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Biomedicine & Pharmacotherapy =... Jun 2024Reactive oxidative species (ROS) generation triggers pyroptosis and induces development of inflammatory osteolysis. Hecogenin (HG) has anti-inflammatory and...
Reactive oxidative species (ROS) generation triggers pyroptosis and induces development of inflammatory osteolysis. Hecogenin (HG) has anti-inflammatory and antioxidative property, but its effects on inflammatory osteolysis remains unclear. In our study, we investigated the mechanism of HG on pyroptosis and its effect on inflammatory osteolysis in vitro and in vivo. The impact of HG on osteoclastogenesis was evaluated using cytotoxicity, TRAcP staining and bone resorption assays. The RNA-sequencing was employed to identify potential signaling pathways, and then RT-qPCR, western blot, immunofluorescence, and ELISA were used to verify. To determine the protective effect of HG in vivo, Lipopolysaccharide (LPS)-induced animal models were utilized, along with micro-CT and histological examination. HG suppressed RANKL-induced osteoclast differentiation, bone resorption, NFATc1 activity and downstream factors. RNA-sequencing results showed that HG inhibited osteoclastogenesis by modulating the inflammatory response and macrophage polarization. Furthermore, HG inhibited the NF-κB pathway, and deactivated the NLRP3 inflammasome. HG activated the expression of nuclear factor E2-related factor 2 (Nrf2) to eliminate ROS generation. Importantly, the inhibitory effect of HG on NLRP3 inflammasome could be reversed by treatment with the Nrf2 inhibitor ML385. In vivo, HG prevented the mice against LPS-induced osteolysis by suppressing osteoclastogenesis and inflammatory factors. In conclusion, HG could activate Nrf2 to eliminate ROS generation, inactivate NLRP3 inflammasome and inhibit pyroptosis, thereby suppressing osteoclastogenesis in vitro and alleviating inflammatory osteolysis in vivo, which indicating that HG might be a promising candidate to treat inflammatory osteolysis.
PubMed: 38901204
DOI: 10.1016/j.biopha.2024.116933 -
ACS Biomaterials Science & Engineering Jun 2024Interfaces between AISI 304 stainless steel screws and cranial bone were investigated after long-term implantation lasting for 42 years. Samples containing the interface...
Interfaces between AISI 304 stainless steel screws and cranial bone were investigated after long-term implantation lasting for 42 years. Samples containing the interface regions were analyzed using state-of-the-art analytical techniques including secondary ion mass, Fourier-transform infrared, Raman, and X-ray photoelectron spectroscopies. Local samples for scanning transmission electron microscopy were cut from the interface regions using the focused ion beam technique. A chemical composition across the interface was recorded in length scales covering micrometric and nanometric resolutions and relevant differences were found between peri-implant and the distant cranial bone, indicating generally younger bone tissue in the peri-implant area. Furthermore, the energy dispersive spectroscopy revealed an 80 nm thick steel surface layer enriched by oxygen suggesting that the AISI 304 material undergoes a corrosion attack. The attack is associated with transport of metallic ions, namely, ferrous and ferric iron, into the bone layer adjacent to the implant. The results comply with an anticipated interplay between released iron ions and osteoclast proliferation. The interplay gives rise to an autocatalytic process in which the iron ions stimulate the osteoclast activity while a formation of fresh bone resorption sites boosts the corrosion process through interactions between acidic osteoclast extracellular compartments and the implant surface. The autocatalytic process thus may account for an accelerated turnover of the peri-implant bone.
PubMed: 38900847
DOI: 10.1021/acsbiomaterials.4c00309 -
Journal of Materials Science. Materials... Jun 2024Calcium phosphate cements, primarily brushite cements, require the addition of setting retarders to ensure adequate processing time and processability. So far, citric...
Calcium phosphate cements, primarily brushite cements, require the addition of setting retarders to ensure adequate processing time and processability. So far, citric acid has been the primary setting retarder used in this context. Due to the poor biocompatibility, it is crucial to explore alternative options for better processing. In recent years, the setting retarder phytic acid (IP6) has been increasingly investigated. This study investigates the biological behaviour of calcium phosphate cements with varying concentrations of IP6, in addition to their physical properties. Therefore cytocompatibility in vitro testing was performed using osteoblastic (MG-63) and osteoclastic (RAW 264.7 differentiated with RANKL) cells. We could demonstrate that the physical properties like the compressive strength of specimens formed with IP6 (brushite_IP6_5 = 11.2 MPa) were improved compared to the reference (brushite = 9.8 MPa). In osteoblast and osteoclast assays, IP6 exhibited significantly better cytocompatibility in terms of cell activity and cell number for brushite cements up to 11 times compared to the brushite reference. In contrast, the calcium-deficient hydroxyapatite (CDHA) cements produced similar results for IP6 (CDHA_IP6_0.25 = 27.0 MPa) when compared to their reference (CDHA = 21.2 MPa). Interestingly, lower doses of IP6 were found to be more effective than higher doses with up to 3 times higher. Additionally, IP6 significantly increased degradation in both passive and active resorption. For these reasons, IP6 is emerging as a strong new competitor to established setting retarders such as citric acid. These cements have potential applications in bone augmentation, the stabilisation of non-load bearing fractures (craniofacial), or the cementation of metal implants.
