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1.
Drug Des Devel Ther ; 18: 979-989, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38562519

RESUMO

As a continuous process comprising bone resorption and formation, bone remodeling, plays an essential role in maintaining the balance of bone metabolism. One type of metabolic osteopathy is osteoporosis, which is defined by low bone mass and deteriorating bone microstructure. Osteoporosis patients are more likely to experience frequent osteoporotic fractures, which makes osteoporosis prevention and treatment crucial. A growing body of research has revealed that exosomes, which are homogenous vesicles released by most cell types, play a major role in mediating a number of pathophysiological processes, including osteoporosis. Exosomes may act as a mediator in cell-to-cell communication and offer a fresh perspective on information sharing. This review discusses the characteristics of exosomes and outlines the exosomes' underlying mechanism that contributes to the onset of osteoporosis. Recent years have seen a rise in interest in the role of exosomes in osteoporosis, which has given rise to innovative therapeutic approaches for the disease prevention and management.


Assuntos
Exossomos , Osteoporose , Humanos , Exossomos/metabolismo , Osteoporose/tratamento farmacológico , Osteoporose/metabolismo , Osso e Ossos/metabolismo , Remodelação Óssea
2.
J Orthop Surg Res ; 19(1): 212, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38561786

RESUMO

BACKGROUND: Osteoporosis (OP) is the result of bone mass reduction and bone structure disorder. Bone marrow mesenchymal stem cells (BMSCs) are the main source of osteogenic precursor cells involved in adult bone remodeling. The involvement of the deubiquitinating enzyme CYLD in OP has recently been discovered. However, the detailed role and mechanism of CYLD remain unknown. METHODS: The OP mouse model was established by performing ovariectomy (OVX) on mice. Hematoxylin and eosin staining, Masson and Immunohistochemical staining were used to assess pathologic changes. Real-time quantitative PCR, Western blot, and immunofluorescence were employed to assess the expression levels of CYLD, WNK1, NLRP3 and osteogenesis-related molecules. The binding relationship between CYLD and WNK1 was validated through a co-immunoprecipitation assay. The osteogenic capacity of BMSCs was determined using Alkaline phosphatase (ALP) and alizarin red staining (ARS). Protein ubiquitination was evaluated by a ubiquitination assay. RESULTS: The levels of both CYLD and WNK1 were decreased in bone tissues and BMSCs of OVX mice. Overexpression of CYLD or WNK1 induced osteogenic differentiation in BMSCs. Additionally, NLRP3 inflammation was activated in OVX mice, but its activation was attenuated upon overexpression of CYLD or WNK1. CYLD was observed to reduce the ubiquitination of WNK1, thereby enhancing its protein stability and leading to the inactivation of NLRP3 inflammation. However, the protective effects of CYLD on osteogenic differentiation and NLRP3 inflammation inactivation were diminished upon silencing of WNK1. CONCLUSION: CYLD mitigates NLRP3 inflammasome-triggered pyroptosis in osteoporosis through its deubiquitination of WNK1.


Assuntos
Doenças Ósseas , Osteoporose , Animais , Feminino , Camundongos , Diferenciação Celular , Células Cultivadas , Enzima Desubiquitinante CYLD , Inflamassomos , Inflamação , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Osteogênese , Osteoporose/metabolismo , Piroptose
3.
Zool Res ; 45(2): 367-380, 2024 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-38485506

RESUMO

Osteoporosis is a prevalent metabolic bone disease. While drug therapy is essential to prevent bone loss in osteoporotic patients, current treatments are limited by side effects and high costs, necessitating the development of more effective and safer targeted therapies. Utilizing a zebrafish ( Danio rerio) larval model of osteoporosis, we explored the influence of the metabolite spermine on bone homeostasis. Results showed that spermine exhibited dual activity in osteoporotic zebrafish larvae by increasing bone formation and decreasing bone resorption. Spermine not only demonstrated excellent biosafety but also mitigated prednisolone-induced embryonic neurotoxicity and cardiotoxicity. Notably, spermine showcased protective attributes in the nervous systems of both zebrafish embryos and larvae. At the molecular level, Rac1 was identified as playing a pivotal role in mediating the anti-osteoporotic effects of spermine, with P53 potentially acting downstream of Rac1. These findings were confirmed using mouse ( Mus musculus) models, in which spermine not only ameliorated osteoporosis but also promoted bone formation and mineralization under healthy conditions, suggesting strong potential as a bone-strengthening agent. This study underscores the beneficial role of spermine in osteoporotic bone homeostasis and skeletal system development, highlighting pivotal molecular mediators. Given their efficacy and safety, human endogenous metabolites like spermine are promising candidates for new anti-osteoporotic drug development and daily bone-fortifying agents.


