RÉSUMÉ
Xianlinggubao formula (XLGB), is a traditional Chinese compound Medicine that has been extensively used in osteoarthritis and aseptic osteonecrosis, but its curative effect on diabetic osteoporosis (DOP) and its pharmacological mechanisms remains not clear. The aim of the present study was to investigate the possible mechanism of drug repurposing of XLGB in DOP therapy. We acquired XLGB active compounds from the traditional Chinese medicine systems pharmacology and traditional Chinese medicines integrated databases and discovered potential targets for these compounds by conducting target fishing using the traditional Chinese medicine systems pharmacology and Swiss Target Prediction databases. Gene Cards and Online Mendelian Inheritance in Man® database were used to identify the DOP targets. Overlapping related targets between XLGB and DOP was selected to build a protein-protein interaction network. Next, the Metascape database was utilized to enrich the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways. In addition, Auto-Dock Vina software was used to verify drug and target binding. In total, 48 hub targets were obtained as the candidate targets responsible for DOP therapy. The anti-DOP effect mediated by XLGB was primarily centralized on the advanced glycation end products (AGEs)-receptor for AGE signaling pathway in diabetic complications and osteoclast differentiation. In addition, AKT serine/threonine kinase 1, tumor necrosis factor, Interleukin-6, vascular endothelial growth factor A and peroxisome proliferator activated receptor gamma, which were considered as potential therapeutic targets. Furthermore, molecular docking results confirm the credibility of the predicted therapeutic targets. This study elucidates that XLGB may through regulating AGEs formation and osteoclast differentiation as well as angiogenesis and adipogenesis against DOP. And this study provides new promising points to find the exact regulatory mechanisms of XLGB mediated anti-DOP effect.
Sujet(s)
Médicaments issus de plantes chinoises , Simulation de docking moléculaire , Pharmacologie des réseaux , Ostéoporose , Médicaments issus de plantes chinoises/pharmacologie , Médicaments issus de plantes chinoises/usage thérapeutique , Ostéoporose/traitement médicamenteux , Humains , Pharmacologie des réseaux/méthodes , Cartes d'interactions protéiques/effets des médicaments et des substances chimiques , Médecine traditionnelle chinoise/méthodes , Transduction du signal/effets des médicaments et des substances chimiques , Complications du diabète/traitement médicamenteuxRÉSUMÉ
Osteoclastic inhibition using antiresorptive bisphosphonates and osteogenic promotion using antisclerostin agents represent two distinct osteoporosis treatments in clinical practice, each individual treatment suffers from unsatisfactory therapeutic efficacy due to its indirect intervention in osteoclasis and promotion of osteogenesis simultaneously. Although this issue is anticipated to be resolved by drug synergism, a tempting carrier-free dual-medication nanoassembly remains elusive. Herein, we prepare such a nanoassembly made of antiresorptive alendronate (ALN) crystal and antisclerostin polyaptamer (Apt) via a nucleic acid-driven crystallization method. This nanoparticle can protect Apt from rapid nuclease degradation, avoid the high cytotoxicity of free ALN, and effectively concentrate in the cancellous bone by virtue of the bone-binding ability of DNA and ALN. More importantly, the acid microenvironment of cancellous bone triggers the disassociation of nanoparticles for sustained drug release, from which ALN inhibits the osteoclast-mediated bone resorption while Apt promotes osteogenic differentiation. Our work represents a pioneering demonstration of nucleic acid-driven crystallization of a bisphosphonate into a tempting carrier-free dual-medication nanoassembly. This inaugural advancement augments the antiosteoporosis efficacy through direct inhibition of osteoclasis and promotion of osteogenesis simultaneously and establishes a paradigm for profound understanding of the underlying synergistic antiosteoporosis mechanism of antiresorptive and antisclerostin components. It is envisioned that this study provides a highly generalizable strategy applicable to the tailoring of a diverse array of DNA-inorganic nanocomposites for targeted regulation of intricate pathological niches.
Sujet(s)
Alendronate , Cristallisation , Ostéoclastes , Ostéogenèse , Ostéoporose , Alendronate/composition chimique , Alendronate/pharmacologie , Ostéogenèse/effets des médicaments et des substances chimiques , Ostéoclastes/effets des médicaments et des substances chimiques , Ostéoclastes/métabolisme , Ostéoporose/traitement médicamenteux , Animaux , Souris , Agents de maintien de la densité osseuse/pharmacologie , Agents de maintien de la densité osseuse/composition chimique , Aptamères nucléotidiques/composition chimique , Aptamères nucléotidiques/pharmacologie , Cellules RAW 264.7 , Humains , Synergie des médicamentsRÉSUMÉ
RATIONALE: Isopsoralen (ISO), a quality control marker (Q-marker) in Psoraleae Fructus, is proven to present an obvious anti-osteoporosis effect. Until now, the metabolism and anti-osteoporosis mechanisms of ISO have not been fully elucidated, greatly restricting its drug development. METHODS: The metabolites of ISO in rats were profiled by using ultrahigh-performance liquid chromatography coupled with time-of-flight mass spectrometry. The potential anti-osteoporosis mechanism of ISO in vivo was predicted by using network pharmacology. RESULTS: A total of 15 metabolites were characterized in rats after ingestion of ISO (20 mg/kg/day, by gavage), including 2 in plasma, 12 in urine, 6 in feces, 1 in heart, 3 in liver, 1 in spleen, 1 in lung, 3 in kidney, and 2 in brain. The pharmacology network results showed that ISO and its metabolites could regulate AKT1, SRC, NFKB1, EGFR, MAPK3, etc., involved in the prolactin signaling pathway, ErbB signaling pathway, thyroid hormone pathway, and PI3K-Akt signaling pathway. CONCLUSIONS: This is the first time for revealing the in vivo metabolism features and potential anti-osteoporosis mechanism of ISO by metabolite profiling and network pharmacology, providing data for further verification of pharmacological mechanism.
