Osteoclast Activity Research Articles

Preventing osteoporotic bone loss in mice by promoting balanced bone remodeling through M-CSFRGD, a dual antagonist to c-FMS and αvβ3 receptors

Osteoporosis is a common, age-related disease caused by imbalanced bone remodeling. Current treatments either shut down bone resorption or robustly stimulate bone formation. Here, we describe a novel compound that inhibits osteoclast activity without causing apparent disruptions to bone formation by targeting both c-FMS (i.e., osteoclast differentiation) and αvβ3 integrin (i.e., osteoclastic bone resorption) receptors. We show that human serum albumin (HSA)-conjugated M-CSFRGD protein (M-CSFRGD-HSA) effectively inhibits the activity of both receptors, with a three-fold higher serum half-life compared to the unconjugated M-CSFRGD. We then treated ovariectomized mice with different doses of M-CSFRGD-HSA, alendronate, or a monospecific control protein. The bispecific M-CSFRGD-HSA was superior to a monospecific control in alleviating bone loss and reducing osteoclast distribution and function. M-CSFRGD-HSA and alendronate effectively prevented ovariectomy-induced bone loss, but M-CSFRGD-HSA had a milder inhibitory effect on osteoclast distribution and activity. Moreover, alendronate halted bone formation, while M-CSFRGD-HSA-treated mice showed an increased level of serum amino-terminal propeptide of type I collagen, a bone formation marker. Our data indicate that the mild reduction in osteoclast activity facilitated by the bispecific M-CSFRGD-HSA allows the maintenance of certain levels of bone formation and may be superior to treatments that induce osteoclast depletion.

Semaglutide exposure and its association with adverse outcomes in diabetic patients undergoing transforaminal lumbar interbody fusion for lumbar degenerative disc disease.

Semaglutide, a novel glucagon-like peptide-1 receptor agonist, has transformed the therapeutic landscape for type 2 diabetes mellitus. However, its effect on osteoclast activity and its potential to induce weight-related muscle loss raises concerns about its impact on spine surgery outcomes. As such, evaluating semaglutide's influence on transforaminal lumbar interbody fusion (TLIF) is imperative, given the procedure's reliance on successful bony fusion to prevent postoperative instability and further interventions. Using an all-payer database (MARINER), the authors analyzed data from patients with type 2 diabetes mellitus who were 18-74 years of age and who underwent short-segment fusion (≤ 3-level) TLIFs between January 2018 and October 2022. Patients were either exposed to semaglutide or not. A comprehensive 1:3 (exposure vs no exposure) matching was performed based on age, sex, obesity, hypertension, coronary artery disease, chronic kidney disease, smoking status, osteoporosis, levels of surgery, and basal-bolus insulin dependence. Kaplan-Meier survival curves and log-rank testing were performed to study the probability of additional lumbar fusion surgery within 1 year. After the 1:3 matching, 1781 patients were identified, with 447 in the semaglutide-exposed cohort and 1334 in the nonexposed cohort. Most patients in both groups were 55-69 years old, and 59.3% were female. Analysis showed that the likelihood of undergoing additional lumbar fusion surgery within 1 year post-TLIF was significantly higher in the semaglutide-exposed group than in the nonexposed group (OR 11.79, 95% CI 8.17-17.33). Kaplan-Meier plots and log-rank testing further confirmed a statistically significant divergent probability in the need for additional surgery within 1 year between the cohorts (log-rank, p < 0.001). Semaglutide exposure appears to be associated with a higher likelihood of additional lumbar fusion surgeries within 1 year post-TLIF, especially in patients receiving the medication for longer durations. Although the mechanisms remain speculative, potential impacts on bone turnover and the onset of muscle loss may be contributory factors. Further research is needed to elucidate the exact mechanisms and to develop strategies for optimizing surgical outcomes in these patients.

HTLV-1 infected T cells cause bone loss via small extracellular vesicles.