Assuntos
Osteoporose , Doenças dos Roedores , Humanos , Camundongos , Animais , Peixe-Zebra , Espermina/uso terapêutico , Osteoporose/tratamento farmacológico , Osteoporose/metabolismo , Osteoporose/prevenção & controle , Osteoporose/veterinária , Prednisolona/efeitos adversos , Glucocorticoides , Doenças dos Roedores/induzido quimicamente , Doenças dos Roedores/tratamento farmacológico
4.
Life Sci ; 345: 122592, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38554947

RESUMO

Osteoporosis, characterized by bone metabolism disruption leading to gradual bone loss and increased fracture susceptibility, is linked to the excessive activation of osteoclasts. Pseudolaric acid B (PAB), identified as an NF-κB signaling inhibitor crucial for osteoclastogenesis, is explored here for its protective effects in osteoporosis. Noncytotoxic PAB's impact on osteoclast differentiation was assessed through cell viability and osteoclast formation assays, with subsequent testing of osteoclast function via bone resorption assays. Quantitative real-time polymerase chain reaction evaluated PAB's genetic-level impact on osteoclastogenesis. Network pharmacology, western blot, and luciferase reporter gene assays were employed to elucidate PAB's regulatory mechanism. In an in vivo model of osteoporosis induced by ovariectomy (OVX) in mice, micro-CT, H&E staining, and TRAP staining facilitated histomorphometry analysis, while flow cytometry verified macrophage polarization. PAB demonstrated inhibitory effects on osteoclast formation and bone resorption in BMM and RAW264.7 cells, suppressing osteoclast-specific genes. Bioinformatic analysis, western blot, and luciferase assay results indicated PAB's inhibition of IκBα phosphorylation in the NF-κB signaling pathway and ERK in MAPKs, elucidating its mechanism. In vivo experiments confirmed PAB's attenuation of osteoporosis by reducing osteoclast formation in OVX mice. PAB further facilitated macrophage conversion from M1 to M2 and suppressed IL-1ß, TNF-α, and IL-6 synthesis. In conclusion, PAB prevents osteoporosis by inhibiting RANKL-induced osteoclastogenesis through NF-κB and ERK signaling pathway suppression, coupled with macrophage polarization. These findings indicate the potential therapeutic role of PAB in osteoporosis.


Assuntos
Reabsorção Óssea , Diterpenos , Osteoporose , Feminino , Camundongos , Animais , Humanos , Osteoclastos , NF-kappa B/metabolismo , Diferenciação Celular , Transdução de Sinais , Macrófagos/metabolismo , Reabsorção Óssea/metabolismo , Osteogênese , Osteoporose/metabolismo , Luciferases/metabolismo , Ligante RANK/metabolismo , Ovariectomia
5.
Front Endocrinol (Lausanne) ; 15: 1323647, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38481438

RESUMO

Purpose: Metabolic and immune changes in the early stages of osteoporosis are not well understood. This study aimed to explore the changes in bone metabolites and bone marrow lymphocyte subsets and their relationship during the osteoporosis onset. Methods: We established OVX and Sham mouse models. After 5, 15, and 40 days, five mice in each group were sacrificed. Humeri were analyzed by microCT. The bone marrow cells of the left femur and tibia were collected for flow cytometry analysis. The right femur and tibia were analyzed by LC-MS/MS for metabolomics analysis. Results: Bone microarchitecture was significantly deteriorated 15 days after OVX surgery. Analysis of bone metabolomics showed that obvious metabolite changes had happened since 5 days after surgery. Lipid metabolism was significant at the early stage of the osteoporosis. The proportion of immature B cells was increased, whereas the proportion of mature B cells was decreased in the OVX group. Metabolites were significantly correlated with the proportion of lymphocyte subsets at the early stage of the osteoporosis. Conclusion: Lipid metabolism was significant at the early stage of the osteoporosis. Bone metabolites may influence bone formation by interfering with bone marrow lymphocyte subsets.