Sujet(s)
Furocoumarines , Pharmacologie des réseaux , Psoralea , Rat Sprague-Dawley , Animaux , Furocoumarines/pharmacologie , Furocoumarines/composition chimique , Psoralea/composition chimique , Rats , Chromatographie en phase liquide à haute performance/méthodes , Mâle , Ostéoporose/traitement médicamenteux , Ostéoporose/métabolisme , Contrôle de qualité , Marqueurs biologiques/analyse , Marqueurs biologiques/métabolisme , Marqueurs biologiques/urine , Fruit/composition chimique , Médicaments issus de plantes chinoises/pharmacologie , Médicaments issus de plantes chinoises/administration et posologie , Spectrométrie de masse/méthodes , Agents de maintien de la densité osseuse/pharmacologie , Métabolome/effets des médicaments et des substances chimiques , Métabolomique/méthodesRÉSUMÉ
PURPOSE: To investigate the effect of Sophora japonica extract on alveolar bone mass in ovariectomized osteoporosis mice. METHODS: Six-week-old female non-pregnant wild-type C57BL/6J mice were randomly divided into sham operation group, ovariectomy(OVX) group and OVX+Sophora japonica extract group. Ovaries of the mice in the OVX group and the OVX+Sophora japonica extract group were removed, and the mice in the OVX+Sophora japonica extract group were treated by Sophora japonica extract at a dose of 150 mg/kg, three times a week for 4 weeks; while mice of the other two groups were given an equal volume of normal saline at the same time. Body weight was measured 3 times a week, and the micro-parameters of alveolar bone were detected by Micro-CT after 4 weeks. The data were analyzed by GraphPad Prism 9 software. RESULTS: Compared with the sham-operated group, the trabecular bone parameters of the alveolar bone in the OVX group were significantly decreased 1 month after operation (Pï¼0.05). One month after intervention with Sophora japonica extract, alveolar bone mineral density (BMD), trabecular number (Tb.N) and trabecular separation(Tb.Sp) in OVX mice was significantly rescued, with no significant difference compared to the sham surgery group(Pï¼0.05); but bone volume fraction(BV/TV) and trabecular thickness (Tb.Th) had not completely recovered to the levels of the sham-operated group(Pï¼0.05). CONCLUSIONS: Sophora japonica extract can effectively increase the alveolar bone mass reduced by estrogen deficiency and may be used as one of the potential drugs for the treatment of menopausal alveolar bone osteoporosis.
Sujet(s)
Densité osseuse , Souris de lignée C57BL , Ostéoporose , Ovariectomie , Extraits de plantes , Sophora japonica , Animaux , Femelle , Souris , Densité osseuse/effets des médicaments et des substances chimiques , Ostéoporose/traitement médicamenteux , Extraits de plantes/pharmacologie , Sophora japonica/composition chimique , Microtomographie aux rayons XRÉSUMÉ
Osteoporosis is the most common bone disorder, which is a highly dangerous condition that can promote bone metastases. As the current treatment for osteoporosis involves long-term medication therapy and a cure for bone metastasis is not known, ongoing efforts are required for drug development for osteoporosis. Animal experiments, traditionally used for drug development, raise ethical concerns and are expensive and time-consuming. Organ-on-a-chip technology is being developed as a tool to supplement such animal models. In this study, we developed a bone-on-a-chip by co-culturing osteoblasts, osteocytes, and osteoclasts in an extracellular matrix environment that can represent normal bone, osteopenia, and osteoporotic conditions. We then simulated bone metastases using breast cancer cells in three different bone conditions and observed that bone metastases were most active in osteoporotic conditions. Furthermore, it was revealed that the promotion of bone metastasis in osteoporotic conditions is due to increased vascular permeability. The bone-on-a-chip developed in this study can serve as a platform to complement animal models for drug development for osteoporosis and bone metastasis.