Topics: Phytic Acid; Animals; Calcium Phosphates; Mice; Materials Testing; Bone Cements; Osteoblasts; RAW 264.7 Cells; Humans; Osteoclasts; Compressive Strength; Biocompatible Materials; Durapatite
PubMed: 38900219
DOI: 10.1007/s10856-024-06805-y -
Chemistry (Weinheim An Der Bergstrasse,... Jun 2024The construction of a chemical library based on natural products is a promising method for the synthesis of natural product-like compounds. In this study, we synthesized...
The construction of a chemical library based on natural products is a promising method for the synthesis of natural product-like compounds. In this study, we synthesized a terpenoid alkaloid-like compound library based on the humulene skeleton. Our strategy, which enables access to diverse ring systems such as 11-membered monocyclic, oxabicyclic, and medium-sized aza ring-containing scaffolds, involves the introduction of a nitrogen atom, an intermolecular C-O bond formation via Lewis acid-mediated epoxide-opening transannulation, and a ring-reconstruction strategy based on olefin metathesis. A cheminformatics analysis based on their structural and physicochemical properties revealed that the synthesized compounds have high three-dimensionality and high natural product likeness scores but with structural novelty. The usefulness of the terpenoid alkaloid-like compound library for drug discovery and the accessibility to structure-activity relationship studies were validated by performing an assay for osteoclast-specific tartrate-resistant acid phosphatase activity, resulting in the identification of a lead compound for bone-resorptive diseases such as osteoporosis.
PubMed: 38897925
DOI: 10.1002/chem.202402082 -
International Journal of Surgery Case... Jul 2024Giant cell tumors of bone (GCTB) are infrequent tumors that usually impact the epiphyses of long bones and uncommonly manifest in the ribs. Herein, we report a case of...
INTRODUCTION AND IMPORTANCE
Giant cell tumors of bone (GCTB) are infrequent tumors that usually impact the epiphyses of long bones and uncommonly manifest in the ribs. Herein, we report a case of asymptomatic GCTB directly invading the lung tissue.
CASE PRESENTATION
A 36-year-old man was referred to our emergency department with only left chest pain. Computed tomography revealed a large heterogeneous solid cystic mass in the left lung apex and amorphous calcification and distraction in the posterior part of the left fourth rib. Histological examination also exhibited that the GCTB originated from the rib. The patient underwent an en-bloc resection with no recurrence in his one-year follow-up.
CLINICAL DISCUSSION
GCTB is characterized by osteoclast-like multinucleated giant cells and can exhibit aggressive local behavior. GCTB in the rib is rare, mainly found in the posterior arc. Radiographic features include lytic lesions with bone remodeling, often seen eccentrically in long bone epiphyses. Aggressive tumors may show cortical destruction and soft tissue extension. Surgery is often recommended for GCTB management, aiming for complete resection with sufficient surgical margins.
CONCLUSION
The absence of well-defined diagnostic criteria hinders the accurate diagnosis of GCTB, making a comprehensive assessment through radiological and histological examinations crucial. Upon physical examination, GCTB should be considered in the differential diagnosis for mediastinal lesions, regardless of their size. Furthermore, surgical removal can be taken into account as the primary treatment strategy for tumors that originate from the posterior arc of the ribs, such as GCTB.
PubMed: 38896991
DOI: 10.1016/j.ijscr.2024.109896 -
Differentiation; Research in Biological... Jun 2024Osteoclast (OC) differentiation, vital for bone resorption, depends on osteoclast and precursor fusion. Osteoprotegerin (OPG) inhibits osteoclast differentiation. OPG's...