Assuntos
Osteoporose Pós-Menopausa , Osteoporose , Humanos , Feminino , Camundongos , Animais , Osteoporose Pós-Menopausa/etiologia , Osteoporose Pós-Menopausa/metabolismo , Cromatografia Líquida , Espectrometria de Massas em Tandem , Osteoporose/etiologia , Osteoporose/metabolismo , Modelos Animais de Doenças , Subpopulações de Linfócitos/metabolismo
6.
Front Immunol ; 15: 1333086, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38504994

RESUMO

Osteoporosis is a common chronic metabolic bone disorder. Recently, increasing numbers of studies have demonstrated that Toll-like receptor 4 (TLR4, a receptor located on the surface of osteoclasts and osteoblasts) plays a pivotal role in the development of osteoporosis. Herein, we performed a comprehensive review to summarize the findings from the relevant studies within this topic. Clinical data showed that TLR4 polymorphisms and aberrant TLR4 expression have been associated with the clinical significance of osteoporosis. Mechanistically, dysregulation of osteoblasts and osteoclasts induced by abnormal expression of TLR4 is the main molecular mechanism underlying the pathological processes of osteoporosis, which may be associated with the interactions between TLR4 and NF-κB pathway, proinflammatory effects, ncRNAs, and RUNX2. In vivo and in vitro studies demonstrate that many promising substances or agents (i.e., methionine, dioscin, miR-1906 mimic, artesunate, AEG-1 deletion, patchouli alcohol, and Bacteroides vulgatus) have been able to improve bone metabolism (i.e., inhibits bone resorption and promotes bone formation), which may partially attribute to the inhibition of TLR4 expression. The present review highlights the important role of TLR4 in the clinical significance and the pathogenesis of osteoporosis from the aspects of inflammation and immunity. Future therapeutic strategies targeting TLR4 may provide a new insight for osteoporosis treatment.


Assuntos
Osteoporose , Receptor 4 Toll-Like , Humanos , Receptor 4 Toll-Like/metabolismo , Osteoclastos/metabolismo , Remodelação Óssea , Osteoporose/metabolismo , Inflamação/metabolismo
7.
J Agric Food Chem ; 72(14): 8149-8166, 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38551844

RESUMO

Declining estrogen production in postmenopausal females causes osteoporosis in which the resorption of bone exceeds the increase in bone formation. Although clinical drugs are currently available for the treatment of osteoporosis, sustained medication use is accompanied by serious side effects. Corydalis bungeana Herba, a famous traditional Chinese herb listed in the Chinese Pharmacopoeia Commission, constitutes various traditional Chinese Medicine prescriptions, which date back to thousands of years. One of the primary active components of C. bungeana Turcz. is Corynoline (Cor), a plant isoquinoline alkaloid derived from the Corydalis species, which possesses bone metabolism disease therapeutic potential. The study aimed at exploring the effects as well as mechanisms of Cor on osteoclast formation and bone resorption. TRAcP staining, F-actin belt formation, and pit formation were employed for assessing the osteoclast function. Western blot, qPCR, network pharmacology, and docking analyses were used for analyzing the expression of osteoclast-associated genes and related signaling pathways. The study focused on investigating how Cor affected OVX-induced trabecular bone loss by using a mouse model. Cor could weaken osteoclast formation and function by affecting the biological receptor activators of NF-κB and its ligand at various concentrations. Mechanistically, Cor inhibited the NF-κB activation, and the MAPKs pathway stimulated by RANKL. Besides, Cor enhanced the protein stability of the Nrf2, which effectively abolished the RANKL-stimulated ROS generation. According to an OVX mouse model, Cor functions in restoring bone mass, improving microarchitecture, and reducing the ROS levels in the distal femurs, which corroborated with its in vitro antiosteoclastogenic effect. The present study indicates that Cor may restrain osteoclast formation and bone loss by modulating NF-κB/MAPKs and Nrf2 signaling pathways. Cor was shown to be a potential drug candidate that can be utilized for the treatment of osteoporosis.