Sujet(s)
Tumeurs osseuses , Laboratoires sur puces , Ostéoporose , Ostéoporose/anatomopathologie , Ostéoporose/traitement médicamenteux , Tumeurs osseuses/secondaire , Tumeurs osseuses/anatomopathologie , Animaux , Humains , Ostéoblastes/métabolisme , Techniques de coculture , Souris , Ostéoclastes/anatomopathologie , Ostéoclastes/métabolisme , Ostéocytes/anatomopathologie , Ostéocytes/métabolisme , Os et tissu osseux/anatomopathologie , Lignée cellulaire tumorale , FemelleRÉSUMÉ
Introduction: Osteoporosis, characterized by dysregulation of osteoclastic bone resorption and osteoblastic bone formation, severely threatens human health during aging. However, there is still no good therapy for osteoporosis, so this direction requires our continuous attention, and there is an urgent need for new drugs to solve this problem. Methods: Traditional Chinese Medicine Salvia divinorum monomer pomolic acid (PA) could effectively inhibit osteoclastogenesis and ovariectomized osteoporosis. However, its poor solubility and lack of targeting severely limits its further application. A novel bone-targeting nanomedicine (PA@TLipo) has been developed to reconstruct the osteoporotic microenvironment by encapsulating pomolic acid in alendronate-functionalized liposomes. Through a series of operations such as synthesis, purification, encapsulation, and labeling, the PA@TLipo have been prepared. Moreover, the cytotoxicity, bone targeting and anti-osteoporosis effect was verified by cell and animal experiments. Results: In the aspect of targeting, the PA@TLipo can effectively aggregate on the bone tissue to reduce bone loss, and in terms of toxicity, PA@TLipo could increase the bone target ability in comparison to nontargeted liposome, thereby mitigating systemic cytotoxicity. Moreover, PA@TLipo inhibited osteoclast formation and bone resorption in vitro and reduced bone loss in ovariectomy-induced osteoporotic mice. Conclusion: In this study, a novel therapeutic agent was designed and constructed to treat osteoporosis, consisting of a liposome material as the drug pocket, PA as the anti-osteoporosis drug, and ALN as the bone-targeting molecule. And our study is the first to employ a bone-targeted delivery system to deliver PA for OVX-induced bone loss, providing an innovative solution for treating osteoporosis.
Sujet(s)
Alendronate , Liposomes , Ostéoporose , Animaux , Liposomes/composition chimique , Alendronate/composition chimique , Alendronate/pharmacologie , Alendronate/administration et posologie , Ostéoporose/traitement médicamenteux , Femelle , Souris , Agents de maintien de la densité osseuse/pharmacologie , Agents de maintien de la densité osseuse/composition chimique , Agents de maintien de la densité osseuse/administration et posologie , Ostéoclastes/effets des médicaments et des substances chimiques , Cellules RAW 264.7 , Humains , Os et tissu osseux/effets des médicaments et des substances chimiques , Résorption osseuse/traitement médicamenteux , Homéostasie/effets des médicaments et des substances chimiques , Ostéogenèse/effets des médicaments et des substances chimiques , OvariectomieRÉSUMÉ
Bone forming agents, also known as anabolic therapies, are essential in managing osteoporosis, particularly for patients at very high-risk of fractures. Identifying candidates who will benefit the most from these treatments is crucial. For example, this group might include individuals with severe osteoporosis, multiple vertebral fractures, a recent fragility fracture or those unresponsive to antiresorptive treatments. Definitions of patients with a very high fracture risk vary across nations, are often based on fracture history, bone mineral density (BMD), and/or fracture risk calculated by FRAX® or other algorithms. However, for very high-risk patients, anabolic agents such as teriparatide, abaloparatide, or romosozumab are commonly recommended as first-line therapies due to their ability to stimulate new bone formation and improve bone microarchitecture, offering significant benefits in rapid fracture reduction over antiresorptive therapies. The cost-effectiveness of these agents is a critical consideration for decision-makers. Despite their higher costs, their effectiveness in significantly reducing fracture risk and improving quality of life can justify the investment, especially when long-term savings from reduced fracture rates and associated healthcare costs are considered. Additionally, after completing a course of anabolic therapy, transitioning to antiresorptive agents like bisphosphonates or denosumab is crucial to maintain the gains in bone density and minimize subsequent fracture risks. This sequential treatment approach ensures sustained protection and optimal resource utilization. In summary, the effective use of bone forming agents in osteoporosis requires a comprehensive strategy that includes accurate patient identification, consideration of cost-effectiveness, and implementation of appropriate sequential treatments, ultimately maximizing patient outcomes and healthcare efficiency.