Osteoclast (OC) differentiation, vital for bone resorption, depends on osteoclast and precursor fusion. Osteoprotegerin (OPG) inhibits osteoclast differentiation. OPG's influence on fusion and mechanisms is unclear. Osteoclasts and precursors were treated with OPG alone or with ATP. OPG significantly reduced OC number, area and motility and ATP mitigated OPG's inhibition. However, OPG hardly affected the motility of precusors. OPG downregulated fusion-related molecules (CD44, CD47, DC-STAMP, ATP6V0D2) in osteoclasts, reducing only CD47 in precursors. OPG reduced Connexin43 phosphorylated forms (P1 and P2) in osteoclasts, affecting only P2 in precursors. OPG disrupted subcellular localization of CD44, CD47, DC-STAMP, ATP6V0D2, and Connexin43 in both cell types. Findings underscore OPG's multifaceted impact, inhibiting multinucleated osteoclast and mononuclear precursor fusion through distinct molecular mechanisms. Notably, ATP mitigates OPG's inhibitory effect, suggesting a potential regulatory role for the ATP signaling pathway. This study enhances understanding of intricate processes in osteoclast differentiation and fusion, offering insights into potential therapeutic targets for abnormal bone metabolism.
PubMed: 38896972
DOI: 10.1016/j.diff.2024.100789 -
Environmental Health Perspectives Jun 2024Cadmium (Cd) is a highly toxic and widespread environmental oxidative stressor that causes a myriad of health problems, including osteoporosis and bone damage. Although...
BACKGROUND
Cadmium (Cd) is a highly toxic and widespread environmental oxidative stressor that causes a myriad of health problems, including osteoporosis and bone damage. Although nuclear factor erythroid 2-related factor 2 (NRF2) and its Cap 'n' Collar and basic region Leucine Zipper (CNC-bZIP) family member nuclear factor erythroid 2-related factor 1 (NRF1) coordinate various stress responses by regulating the transcription of a variety of antioxidant and cytoprotective genes, they play distinct roles in bone metabolism and remodeling. However, the precise roles of both transcription factors in bone loss induced by prolonged Cd exposure remain unclear.
OBJECTIVES
We aimed to understand the molecular mechanisms underlying Cd-induced bone loss, focusing mainly on the roles of NRF2 and NRF1 in osteoclastogenesis provoked by Cd.
METHODS
Male wild-type (WT), global -knockout () and myeloid-specific knockout [(M)-KO] mice were administered Cd (50 or ) via drinking water for 8 or 16 wk, followed by micro-computed tomography, histological analyses, and plasma biochemical testing. Osteoclastogenesis was evaluated using bone marrow-derived osteoclast progenitor cells (BM-OPCs) and RAW 264.7 cells in the presence of Cd (10 or ) with a combination of genetic and chemical modulations targeting NRF2 and NRF1.
RESULTS
Compared with relevant control mice, global or (M)-KO mice showed exacerbated bone loss and augmented osteoclast activity following exposure to Cd in drinking water for up to 16 wk. osteoclastogenic analyses suggested that -deficient BM-OPCs and RAW 264.7 cells responded more robustly to low levels of Cd (up to ) with regard to osteoclast differentiation compared with WT cells. Further mechanistic studies supported a compensatory up-regulation of long isoform of NRF1 (L-NRF1) and subsequent induction of nuclear factor of activated T cells, cytoplasmic, calcineurin dependent 1 (NFATc1) as the key molecular events in the deficiency-worsened and Cd-provoked osteoclastogenesis. L- silenced (via lentiviral means) -knockdown (KD) RAW cells exposed to Cd showed dramatically different NFATc1 and subsequent osteoclastogenesis outcomes compared with the cells of -KD alone exposed to Cd, suggesting a mitigating effect of the silencing. In addition, suppression of reactive oxygen species by exogenous antioxidants -acetyl-l-cysteine () and mitoquinone mesylate (MitoQ; ) mitigated the L-NRF1-associated effects on NFATc1-driven osteoclastogenesis outcomes in Cd-exposed -KD cells.
CONCLUSIONS
This and study supported the authors' hypothesis that Cd exposure caused bone loss, in which NRF2 and L-NRF1 responded to Cd and osteoclastogenic stimuli in a cooperative, but contradictive, manner to coordinate expression, osteoclastogenesis and thus bone homeostasis. Our study suggests a novel strategy targeting NRF2 and L-NRF1 to prevent and treat the bone toxicity of Cd. https://doi.org/10.1289/EHP13849.
Topics: Animals; Mice; Male; Cadmium; NF-E2-Related Factor 2; Osteoclasts; Osteogenesis; Mice, Knockout; NF-E2-Related Factor 1; Mice, Inbred C57BL; Cell Differentiation
PubMed: 38896780
DOI: 10.1289/EHP13849 -
ELife Jun 2024Spinal pain affects individuals of all ages and is the most common musculoskeletal problem globally. Its clinical management remains a challenge as the underlying...