Assuntos
Alcaloides de Berberina , Reabsorção Óssea , Osteoporose , Feminino , Humanos , Osteogênese , NF-kappa B/genética , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais , Osteoclastos , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/genética , Reabsorção Óssea/metabolismo , Osteoporose/tratamento farmacológico , Osteoporose/genética , Osteoporose/metabolismo , Ligante RANK/genética , Ligante RANK/metabolismo , Diferenciação Celular
8.
J Pharm Biomed Anal ; 243: 116104, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38513501

RESUMO

Osteoporosis is a metabolic bone disease closely associated with oxidative stress. We had previously confirmed that the Viscozyme-assisted polysaccharide from Portulaca oleracea L (VPOP1) protects against antioxidant stress and evaluated the structure of VPOP1. In this study, we aimed to explore the anti-osteoporotic effects of VPOP1 on H2O2-induced osteoblast apoptosis. In addition, untargeted zebrafish metabolomics based on UPLC-Q-Orbitrap-HRMS was used to investigate the potential anti-osteoporotic mechanisms of VPOP1. The levels of Bcl-2 decreased significantly and those of caspase-3, Bax, and cytochrome C increased after treatment with H2O2. VPOP1 inhibited apoptosis in H2O2-induced MC3T3 cells. Metabolomic analyses showed that 28 potential biomarkers were gradually restored to normal levels after treatment with VPOP1 compared with that in the model group. Among them, leukotrienes D4 and A4, L-dopa, and L-tyrosine are important biomarkers and therapeutic targets. Pathway analysis revealed that arachidonic acid, tyrosine, phenylalanine, and sphingolipid metabolism were the major intervening pathways. Collectively, these results help us understand the protective activity of large molecular weight compounds, such as VPOP1, against osteoporosis.


Assuntos
Osteoporose , Portulaca , Animais , Portulaca/química , Farmacologia em Rede , Peixe-Zebra , Peróxido de Hidrogênio , Osteoporose/tratamento farmacológico , Osteoporose/metabolismo , Biomarcadores
9.
J Med Food ; 27(4): 287-300, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38442325

RESUMO

Secondary osteoporosis is frequently due to the use of high-dose glucocorticoids (GCs). The existing strategy for managing glucocorticoid-induced osteoporosis (GIOP) is considered insufficient and remains in a state of ongoing evolution. Therefore, it is crucial to develop more precise and effective agents for the treatment of GIOP. The constituents of Reynoutria multiflora (Thunb.) Moldenke, specifically Polygonum multiflorum (PM) Thunb, have previously shown promise in mitigating osteopenia. This study aimed to investigate the therapeutic effects of an ethanolic PM extract (PMR30) against GIOP in male rats. Prednisone (6 mg/kg/day, GC) was continuously administered to rats to induce GIOP, and they were subjected to treatment with or without ethanolic PMR30 for a duration of 120 days. Serum was collected for biochemical marker analysis. Bone histomorphometric, histological, and TUNEL analyses were performed on tibia samples. The protein expressions of LC3, Agt5, and Beclin 1 in the femur underwent examination through western blotting. Prolonged and excessive GC treatment significantly impeded bone formation, concomitant with reduced bone mass and body weight. It also suppressed OCN and OPG/RANKL in serum, and decreased Beclin 1 and LC3 in bone. Simultaneously, there was an elevation in bone resorption markers and apoptosis. Treatments with both high dose and low dose of PMR30 alleviated GIOP, stimulated bone formation, and upregulated OCN and OPG/RANKL, while suppressing TRACP-5b, CTX-I, and apoptosis. The impact of PMR30 possibly involves the enhancement of autophagy proteins (LC3, Agt5, and Beclin 1) and the inhibition of apoptosis within the bone. PMR30 holds promise as a prospective therapeutic agent for preventing and treating GIOP.


Assuntos
Fallopia multiflora , Osteoporose , Ratos , Masculino , Animais , Glucocorticoides/efeitos adversos , Reynoutria , Proteína Beclina-1 , Osteoporose/induzido quimicamente , Osteoporose/tratamento farmacológico , Osteoporose/metabolismo
10.
Food Chem ; 446: 138763, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38428077

RESUMO

Calcium deficiency is prone to fractures, osteoporosis and other symptoms. In this study, sheep bone protein hydrolysates (SBPHs) were obtained by protease hydrolysis. A low-calcium-diet-induced calcium-deficiency rat model was established to investigate the effects of SBPHs on calcium absorption and intestinal flora composition. The results showed that an SBPHs + CaCl2 treatment significantly increased the bone calcium content, bone mineral density, trabecular bone volume, and trabecular thickness, and reduced trabecular separation, and changed the level of bone turnover markers (P < 0.05). Supplementation of SBPHs + CaCl2 can remarkably enhance the bone mechanical strength, and the microstructure of bone was improved, and the trabecular network was more continuous, complete, and thicker. Additionally, SBPHs + CaCl2 dietary increased the abundance of Firmicutes and reduced the abundance of Proteobacteria and Verrucomicrobiota, and promoted the production of short chain fatty acids. This study indicated that SBPHs promoted calcium absorption and could be applied to alleviate osteoporosis.