Sujet(s)
Agents de maintien de la densité osseuse , Densité osseuse , Ostéoporose , Humains , Ostéoporose/traitement médicamenteux , Agents de maintien de la densité osseuse/usage thérapeutique , Densité osseuse/effets des médicaments et des substances chimiques , Fractures ostéoporotiques/prévention et contrôle , Anabolisants/usage thérapeutique , Tériparatide/usage thérapeutique , Analyse coût-bénéficeRÉSUMÉ
Rhodiola rosea, a long-lived herbaceous plant from the Crassulaceae group, contains the active compound salidroside, recognized as an adaptogen with significant therapeutic potential for bone metabolism. Salidroside promotes osteoblast proliferation and differentiation by activating critical signaling pathways, including bone morphogenetic protein-2 and adenosine monophosphate-activated protein kinase, essential for bone formation and growth. It enhances osteogenic activity by increasing alkaline phosphatase activity and mineralization markers, while upregulating key regulatory proteins including runt-related transcription factor 2 and osterix. Additionally, salidroside facilitates angiogenesis via the hypoxia-inducible factor 1-alpha and vascular endothelial growth factor pathway, crucial for coupling bone development with vascular support. Its antioxidant properties offer protection against bone loss by reducing oxidative stress and promoting osteogenic differentiation through the nuclear factor erythroid 2-related factor 2 pathway. Salidroside has the capability to counteract the negative effects of glucocorticoids on bone cells and prevents steroid-induced osteonecrosis. Additionally, it exhibits multifaceted anti-inflammatory actions, notably through the inhibition of tumor necrosis factor-alpha and interleukin-6 expression, while enhancing the expression of interleukin-10. This publication presents a comprehensive review of the literature on the impact of salidroside on various aspects of bone tissue metabolism, emphasizing its potential role in the prevention and treatment of osteoporosis and other diseases affecting bone physiology.
Sujet(s)
Os et tissu osseux , Glucosides , Ostéoblastes , Ostéogenèse , Ostéoporose , Phénols , Glucosides/pharmacologie , Humains , Phénols/pharmacologie , Os et tissu osseux/effets des médicaments et des substances chimiques , Os et tissu osseux/métabolisme , Ostéogenèse/effets des médicaments et des substances chimiques , Ostéoporose/traitement médicamenteux , Animaux , Ostéoblastes/effets des médicaments et des substances chimiques , Ostéoblastes/métabolisme , Rhodiola/composition chimique , Transduction du signal/effets des médicaments et des substances chimiques , Antioxydants/pharmacologie , Différenciation cellulaire/effets des médicaments et des substances chimiques , Anti-inflammatoires/pharmacologieRÉSUMÉ
Despite advancements in therapeutic techniques, restoring bone tissue after damage remains a challenging task. Tissue engineering or targeted drug delivery solutions aim to meet the pressing clinical demand for treatment alternatives by creating substitute materials that imitate the structural and biological characteristics of healthy tissue. Polymers derived from natural sources typically exhibit enhanced biological compatibility and bioactivity when compared to manufactured polymers. Chitosan is a unique polysaccharide derived from chitin through deacetylation, offering biodegradability, biocompatibility, and antibacterial activity. Its cationic charge sets it apart from other polymers, making it a valuable resource for various applications. Modifications such as thiolation, alkylation, acetylation, or hydrophilic group incorporation can enhance chitosan's swelling behavior, cross-linking, adhesion, permeation, controllable drug release, enzyme inhibition, and antioxidative properties. Chitosan scaffolds possess considerable potential for utilization in several biological applications. An intriguing application is its use in the areas of drug distribution and bone tissue engineering. Due to their excellent biocompatibility and lack of toxicity, they are an optimal material for this particular usage. This article provides a comprehensive analysis of osteoporosis, including its pathophysiology, current treatment options, the utilization of natural polymers in disease management, and the potential use of chitosan scaffolds for drug delivery systems aimed at treating the condition.
Sujet(s)
Chitosane , Ostéoporose , Structures d'échafaudage tissulaires , Chitosane/composition chimique , Humains , Ostéoporose/traitement médicamenteux , Structures d'échafaudage tissulaires/composition chimique , Ingénierie tissulaire , Animaux , Systèmes de délivrance de médicaments , Matériaux biocompatibles/composition chimiqueRÉSUMÉ
Anabolic bone agents, such as parathyroid hormone receptor agonists (teriparatide and abaloparatide) and sclerostin-inhibiting monoclonal antibody (romosozumab), are superior at preventing clinically significant fractures and/or vertebral fractures in women with and without severe osteoporosis compared with bisphosphonates.