Spinal pain affects individuals of all ages and is the most common musculoskeletal problem globally. Its clinical management remains a challenge as the underlying mechanisms leading to it are still unclear. Here, we report that significantly increased numbers of senescent osteoclasts (SnOCs) are observed in mouse models of spinal hypersensitivity, like lumbar spine instability (LSI) or aging, compared to controls. The larger population of SnOCs is associated with induced sensory nerve innervation, as well as the growth of H-type vessels, in the porous endplate. We show that deletion of senescent cells by administration of the senolytic drug Navitoclax (ABT263) results in significantly less spinal hypersensitivity, spinal degeneration, porosity of the endplate, sensory nerve innervation, and H-type vessel growth in the endplate. We also show that there is significantly increased SnOC-mediated secretion of Netrin-1 and NGF, two well-established sensory nerve growth factors, compared to non-senescent OCs. These findings suggest that pharmacological elimination of SnOCs may be a potent therapy to treat spinal pain.
Topics: Animals; Mice; Osteoclasts; Cellular Senescence; Sensory Receptor Cells; Disease Models, Animal; Male; Nerve Growth Factor; Netrin-1; Mice, Inbred C57BL
PubMed: 38896465
DOI: 10.7554/eLife.92889 -
Journal of Biomedical Materials... Jun 2024Increasing bone diseases and anomalies significantly challenge bone regeneration, necessitating the development of innovative implantable devices for effective healing....
Increasing bone diseases and anomalies significantly challenge bone regeneration, necessitating the development of innovative implantable devices for effective healing. This study explores the potential of 3D-printed calcium phosphate (CaP) scaffolds functionalized with natural medicine to address this issue. Specifically, quercetin and vitamin D3 (QVD) encapsulated solid lipid nanoparticles (QVD-SLNs) are incorporated into the scaffold to enhance bone regeneration. The melt emulsification method is utilized to achieve high drug encapsulation efficiency (~98%) and controlled biphasic release kinetics. The process-structure-property performance of these systems allows more controlled release while maintaining healthy cell-material interactions. The functionalized scaffolds show ~1.3- and ~-1.6-fold increase in osteoblast cell proliferation and differentiation, respectively, as compared with the control. The treated scaffold demonstrates a reduction in osteoclastic activity as compared with the control. The QVD-SLN-loaded scaffolds show ~4.2-fold in vitro chemopreventive potential against osteosarcoma cells. Bacterial assessment with both Staphylococcus aureus and Pseudomonas aeruginosa shows a significant reduction in bacterial colony growth over the treated scaffold. These findings summarize that the release of QVD-SLNs through a 3D-printed CaP scaffold can treat various bone-related disorders for low or non-load-bearing applications.
PubMed: 38894584
DOI: 10.1002/jbm.a.37756 -
Anti-Inflammatory Activity of No-Ozone Cold Plasma in Lipopolysaccharide-Induced Periodontitis Rats.International Journal of Molecular... Jun 2024Periodontitis is an inflammatory disease caused by () in the oral cavity. This periodontal disease causes damage to the periodontal ligament and alveolar bone and can...
Periodontitis is an inflammatory disease caused by () in the oral cavity. This periodontal disease causes damage to the periodontal ligament and alveolar bone and can cause tooth loss, but there is no definite treatment yet. In this study, we investigated the possibility of using no-ozone cold plasma to safely treat periodontitis in the oral cavity. First, human gingival fibroblasts (HGFs) were treated with -derived lipopolysaccharide (PG-LPS) to induce an inflammatory response, and then the anti-inflammatory effect of NCP was examined, and a study was conducted to identify the mechanism of action. Additionally, the anti-inflammatory effect of NCP was verified in rats that developed an inflammatory response similar to periodontitis. When NCP was applied to PG-LPS-treated HGFs, the activities of inflammatory proteins and cytokines were effectively inhibited. It was confirmed that the process of denaturing the medium by charged particles of NCP is essential for the anti-inflammatory effect of NCP. Also, it was confirmed that repeated treatment of periodontitis rats with NCP effectively reduced the inflammatory cells and osteoclast activity. As a result, this study suggests that NCP can be directly helpful in the treatment of periodontitis in the future.
Topics: Animals; Porphyromonas gingivalis; Periodontitis; Lipopolysaccharides; Rats; Anti-Inflammatory Agents; Humans; Gingiva; Fibroblasts; Ozone; Plasma Gases; Male; Cytokines; Disease Models, Animal; Nitric Oxide; Cells, Cultured
PubMed: 38892350
DOI: 10.3390/ijms25116161