Assuntos
Cálcio , Osteoporose , Ratos , Animais , Ovinos , Cálcio/metabolismo , Hidrolisados de Proteína/farmacologia , Cloreto de Cálcio/farmacologia , Cálcio da Dieta , Densidade Óssea , Osteoporose/metabolismo , Dieta
11.
Eur J Endocrinol ; 190(3): K27-K31, 2024 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-38430550

RESUMO

BACKGROUND: Osteoporosis (OP) is a pathology characterized by bone fragility affecting 30% of postmenopausal women, mainly due to estrogen deprivation and increased oxidative stress. An autophagy involvement is suspected in OP pathogenesis but a definitive proof in humans remains to be obtained. METHODS: Postmenopausal women hospitalized for femoral neck fracture (OP group) or total hip replacement (Control group) were enrolled using very strict exclusion criteria. Western blot was used to analyze autophagy level. RESULTS: The protein expression level of the autophagosome marker LC3-II was significantly decreased in bone of OP patients relative to the control group. In addition, the protein expression of the hormonally upregulated neu-associated kinase (HUNK), which is upregulated by female hormones and promotes autophagy, was also significantly reduced in bone of the OP group. CONCLUSIONS: These results demonstrate for the first time that postmenopausal OP patients have a deficit in bone autophagy level and suggest that HUNK could be the factor linking estrogen loss and autophagy decline. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT03175874, 2/6/2017.


Assuntos
Fraturas do Quadril , Osteoporose , Humanos , Feminino , Densidade Óssea , Fraturas do Quadril/patologia , Osteoporose/metabolismo , Autofagia , Estrogênios
12.
Mol Biol Rep ; 51(1): 398, 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38453825

RESUMO

The worldwide trend toward an aging population has resulted in a higher incidence of chronic conditions, such as osteoporosis. Osteoporosis, a prevalent skeletal disorder characterized by decreased bone mass and increased fracture risk, encompasses primary and secondary forms, each with distinct etiologies. Mechanistically, osteoporosis involves an imbalance between bone resorption by osteoclasts and bone formation by osteoblasts. Current pharmacological interventions for osteoporosis, such as bisphosphonates, denosumab, and teriparatide, aim to modulate bone turnover and preserve bone density. Hormone replacement therapy and lifestyle modifications are also recommended to manage the condition. While current medications offer therapeutic options, they are not devoid of limitations. Recent studies have highlighted the importance of epigenetic mechanisms, including DNA methylation and histone modifications, in regulating gene expression during bone remodeling. The use of epigenetic drugs, or epidrugs, to target these mechanisms offers a promising avenue for therapeutic intervention in osteoporosis. In this review, we comprehensively examine the recent advancements in the application of epidrugs for treating osteoporosis.


Assuntos
Conservadores da Densidade Óssea , Fraturas Ósseas , Osteoporose , Humanos , Idoso , Osteoporose/tratamento farmacológico , Osteoporose/genética , Osteoporose/metabolismo , Densidade Óssea , Fraturas Ósseas/genética , Epigênese Genética
13.
Sci Rep ; 14(1): 7042, 2024 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-38528074

RESUMO

In China, traditional medications for osteoporosis have significant side effects, low compliance, and high costs, making it urgent to explore new treatment options. Probiotics have demonstrated superiority in the treatment of various chronic diseases, and the reduction of bone mass in postmenopausal osteoporosis (PMOP) is closely related to the degradation and metabolism of intestinal probiotics. It is crucial to explore the role and molecular mechanisms of probiotics in alleviating PMOP through their metabolites, as well as their therapeutic effects. We aim to identify key probiotics and their metabolites that affect bone loss in PMOP through 16srDNA sequencing combined with non-targeted metabolomics sequencing, and explore the impact and possible mechanisms of key probiotics and their metabolites on the progression of PMOP in the context of osteoporosis caused by estrogen deficiency. The sequencing results showed a significant decrease in Lactobacillus acidophilus and butyrate in PMOP patients. In vivo experiments confirmed that the intervention of L. acidophilus and butyrate significantly inhibited osteoclast formation and bone resorption activity, improved intestinal barrier permeability, suppressed B cells, and the production of RANKL on B cells, effectively reduced systemic bone loss induced by oophorectomy, with butyric acid levels regulated by L. acidophilus. Consistently, in vitro experiments have confirmed that butyrate can directly inhibit the formation of osteoclasts and bone resorption activity. The above research results indicate that there are various pathways through which L. acidophilus inhibits osteoclast formation and bone resorption activity through butyrate. Intervention with L. acidophilus may be a safe and promising treatment strategy for osteoclast related bone diseases, such as PMOP.