Sujet(s)
Agents de maintien de la densité osseuse , Ostéoporose , Humains , Agents de maintien de la densité osseuse/usage thérapeutique , Ostéoporose/traitement médicamenteux , Femelle , Anticorps monoclonaux/usage thérapeutique , Fractures ostéoporotiques/prévention et contrôle , Fractures ostéoporotiques/étiologie , Protéine apparentée à l'hormone parathyroïdienne , Tériparatide/usage thérapeutique , Diphosphonates/usage thérapeutiqueSujet(s)
Agents de maintien de la densité osseuse , Diphosphonates , Humains , Diphosphonates/effets indésirables , Diphosphonates/usage thérapeutique , Agents de maintien de la densité osseuse/effets indésirables , Agents de maintien de la densité osseuse/usage thérapeutique , Ostéonécrose de la mâchoire associée aux biphosphonates/étiologie , Ostéonécrose de la mâchoire associée aux biphosphonates/prévention et contrôle , Ostéoporose/traitement médicamenteuxRÉSUMÉ
Background: Among bone diseases, osteoporosis-like skeleton, such as trabecular thinning, fracture and so on, is the main pathological change of cadmium-induced osteoporosis(Cd-OP), accompanied by brittle bone and increased fracture rate. However, the mechanism underlying cadmium-induced osteoporosis has remained elusive. Compound Lurong Jiangu Capsule (CLJC) is an experienced formula for the treatment of bone diseases, which has the effect of tonifying kidney and strengthening bones, promoting blood circulation and relieving pain. Objective: Network pharmacology and molecular docking technology combined with experiments were used to investigate the potential mechanism of CLJC in treating Cd-OP. Method: The active compounds and corresponding targets of each herb in CLJC were searched in the TCMSP and BATMAN-TCM databases. The DisGeNet, OMIM, and GeneCards databases searched for Cd-OP targets. The relationship between both of them was visualized by establishing an herb-compound-target network using Cytoscape 3.9.1 software. Gene ontology (GO), and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analyses were performed after determining the intersection of the targets from CLJC and Cd-OP. What's more, molecular docking was performed to validate the results. All of them were aim to obtain hud signaling pathways for further study. Finally, BAX, BCL-2, and CASPASE-3 were screened and selected for further experiments, which included bone imaging and reconstruction analysis (Micro-CT), hematoxylin-eosin Staining (HE), and western blot (WB). Results: 106 common targets from CLJC and Cd-OP targets were identified. KEGG pathway analysis suggested that multiple signaling pathways, such as the pathways in cancer, may play roles in treatment. Verification of the molecular docking was successful. Here we showed that Cd-OP displayed Tb.Th and Tb.N significantly reduced and even broke, irregular proliferation of bone cortex, uneven and loose trabecular bone arrangement, changed in apoptosis-related proteins, such as significant upregulation of CASPASE-3, BAX protein and significant downregulation of BCL-2 protein in vivo, while CLJC rescued these phenotypes. Conclusion: This study revealed that CLJC can reduce the expression of apoptosis-related proteins, and multiple components and multiple targets inhibit Cd-OP through apoptosis signaling pathway.
Sujet(s)
Cadmium , Médicaments issus de plantes chinoises , Simulation de docking moléculaire , Pharmacologie des réseaux , Ostéoporose , Médicaments issus de plantes chinoises/pharmacologie , Médicaments issus de plantes chinoises/usage thérapeutique , Ostéoporose/traitement médicamenteux , Ostéoporose/induit chimiquement , Ostéoporose/métabolisme , Ostéoporose/anatomopathologie , Cadmium/toxicité , Animaux , Rats , Apoptose/effets des médicaments et des substances chimiques , Femelle , Rat Sprague-Dawley , Transduction du signal/effets des médicaments et des substances chimiques , CapsulesRÉSUMÉ
Epimedium is thought to enhance the integrity of tendons and bones, ease joint discomfort and rigidity and enhance kidney function. Although glucocorticoids are commonly used in clinical practice, the mechanism by which the active compound Epimedin C (EC) alleviates glucocorticoid-induced osteoporosis (GIOP) is not well understood. The therapeutic potential of EC in treating GIOP was evaluated using alizarin red S staining, calcein immersion and fluorescence imaging, and bone mineralization, bone mass accumulation and bone density in zebrafish larvae were determined. Using the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, the key signalling pathways related to bone development were identified. A protein-protein interaction network (PPIN) was constructed to identify osteoclast characteristic genes and the findings were verified using real-time quantitative PCR (RT-qPCR). The bone tissue damage caused by prednisolone was reduced by EC. It also altered physiological processes, improved bone density, boosted mineralization and increased bone mass and activity. Subsequent empirical investigations showed that EC impacted the major signalling pathways involved in bone development, such as osteoclast differentiation, oestrogen, MAPK, insulin resistance, PPAR and AMPK signalling pathways. It also decreased the expression of genes typical of osteoclasts. The results of our study uncover a previously unknown function of EC in controlling bone formation and emphasize the potential of EC as a therapeutic target. The osteoprotective effect of EC indicates its potential as a cost-effective strategy for treating GIOP.
