vertebrae (2.01 ± 0.05 g/cm3 in H-Iso group vs. 1.74 ± 0.07 g/cm3 in model group) and femur (1.46 ± 0.06 g/cm3 vs. 1.19 ± 0.03 g/cm3), increased the trabecular bone number (1.97 ± 0.03 vs. 1.18 ± 0.13) and thickness (0.27 ± 0.02 vs. 0.16 ± 0.03 mm). Isoorientin decreased the separation degree of trabecular bone, ameliorated bone histomorphology changes, and significantly improved the mechanical properties. Isoorientin diminished MDA (by 60%) and increased SOD (by 49.2%), and GSH-Px (by 159%) activity. Furthermore, osteoprotegerin (OPG), nuclear factor erythroid 2-like 2 (Nrf2), haem oxygenase (HO-1), NAD(P)H quinone dehydrogenase 1(NQO1), and oestrogen receptor 1(ESR1) protein expression increased, while receptor activator of nuclear factor-κB ligand (RANKL) protein expression decreased after treatment. CONCLUSIONS: Isoorientin ameliorates osteoporosis via upregulating OPG and Nrf2/ARE signalling, suggesting isoorientin maybe a potential therapeutic drug for PMOP.


Assuntos
Osteoporose Pós-Menopausa , Osteoporose , Feminino , Humanos , Ratos , Animais , Osteoporose Pós-Menopausa/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Pós-Menopausa , Ratos Sprague-Dawley , Ovariectomia , Osteoprotegerina/metabolismo , Osteoprotegerina/farmacologia , Osteoporose/metabolismo , Ligante RANK/metabolismo , Ligante RANK/farmacologia , Densidade Óssea , Estresse Oxidativo
14.
Free Radic Biol Med ; 193(Pt 2): 595-609, 2022 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-36372285

RESUMO

NADPH oxidase 4 (Nox4) is the main source of reactive oxygen species, which promote osteoclast formation and lead to bone loss, thereby causing osteoporosis. However, the role of Nox4 in osteoblasts during early development remains unclear. We used zebrafish to study the effect of Nox4 deletion on bone mineralization in early development. nox4-/- zebrafish showed decreased bone mineralization during early development and significantly reduced numbers of osteoblasts, osteoclasts, and chondrocytes. Transcriptome sequencing showed that the TGF-ß signaling pathway was significantly disrupted in nox4-/- zebrafish. Inhibiting TGF-ß signaling rescued the abnormal bone development caused by nox4 deletion and increased the number of osteoblasts. We used Saos-2 human osteosarcoma cells to confirm our results, which clarified the role of Nox4 in human osteoblasts. Our results demonstrate the mechanism of reduced bone mineralization in early development and provide a basis for the clinical treatment of osteoporosis.


Assuntos
Osteoporose , Fator de Crescimento Transformador beta , Animais , Humanos , NADPH Oxidase 4/genética , NADPH Oxidase 4/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Osteoblastos/metabolismo , Transdução de Sinais , Osteoporose/metabolismo
15.
Int Immunopharmacol ; 113(Pt A): 109370, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36327872

RESUMO

As a common disease in modern society, osteoporosis is caused by osteoclast hyperactivation, leading to enhanced bone resorption. Reactive oxygen species (ROS) metobolism and nuclear factor-activated T cells 1 (NFATc1) activities are two crucial processes during osteoclastogenesis. AZD1390 (AZD), an inhibitor of ataxia telangiectasia mutated (ATM), has been reported for antitumor effects, but little is known about how it plays a function in metabolic bone disease. Here, we found that AZD inhibitsthe generation, function and ROS-scavenging enzyme activity of mature osteoclast induced by RANKL stimulation, in a dose-dependent manner.Mechanistic analysis shows thatAZD affects osteoclast function and differentiation by inhibiting RANKL-induced NFATc1 signaling pathway and by increasing ROS-scavenging enzymes production in oxidative stress pathways. Preclinical studies have shown that AZD protects against bone loss in an ovariectomy (OVX) mouse model. Finally, our data confirm that AZD may prevent OVX-induced bone loss by abrogating RANKL-induced AKT/GSK3ß/NFATc1 signaling pathways, and by promoting the expression of ROS scavenging enzymes in oxidative stress pathways.Collectively, our research shows that AZD has the potential as a new therapeutic agent for osteoporosis.