Assuntos
Reabsorção Óssea , Osteoporose Pós-Menopausa , Osteoporose , Probióticos , Feminino , Humanos , Osteoclastos/metabolismo , Osteoporose Pós-Menopausa/etiologia , Lactobacillus acidophilus , Butiratos/metabolismo , Osteoporose/metabolismo , Reabsorção Óssea/metabolismo , Probióticos/farmacologia , Probióticos/uso terapêutico , Diferenciação Celular , Ovariectomia/efeitos adversos
14.
Lipids Health Dis ; 23(1): 88, 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38528544

RESUMO

The accumulation of reactive oxygen species (ROS) within the bone marrow microenvironment leads to diminished osteogenic differentiation and heightened lipogenic differentiation of mesenchymal stem cells residing in the bone marrow, ultimately playing a role in the development of osteoporosis (OP). Mitigating ROS levels is a promising approach to counteracting OP. In this study, a nanozyme composed of magnesium-based zeolitic imidazolate frameworks (Mg-ZIF) was engineered to effectively scavenge ROS and alleviate OP. The results of this study indicate that Mg-ZIF exhibits significant potential in scavenging ROS and effectively promoting osteogenic differentiation of bone mesenchymal stem cells (BMSCs). Additionally, Mg-ZIF was found to inhibit the differentiation of BMSCs into adipose cells. In vivo experiments further confirmed the ability of Mg-ZIF to mitigate OP by reducing ROS levels. Mechanistically, Mg-ZIF enhances the differentiation of BMSCs into osteoblasts by upregulating lipid metabolic pathways through ROS scavenging. The results indicate that Mg-ZIF has potential as an effective therapeutic approach for the treatment of osteoporosis.


Assuntos
Células-Tronco Mesenquimais , Osteoporose , Humanos , Osteogênese/genética , Magnésio , Metabolismo dos Lipídeos/genética , Espécies Reativas de Oxigênio/metabolismo , Células Cultivadas , Diferenciação Celular , Osteoporose/tratamento farmacológico , Osteoporose/genética , Osteoporose/metabolismo , Células da Medula Óssea
15.
Biomed Pharmacother ; 173: 116364, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38447449

RESUMO

This study was to investigate the potential mechanisms of treatment with metformin (Met) combined with kaempferol (Kae) against postmenopausal osteoporosis. Experiments were conducted in both ovariectomy (OVX)-induced osteoporosis rats and in vitro using RAW264.7 cells, MC3T3-E1 cells, and HUVECs. Results demonstrated the therapeutic effect of Met combined with Kae on osteoporosis. In vivo, Kae alone and in combination with Met treatments enhanced tibial trabecular microstructure, bone mineral density (BMD), and mechanical properties in OVX rats without causing hepatotoxicity and nephrotoxicity. It also reduced bone resorption markers (CTX-1 and TRAP) and increased the bone formation marker (PINP) level in the serum of OVX rats. The expression of bone resorption marker TRAP was reduced, while bone formation markers Runx2 and ALP were enhanced in the bone tissue of OVX rats. Furthermore, Met combined with Kae also promoted the expression of angiogenesis-related markers CD31 and VEGF in OVX rats. In vitro, MC3T3-E1s cells treated with Met combined with Kae showed higher expression of ALP, Runx2, and VEGF. Interestingly, the treatment did not directly promote HUVECs migration and angiogenesis, but enhanced osteoblast-mediated angiogenesis by upregulating VEGF levels. Additionally, Met combined with Kae treatment promoted VEGF secretion in MC3T3-E1, and activated the Notch intracelluar pathway by upregulating HES1 and HEY1 in HUVECs. Meantime, their stimulation on CD31 expression were inhibited by DAPT, a Notch signaling inhibitor. Overall, this study demonstrates the positive effects of Met combined with Kae on osteoporotic rats by promoting osteogenesis-angiogenesis coupling, suggesting their potential application in postmenopausal osteoporosis.