Sujet(s)
Modèles animaux de maladie humaine , Flavonoïdes , Glucocorticoïdes , Ostéoclastes , Ostéoporose , Transduction du signal , Danio zébré , Animaux , Ostéoporose/induit chimiquement , Ostéoporose/métabolisme , Ostéoporose/génétique , Ostéoporose/anatomopathologie , Ostéoporose/traitement médicamenteux , Flavonoïdes/pharmacologie , Glucocorticoïdes/effets indésirables , Glucocorticoïdes/pharmacologie , Ostéoclastes/métabolisme , Ostéoclastes/effets des médicaments et des substances chimiques , Transduction du signal/effets des médicaments et des substances chimiques , Densité osseuse/effets des médicaments et des substances chimiques , Cartes d'interactions protéiques , Ostéogenèse/effets des médicaments et des substances chimiques , Ostéogenèse/génétique , Calcification physiologique/effets des médicaments et des substances chimiquesRÉSUMÉ
BACKGROUND: Artesunate (ART) has the potential to modulate the nuclear factor kappa B (NF-κB) and Notch1/Hes1 signaling pathways, which play crucial roles in the pathogenesis of osteoporosis. This study aims to explore whether ART participates in the progression of osteoporosis by regulating these signaling pathways. METHODS: In the in vitro experiments, we treated bone marrow mesenchymal stem cells (BMSCs) with different concentrations of ART (0, 3, 6, 12 µM) and evaluated osteogenic differentiation using alkaline phosphatase staining (ALP) and alizarin red S staining (ARS) staining. The expression levels of osteocalcin (OCN), RUNT-related transcription factor 2 (RUNX2), osteoprotegerin (OPG), and receptor activator of the nuclear factor kappa ligand (RANKL) were detected by real-time quantitative PCR (RT-qPCR). The effects of ART on NF-κB p65 and Notch1 protein expression were analyzed by Western blot (WB) and immunofluorescence (IF). In the in vivo experiments, a postmenopausal osteoporosis rat model was established via ovariectomy. Bone tissue pathological injury was evaluated using hematoxylin eosin (HE) staining. Serum ALP levels were measured using a kit, bone density was determined by dual-energy X-ray absorptiometry, and serum levels of bone gla protein (BGP), OPG, RANKL, tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), and IL-1ß were measured by enzyme-linked immunosorbent assay (ELISA). Additionally, the expression of NF-κB p65 and Notch1 in tissues was assessed by immunohistochemistry. RESULTS: In vitro experiments revealed that compared to the control group, ART dose-dependently promoted BMSCs proliferation and enhanced their osteogenic differentiation capability. The expression of OCN, RUNX2, and OPG significantly increased in the ART-treated group, while RANKL expression decreased significantly (p < 0.05). ART significantly inhibited the expression of NF-κB p65 and Notch1/Hes1 signaling pathway proteins (p < 0.05). Compared to ART treatment alone, combined treatment with ART and phorbol myristate acetate (PMA) or valproic acid (VPA) resulted in increased expression of NF-κB p65 and Notch1 proteins and decreased osteogenic differentiation capability (p < 0.05). In vivo experiments showed that in rats treated with ART, bone damage was significantly reduced, bone density and mineral content were restored considerably, and the expression of inflammatory factors (TNF-α, IL-6, IL-1ß) decreased significantly (p < 0.05). Additionally, ART treatment significantly reduced the expression of NF-κB p65 and Notch1 proteins, increased OPG expression, and decreased BGP and RANKL levels (p < 0.05). CONCLUSION: In summary, ART facilitates the osteogenic differentiation of BMSCs by inhibiting the NF-κB and Notch1/Hes1 signaling pathways, thereby exerting significant protective effects against osteoporosis.
Sujet(s)
Artésunate , Facteur de transcription NF-kappa B , Ostéoporose , Ovariectomie , Rat Sprague-Dawley , Récepteur Notch1 , Transduction du signal , Animaux , Artésunate/pharmacologie , Artésunate/usage thérapeutique , Femelle , Transduction du signal/effets des médicaments et des substances chimiques , Récepteur Notch1/métabolisme , Facteur de transcription NF-kappa B/métabolisme , Ostéoporose/métabolisme , Ostéoporose/traitement médicamenteux , Ostéoporose/étiologie , Rats , Ostéogenèse/effets des médicaments et des substances chimiques , Artémisinines/pharmacologie , Artémisinines/usage thérapeutique , Cellules souches mésenchymateuses/métabolisme , Cellules souches mésenchymateuses/effets des médicaments et des substances chimiques , Inflammation/métabolisme , Différenciation cellulaire/effets des médicaments et des substances chimiques , Facteur de transcription HES-1RÉSUMÉ
INTRODUCTION: Potential associations between Chronic Obstructive Pulmonary Disease (COPD) and osteoporosis have been studied, but areas of uncertainty remain. OBJECTIVE: This scoping review aimed to identify the published evidence on the epidemiological relationships between COPD and osteoporosis. METHODS: Experimental and observational evidence evaluating relationships between COPD and osteoporosis on epidemiology, clinical manifestations, risk factors (RFs), therapeutic management and quality of life (QoL) was searched on PubMed and Embase (until May 2023). The studies were categorized according to their objectives and characteristics. Data were analyzed using descriptive statistics. RESULTS: Ninety-nine studies were selected, namely 33 (33%) reporting epidemiologic measures, 11 (11%) clinical manifestations, 74 (75%) RFs (45 ones, of which body mass index [BMI; n = 22 studies], corticosteroids' use [n = 20], and COPD severity [n = 15] were the most studied), 7 (7%) therapeutic management, and 3 (3%) QoL. Twenty-seven (27.6%) studies evaluated ≥2 domains. Most studies followed a cross-sectional design (n = 37; 37.4%). Eighty-nine studies (90%) assessed patients with COPD at baseline and studied its relationship with osteoporosis. CONCLUSION: There are well-established features linking COPD and osteoporosis, including shared RFs, such as smoking, elderly, physical inactivity, or low BMI. Others deserve clarification, including the impact of COPD severity, or the use of inhaled corticosteroids on the incidence of osteoporosis and fractures, as well as the value of performing routine imaging tests, or prescribing anti-resorptive medications in COPD to prevent osteoporotic-related outcomes. QoL studies are also lacking. Investigating such issues is needed to propose clinical guidelines for managing osteoporosis in patients with COPD.