Assuntos
Reabsorção Óssea , Osteoporose , Camundongos , Animais , Feminino , Osteoclastos , Espécies Reativas de Oxigênio/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fatores de Transcrição NFI/metabolismo , Fatores de Transcrição NFI/farmacologia , Linfócitos T/metabolismo , Ligante RANK/metabolismo , Reabsorção Óssea/prevenção & controle , Osteoporose/metabolismo , Osteogênese , Diferenciação Celular , Fatores de Transcrição NFATC/metabolismo
16.
BMC Musculoskelet Disord ; 23(1): 1015, 2022 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-36434613

RESUMO

BACKGROUND: Nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial transcription factor for cellular redox homeostasis. The association of Nrf2 with elderly female osteoporotic has yet to be fully described. The aim was to elucidate a potential age-dependent Nrf2 contribution to female osteoporosis in mice. METHODS: Eighteen female wild type (WT) and 16 Nrf2-knockout (KO) mice were sacrificed at different ages (12 weeks = young mature adult and 90 weeks = old) to analyze their femurs. The morphological properties (trabecular and cortical) were evaluated by micro-computed tomography (µCT) and compared to gold standard histochemistry analysis. The quasi-static compression tests were performed to calculate the mechanical properties of bones. Additionally, the population of bone resorbing cells and aromatase expression by osteocytes was immunohistochemically evaluated and empty osteocyte lacunae was counted in cortical bone. RESULTS: Old Nrf2-KO mice revealed a significantly reduced trabecular bone mineral density (BMD), cortical thickness, cortical area, and bone fraction compared to old WT mice, regardless of no significant difference in skeletally mature young adult mice between WT and KO. Specifically, while all old WT mice showed thin metaphyseal trabeculae, trabecular bone was completely absent in 60% of old KO mice. Additionally, old KO mice showed significantly more osteoclast-like cells and fewer aromatase-positive osteocytes than WT mice, whereas the occurrence of empty osteocyte lacunae did not differ between both groups. Nrf2-KO mice further showed an age-dependently reduced fracture resilience compared to age-matched WT mice. CONCLUSION: Our results suggest that chronic Nrf2 loss can lead to age-dependent progression of female osteoporosis.


Assuntos
Fator 2 Relacionado a NF-E2 , Osteoporose , Feminino , Camundongos , Animais , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Aromatase , Microtomografia por Raio-X , Camundongos Endogâmicos C57BL , Osteoporose/diagnóstico por imagem , Osteoporose/genética , Osteoporose/metabolismo , Camundongos Knockout
17.
J Nutr Sci Vitaminol (Tokyo) ; 68(Supplement): S113-S115, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36436988

RESUMO

Bone health is an important medical concern in rapidly aging demographics worldwide. Excessive bone resorption, due to enhanced activity of osteoclasts, is a major underlying cause of bone disorders such as osteoporosis. Inflammation and oxidative stress are key factors contributing to increased osteoclastic activity. Like increased activity of osteoclasts, depletion of osteoblasts also contributes to weakened structural integrity of bone. Considering the epidemiology of bone disorders and aging demographics there is a substantial need for novel bone health therapeutics. IRW (Ile-Arg-Trp), an egg-derived tripeptide, exhibits a spectrum of pharmacological activity. In our recent work, we have shown that IRW inhibits osteoclastogenesis and promotes osteogenesis in the mouse macrophage RAW 264.7 and MC3T3-E1 cells. IRW treatment (25 and 50 µM) significantly inhibited osteoclastogenesis-associated factors [TRAF6 (TNF Receptor Associated Factor 6), Fos Proto-Oncogene (c-Fos), Nuclear Factor of Activated T Cells 1 (NFATc1), and cathepsin K] and upregulated osteogenesis-associated factors [RUNX2 (Runt-related transcription factor 2) and RANKL (Receptor activator of nuclear factor kappa-B ligand)] in the two cell lines. Currently, we are conducting studies to analyze the impact of IRW on Angiotensin II (Ang II)-induced stress in vitro and in vivo. In summary, our recent work presents the ability of IRW to prevent LPS-induced inflammatory bone resorption and activation of osteogenesis activity via multiple signaling pathways.


Assuntos
Reabsorção Óssea , Osteoporose , Camundongos , Animais , Osteoclastos/metabolismo , Osteoporose/prevenção & controle , Osteoporose/metabolismo , Reabsorção Óssea/prevenção & controle , Reabsorção Óssea/metabolismo , Suplementos Nutricionais
18.
Cells ; 11(22)2022 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-36429027

RESUMO

Osteoporosis is a systemic skeletal disorder where osteoclasts are prevalent among osteoblasts. Oxidative stress is one of the main causes of osteoporosis, and nuclear factor erythroid-2-related factor 2 (Nrf2) is the master regulator of antioxidant responses. Phytol, a diterpene isolated from Stevia rebaudiana leaves, has many biological effects, including antimicrobial, antioxidant, and anti-inflammatory effects. This study investigated the crosstalk between Nrf2 and osteoclast differentiation in the presence of phytol. Phytol inhibited osteoclast differentiation through TRAP-positive and F-actin formation. The expression of anti-nuclear factor of activated T cells-c1 (NFATc1) and c-Fos was suppressed by phytol, as shown using Western blot and RT-PCR analysis. Phytol inhibited oxidative stress by suppressing reactive oxidant species (ROS) accumulation while recovering antioxidant enzymes, including superoxide dismutase and catalase. Additionally, phytol ameliorated osteoclast-specific differentiation, function, and oxidative stress through Nrf2 regulation by siRNA transfection. In conclusion, these data demonstrate the inhibitory effect of phytol on osteoclast differentiation through Nrf2 regulation, suggesting its potential use in oxidative stress-related osteoporosis and bone diseases.