Assuntos
Reabsorção Óssea , Osteoporose Pós-Menopausa , Osteoporose , Feminino , Humanos , Ratos , Animais , Osteogênese , Osteoporose Pós-Menopausa/tratamento farmacológico , Subunidade alfa 1 de Fator de Ligação ao Core , Fator A de Crescimento do Endotélio Vascular/farmacologia , Quempferóis/farmacologia , Quempferóis/uso terapêutico , 60489 , Osso e Ossos/metabolismo , Osteoporose/tratamento farmacológico , Osteoporose/prevenção & controle , Osteoporose/metabolismo , Reabsorção Óssea/tratamento farmacológico , Ovariectomia
16.
Biomed Pharmacother ; 173: 116422, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38471268

RESUMO

Osteoporosis, characterized by low bone mass and bone microarchitecture breakdown, has become a growing public health problem. The increase in oxidative stress could lead to an imbalance between osteoblasts-mediated osteogenesis and osteoclast-mediated bone resorption, which gives rise to osteoporosis. Nrf2 is a master transcription factor that regulates oxidative stress and has recently been reported to take part in the development of osteoporosis. Icariin, a leading active flavonoid in herbal Epimedium pubescens, has significant antioxidant activity in and is widely applied for treating bone diseases. In this study, we aimed to explore the effect of icariin on osteoclastogenesis and its potential mechanism from the perspective of oxidative stress inhibition, using ovariectomized (OVX) rats and RANKL-induced RAW264.7 cells. Our results demonstrated that icariin-treated OVX rats exhibited higher bone density, fewer tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts, and lower ROS levels in bone tissues than vehicle-treated OVX rats. Also, icariin suppressed osteoclast differentiation and inhibited the expression of osteoclastogenesis-related genes, such as NFATc1, Ctsk, Trap, and c-Fos, in RANKL-induced RAW264.7 cells. Icariin also reduced intracellular ROS levels by increasing the expression of nuclear Nrf2 and HO-1. Further mechanistic studies showed icariin inhibited Cullin 3 expression and could delay Nrf2 degradation by reducing the ubiquitination of endogenous Nrf2 in RANKL-stimulated RAW264.7 cells, and these effects were markedly reversed by cullin three overexpression. These findings suggest icariin alleviated osteoporosis by suppressing osteoclastogenesis via targeting the Cullin 3/Nrf2/OH signaling pathway. Our study implied that icariin may be a potential candidate to treat osteoporosis.


Assuntos
Osteoclastos , Osteoporose , Ratos , Animais , Proteínas Culina/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Diferenciação Celular , Osteoporose/tratamento farmacológico , Osteoporose/metabolismo , Osteogênese , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Flavonoides/metabolismo , Ligante RANK/metabolismo , Fatores de Transcrição NFATC/metabolismo , NF-kappa B/metabolismo
17.
Int J Mol Sci ; 25(6)2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38542323

RESUMO

As the global population ages, the number of patients with osteoporosis is rapidly rising. The existing first-line clinical drugs are bone resorption inhibitors that have difficulty restoring the bone mass of elderly patients to the safe range. The range and period of use of existing peptides and monoclonal antibodies are limited, and small-molecule bone formation-promoting drugs are urgently required. We established an I-9 synthesis route with high yield, simple operation, and low cost that was suitable for future large-scale production. I-9 administration promoted bone formation and increased bone mass in mice with low bone mass in an aged C57 mouse model. Our findings revealed a hitherto undescribed pathway involving the BMP2-ERK-ATF4 axis that promotes osteoblast differentiation; I-9 has favorable biosafety in mice. This study systematically investigated the efficacy, safety, and mechanism of I-9 for treating osteoporosis and positions this drug for preclinical research in the future. Thus, this study has promoted the development of small-molecule bone-promoting drugs.


Assuntos
Conservadores da Densidade Óssea , Osteoporose , Idoso , Camundongos , Humanos , Animais , Osteogênese , Preparações Farmacêuticas/metabolismo , Osteoporose/tratamento farmacológico , Osteoporose/metabolismo , Conservadores da Densidade Óssea/uso terapêutico , Peptídeos/metabolismo , Diferenciação Celular , Osteoblastos/metabolismo , Fator 4 Ativador da Transcrição/metabolismo , Proteína Morfogenética Óssea 2/metabolismo
18.
Aging (Albany NY) ; 16(5): 4832-4840, 2024 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-38461437