Sujet(s)
Ostéoporose , Broncho-pneumopathie chronique obstructive , Qualité de vie , Broncho-pneumopathie chronique obstructive/épidémiologie , Broncho-pneumopathie chronique obstructive/complications , Humains , Ostéoporose/épidémiologie , Ostéoporose/traitement médicamenteux , Facteurs de risque , Indice de masse corporelle , Hormones corticosurrénaliennes/usage thérapeutiqueRÉSUMÉ
Osteoporosis and osteoarthritis continue to pose significant challenges to the aging population, with limited preventive options and pharmacological treatments often accompanied by side effects. Amidst ongoing efforts to discover new therapeutic agents, tocotrienols (TTs) have emerged as potential candidates. Derived from annatto bean and palm oil, TTs have demonstrated efficacy in improving skeletal and joint health in numerous animal models of bone loss and osteoarthritis. Mechanistic studies suggest that TTs exert their effects through antioxidant, anti-inflammatory, Wnt-suppressive, and mevalonate-modulating mechanisms in bone, as well as through self-repair mechanisms in chondrocytes. However, human clinical trials in this field remain scarce. In conclusion, TTs hold promise as agents for preventing osteoporosis and osteoarthritis, pending further evidence from human clinical trials.
Sujet(s)
Arthrose , Ostéoporose , Tocotriénols , Tocotriénols/usage thérapeutique , Tocotriénols/pharmacologie , Humains , Animaux , Arthrose/traitement médicamenteux , Arthrose/prévention et contrôle , Ostéoporose/traitement médicamenteux , Ostéoporose/prévention et contrôle , Os et tissu osseux/effets des médicaments et des substances chimiques , Os et tissu osseux/métabolismeRÉSUMÉ
Background: Patients with Cushing's disease (CD) often experience slow recovery of bone mineral density (BMD), and the effectiveness of anti-osteoporosis drugs in young CD patients who have achieved biochemical remission after surgery is not well understood. Therefore, we aimed to explore whether bisphosphonates could help accelerate the recovery of osteoporosis in young CD patients with remission. Methods: We retrospectively enrolled 34 young patients with CD who achieved postoperative biochemical remission. All patients suffered from osteoporosis before surgery and were divided into postoperative bisphosphonate treatment group (16 cases) and without bisphosphonate treatment group (18 cases). Clinical data, BMD (Z Value), and bone turnover markers were collected at the time of diagnosis and one year after successful tumor resection. Results: The Z values in the lumbar spine showed slight improvement in both groups at follow-up compared to baseline, but this improvement was not statistically significant. There was no significant difference observed between the two groups at follow-up. One year after operation, bone formation markers (OC and P1NP) were significantly higher than those at baseline in both groups. However, OC and P1NP in the bisphosphonate treatment group were lower than those in control group at one year follow-up. In without bisphosphonate treatment group, ß-CTX from follow-up visit was higher than that at baseline, while no significant difference was observed in the bisphosphonate treatment group before and after surgery. Conclusion: Young patients with Cushing's disease combined with osteoporosis might not benefit from bisphosphonate therapy for osteoporosis recovery in the first year after achieving biochemical remission.
Sujet(s)
Agents de maintien de la densité osseuse , Densité osseuse , Diphosphonates , Ostéoporose , Hypersécrétion hypophysaire d'ACTH , Humains , Études rétrospectives , Femelle , Diphosphonates/usage thérapeutique , Mâle , Hypersécrétion hypophysaire d'ACTH/traitement médicamenteux , Hypersécrétion hypophysaire d'ACTH/chirurgie , Ostéoporose/traitement médicamenteux , Densité osseuse/effets des médicaments et des substances chimiques , Adulte , Agents de maintien de la densité osseuse/usage thérapeutique , Jeune adulte , Induction de rémission , Adolescent , Résultat thérapeutique , Marqueurs biologiques/sang , Études de suiviRÉSUMÉ
Background: The repair of osteoporotic bone defects remains challenging due to excessive reactive oxygen species (ROS), persistent inflammation, and an imbalance between osteogenesis and osteoclastogenesis. Methods: Here, an injectable H2-releasing hydrogel (magnesium@polyethylene glycol-poly(lactic-co-glycolic acid), Mg@PEG-PLGA) was developed to remodel the challenging bone environment and accelerate the repair of osteoporotic bone defects. Results: This Mg@PEG-PLGA gel shows excellent injectability, shape adaptability, and phase-transition ability, can fill irregular bone defect areas via minimally invasive injection, and can transform into a porous scaffold in situ to provide mechanical support. With the appropriate release of H2 and magnesium ions, the 2Mg@PEG-PLGA gel (loaded with 2 mg of Mg) displayed significant immunomodulatory effects through reducing intracellular ROS, guiding macrophage polarization toward the M2 phenotype, and inhibiting the IκB/NF-κB signaling pathway. Moreover, in vitro experiments showed that the 2Mg@PEG-PLGA gel inhibited osteoclastogenesis while promoting osteogenesis. Most notably, in animal experiments, the 2Mg@PEG-PLGA gel significantly promoted the repair of osteoporotic bone defects in vivo by scavenging ROS and inhibiting inflammation and osteoclastogenesis. Conclusions: Overall, our study provides critical insight into the design and development of H2-releasing magnesium-based hydrogels as potential implants for repairing osteoporotic bone defects.