Assuntos
Fator 2 Relacionado a NF-E2 , Osteoporose , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Fator de Transcrição de Proteínas de Ligação GA/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Osteoclastos/metabolismo , Osteoporose/metabolismo , Estresse Oxidativo , Fitol/metabolismo , Fitol/farmacologia , Animais , Camundongos
19.
Medicina (Kaunas) ; 58(11)2022 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-36363523

RESUMO

Background and Objectives: The majority of research on the effects of osteoporosis drugs has measured the bone mineral density (BMD) of the spine and femur through dual-energy X-ray absorptiometry (DEXA) and compared and analyzed the effects of the drugs through changes in the BMD values. This study aims to compare osteoclast and sclerostin expression in osteocytes after risedronate therapy by obtaining femoral heads from patients with hip fractures. Materials and Methods: We obtained the femoral heads of 10 female patients (age: ≥65 years) who received risedronate therapy for at least 1 year through hip arthroplasty during 2019-2021 (risedronate group). Meanwhile, 10 patients who had never received osteoporosis treatment were selected as controls using propensity scores with age, body mass index, and bone density as covariates (control group). While the osteoclast count was evaluated using tartrate-resistant acid phosphatase (TRAP) staining, the sclerostin expression in osteocytes was assessed using immunohistochemistry. Moreover, Western blotting and polymerase chain reaction (PCR) were performed for receptor activation of nuclear factor kappa-Β ligand (RANKL), RANK, osteoprotegerin (OPG), sclerostin, and bone morphogenetic protein-2 (BMP2). Results: TRAP staining revealed significantly more TRAP-positive cells in the control group (131.75 ± 27.16/mm2) than in the risedronate group (28.00 ± 8.12/mm2). Moreover, sclerostin-positive osteocytes were expressed more in the control group (364.12 ± 28.12/mm2) than in the risedronate group (106.93 ± 12.85/mm2). Western blotting revealed that the expressions of RANKL, RANK, sclerostin, and BMP2 were higher in the control group than in the risedronate group (p < 0.05). Furthermore, RANK, sclerostin, and OPG protein levels were higher in the control group than in the risedronate group. Conclusions: In this study, the risedronate group demonstrated lower osteoclast activity and sclerostin expression in osteocytes in the femoral head than the control group.


Assuntos
Fraturas do Quadril , Osteoporose , Humanos , Feminino , Idoso , Osteócitos/metabolismo , Osteoclastos , Ácido Risedrônico/farmacologia , Ácido Risedrônico/uso terapêutico , Cabeça do Fêmur , Ligante RANK/metabolismo , Estudos Retrospectivos , Osteoporose/metabolismo , Densidade Óssea , Fraturas do Quadril/tratamento farmacológico
20.
Nutrients ; 14(19)2022 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-36235607

RESUMO

Trimethylamine-N-oxide (TMAO), an important gut microbiota (GM)-derived metabolite, has been shown to be abnormally increased in osteoporosis. However, the role and underlying mechanism of TMAO in regulating bone loss during osteoporosis have not been fully investigated. In the current study, we found that 100-400 µM TMAO dose-dependently enhanced TRAP-positive osteoclasts, F-actin ring formation, and resorption area on bovine bone slices and up-regulated osteoclast-related gene expression (Calcr, Traf6, Dcstamp, Acp5, C-Fos, and NFATc1). Western blotting validated that TMAO not only activated NF-κB signaling pathway but also stimulated c-Fos and NFATc1 protein expression in a dose-dependent manner. Furthermore, BAY 11-7082, an NF-κB inhibitor, pretreatment markedly suppressed TRAP-positive osteoclast formation and osteoclast-related genes under TMAO treatment. BAY 11-7082 also inhibited p-p65/p65, c-Fos, and NFATc1 protein expression promoted by TMAO. Moreover, TMAO significantly increased ROS production, which was inhibited by N-acetylcysteine (NAC), an ROS antagonist. In addition, we proved that NAC pretreatment could inhibit TMAO-promoted NF-κB activation. NAC also suppressed TRAP-positive osteoclast formation, osteoclast-related gene expression, and protein expression of c-Fos and NFATc1 under TMAO treatment. In vivo studies showed significantly decreased bone mass and increased TRAP-positive osteoclasts in TMAO-treated C57BL/6 mice. Moreover, western-blotting and immunohistochemical staining showed that TMAO administration markedly stimulated NF-κB p65 expression. Additionally, TMAO administration significantly promoted the gene and protein expression of C-Fos and NFATc1. In conclusion, TMAO could promote osteoclast differentiation and induce bone loss in mice by activating the ROS-dependent NF-κB signaling pathway.


Assuntos
Reabsorção Óssea , Osteoporose , Acetilcisteína/metabolismo , Actinas/metabolismo , Animais , Reabsorção Óssea/metabolismo , Bovinos , Diferenciação Celular , Metilaminas , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/metabolismo , Nitrilas , Osteoclastos/metabolismo , Osteogênese , Osteoporose/metabolismo , Óxidos/metabolismo , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ligante RANK/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Sulfonas , Fator 6 Associado a Receptor de TNF/metabolismo
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