RESUMO

Osteoporosis is a usual bone disease in aging populations, principally in postmenopausal women. Anti-resorptive and anabolic drugs have been applied to prevent and cure osteoporosis and are associated to a different of adverse effects. Du-Zhong is usually applied in Traditional Chinese Medicine to strengthen bone, regulate bone metabolism, and treat osteoporosis. Chlorogenic acid is a major polyphenol in Du-Zhong. In the current study, chlorogenic acid was found to enhance osteoblast proliferation and differentiation. Chlorogenic acid also inhibits the RANKL-induced osteoclastogenesis. Notably, ovariectomy significantly decreased bone volume and mechanical properties in the ovariectomized (OVX) rats. Administration of chlorogenic acid antagonized OVX-induced bone loss. Taken together, chlorogenic acid seems to be a hopeful molecule for the development of novel anti-osteoporosis treatment.


Assuntos
Osteoclastos , Osteoporose , Humanos , Ratos , Feminino , Animais , Ácido Clorogênico/farmacologia , Ácido Clorogênico/uso terapêutico , Ácido Clorogênico/metabolismo , Osteogênese , Osteoporose/metabolismo , Osteoblastos/metabolismo , Diferenciação Celular
19.
Molecules ; 29(5)2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38474436

RESUMO

Diabetic osteoporosis (DOP) is an abnormal metabolic disease caused by long-term hyperglycemia. In this study, a model rat of streptozotocin (STZ)-induced diabetes was established, and chromium picolinate (5 mg·kg-1) was given; the changes in blood glucose and body weight were detected before and after administration; and bone mineral density (BMD), bone morphology, bone turnover markers, inflammatory cytokines, and oxidative stress indicators were observed in each group. We found that after chromium picolinate (CP) intervention for 8 weeks, the blood glucose level was decreased; the BMD, the bone histomorphology parameters, and the pathological structure were improved; the expression of bone resorption-related proteins was downregulated; and the expression of bone formation-related proteins was upregulated. Meanwhile, serum antioxidant activity was increased, and inflammatory cytokine levels were decreased. In conclusion, CP could alleviate DOP by anti-oxidation, inhibition of bone turnover, anti-inflammation, and regulation of the OPG/RANKL/RANK signaling pathway. Therefore, CP has important application values for further development as a functional food or active medicine in DOP treatment.


Assuntos
Doenças Ósseas Metabólicas , Diabetes Mellitus Experimental , Osteoporose , Ácidos Picolínicos , Ratos , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/metabolismo , Densidade Óssea , Osteoporose/metabolismo , Ligante RANK
20.
J Orthop Surg Res ; 19(1): 179, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38468352

RESUMO

BACKGROUND: Cholesterol (CHO) is an essential component of the body. However, high CHO levels in the body can damage bone mass and promote osteoporosis. CHO accumulation can cause osteoblast apoptosis, which has a negative effect on bone formation. The pathogenesis of osteoporosis is a complicate process that includes oxidative stress, endoplasmic reticulum (ER) stress, and inflammation. Geniposide (GEN) is a natural compound with anti-osteoporotic effect. However, the roles of GEN in osteopathogenesis are still unclear. Our previous studies demonstrated that GEN could reduce the accumulation of CHO in osteoblasts and the activation of ER stress in osteoblasts. However, the molecular mechanism of GEN in inhibiting CHO-induced apoptosis in osteoblasts needs to be further investigated. METHODS: MC3T3-E1 cells were treated with osteogenic induction medium (OIM). Ethanol-solubilized cholesterol (100 µM) was used as a stimulator, and 10 µM and 25 µM geniposide was added for treatment. The alterations of protein expression were detected by western blot, and the cell apoptosis was analyzed by a flow cytometer. RESULTS: CHO promoted osteoblast apoptosis by activating ER stress in osteoblasts, while GEN alleviated the activation of ER stress and reduced osteoblast apoptosis by activating the GLP-1R/ABCA1 pathway. Inhibition of ABCA1 or GLP-1R could eliminate the protective activity of GEN against CHO-induced ER stress and osteoblast apoptosis. CONCLUSION: GEN alleviated CHO-induced ER stress and apoptosis in osteoblasts by mediating the GLP-1R/ABCA1 pathway.


Assuntos
Iridoides , Osteoblastos , Osteoporose , Humanos , Osteoblastos/metabolismo , Osteoporose/metabolismo , Apoptose , Estresse do Retículo Endoplasmático , Colesterol/metabolismo , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Transportador 1 de Cassete de Ligação de ATP/farmacologia
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