Sujet(s)
Régénération osseuse , Hydrogels , Hydrogène , Magnésium , Ostéogenèse , Ostéoporose , Polyéthylène glycols , Espèces réactives de l'oxygène , Animaux , Magnésium/composition chimique , Magnésium/administration et posologie , Espèces réactives de l'oxygène/métabolisme , Souris , Polyéthylène glycols/composition chimique , Hydrogels/composition chimique , Ostéoporose/traitement médicamenteux , Ostéogenèse/effets des médicaments et des substances chimiques , Hydrogène/pharmacologie , Hydrogène/administration et posologie , Hydrogène/composition chimique , Cellules RAW 264.7 , Régénération osseuse/effets des médicaments et des substances chimiques , Immunomodulation/effets des médicaments et des substances chimiques , Structures d'échafaudage tissulaires/composition chimique , Macrophages/effets des médicaments et des substances chimiques , Macrophages/métabolisme , PolyestersRÉSUMÉ
Diabetic osteoporosis is a common health problem that is associated with a disruption in bone metabolism. A2A adenosine receptor (A2AAR) signaling seems to play a critical role in bone homeostasis. This study aimed to evaluate the effect of A2AAR stimulation on the treatment of diabetic-induced osteoporosis versus insulin treatment. Forty adult male rats were allocated into control (C), untreated diabetic-induced osteoporosis (DIO), insulin-treated DIO (I-DIO), and A2AAR agonist-treated DIO (A-DIO) groups. Both insulin and A2AAR agonist treatments significantly increased serum insulin level, glutathione peroxidase (GPx) activity, bone expression of osteoprotegerin (Opg) and ß-catenin (Ctnnb1), and cortical and trabecular bone thickness, whereas they decreased serum fasting glucose, malondialdehyde (MDA), tumor necrosis factor α (TNF-α), bone expression of receptor activator of nuclear factor kappa-B ligand (Rankl), runt-related transcription factor-2 (Runx2), and sclerostin (Sost) versus the untreated DIO groups. A2AAR agonist treatment was more effective than insulin in ameliorating diabetic osteoporosis. This might be attributed to the upregulation of ß-catenin gene expression, enhancing its anabolic effect on bone, in addition to the A2AAR agonist's anti-oxidative, anti-inflammatory, and anti-diabetic effects.
Sujet(s)
Diabète expérimental , Ostéoporose , Animaux , Mâle , Rats , Agonistes des récepteurs A2 à l'adénosine/pharmacologie , Agonistes des récepteurs A2 à l'adénosine/usage thérapeutique , Diabète expérimental/métabolisme , Diabète expérimental/traitement médicamenteux , Diabète expérimental/complications , Insuline/métabolisme , Ostéoporose/métabolisme , Ostéoporose/étiologie , Ostéoporose/traitement médicamenteux , Rat Wistar , Récepteur A2A à l'adénosine/métabolisme , Résultat thérapeutiqueRÉSUMÉ
Inhibition of LSD1 was proposed as promising and attractive therapies for treating osteoporosis. Here, we synthesized a series of novel TCP-(MP)-Caffeic acid analogs as potential LSD1 inhibitors to assess their inhibitory effects on osteoclastogenesis by using TRAP-staining assay and try to explore the preliminary SAR. Among them, TCP-MP-CA (11a) demonstrated osteoclastic bone loss both in vitro and in vivo, showing a significant improvement in the in vivo effects compared to the LSD1 inhibitor GSK-LSD1. Additionally, we elucidated a mechanism that 11a and its precursor that 11e directly bind to LSD1/CoREST complex through FAD to inhibit LSD1 demethylation activity and influence its downstream IκB/NF-κB signaling pathway, and thus regulate osteoclastic bone loss. These findings suggested 11a or 11e as potential novel candidates for treating osteoclastic bone loss, and a concept for further development of TCP-(MP)-Caffeic acid analogs for therapeutic use in osteoporosis clinics.