Adult T cell leukaemia (ATL), caused by infection with human T- lymphotropic virus type 1 (HTLV-1), is often complicated by hypercalcemia and osteolytic lesions. Therefore, we studied the communication between patient-derived ATL cells (ATL-PDX) and HTLV-1 immortalized CD4+ T cell lines (HTLV/T) with osteoclasts and their effects on bone mass in mice. Intratibial inoculation of some HTLV/T leads to a profound local decrease in bone mass similar to marrow-replacing ATL-PDX, despite the fact that few HTLV/T cells persisted in the bone. To study the direct effect of HTLV/T and ATL-PDX on osteoclasts, supernatants were added to murine and human osteoclast precursors. ATL-PDX supernatants from hypercalcemic patients promoted the formation of mature osteoclasts, while those from HTLV/T were variably stimulatory, but had largely consistent effects between human and murine cultures. Interestingly, this osteoclastic activity did not correlate with expression of osteoclastogenic cytokine receptor activator of nuclear factor kappa-B ligand (RANKL), suggesting an alternative mechanism. HTLV/T and ATL-PDX produce small extracellular vesicles (sEV), known to facilitate HTLV-1 infection. We hypothesized that these sEV also mediate bone loss by targeting osteoclasts. We isolated sEV from both HTLV/T and ATL-PDX, and found they carried most of the activity found in supernatants. In contrast, sEV from uninfected activated T cells had little effect. Analysis of sEV (both active and inactive) by mass spectrometry and electron microscopy confirmed absence of RANKL and intact virus. Viral proteins Tax and Env were only present in sEV from the active, osteoclast-stimulatory group, along with increased representation of proteins involved in osteoclastogenesis and bone resorption. sEV from osteoclast-active HTLV/T injected over mouse calvaria in the presence of low-dose RANKL caused more osteolysis than osteoclast-inactive sEV or RANKL alone. Thus, HTLV-1 infection of T cells can cause release of sEV with strong osteolytic potential, providing a mechanism beyond RANKL production that modifies the bone microenvironment, even in the absence of overt leukaemia.

How malocclusion interferes with tissue inhibitor of metalloproteinase-1 expression and morphology of the articular cartilage of the mandible in female rats

ObjectiveThe purpose of this study was to investigate morphological alterations and tissue inhibitor of metalloproteinase-1 expression in the articular cartilage of the mandible under conditions of experimentally induced malocclusion. DesignTwenty-four 8-week-old female Wistar rats were used and divided into control and experimental groups with two different treatment periods (2 and 4 weeks). Sagittal malocclusions were orthodontically created, causing mesial movement of the first molars and distalization of the third molars unilaterally and on opposite sides of the arches. Sagittal sections of the articular cartilage of the mandible were subjected to hematoxylin and eosin and immunohistochemistry for tissue inhibitor of metalloproteinase-1. Chi-square and MannWhitney U tests were applied. ResultsAnimals treated for 2 and 4 weeks showed morphological alterations in articular cartilage of the mandible. The main findings were thickening of the posterior third, layer derangement, osteoclast activity and osteophyte formation. Among the cellular aspects, the presence of chondrocytes with condensed nuclei and cytoplasm reduction were observed. The enzyme in control animals was observed only in the mature layer. Treated animals showed immunopositive cells in the proliferative and mature layers, and in the 2-week treated group, the posterior third of the cartilage had more immunolabeled cells than control (P=0.0291). ConclusionsThe occlusal disorder caused morphological changes in articular cartilage of the mandible, probably due to the attempt to adapt to the new condition. Tissue inhibitor of metalloproteinase-1 expression may play a role as an initial modulator in the biological events observed in articular cartilage of the mandible.

Exacerbating orthodontic tooth movement in mice with salt-sensitive hypertension

Background/purposeOrthodontic tooth movement (OTM) is a critical aspect of dental treatment that requires the precise control of bone remodeling processes. Hypertension (HTN) can affect the effectiveness of OTM. Salt-sensitive hypertension (SSHTN) is of particular concern due to its detrimental effects on bone health, potentially altering orthodontic outcomes. This study aimed to investigate the effects of SSHTN on OTM using a mouse model. Materials and methodsMale mice were divided into a normal and an SSHTN group. The SSHTN model was generated by administering N(ω)-nitro-l-arginine methyl ester (l-NAME) followed by a high-salt diet. The OTM was performed using a nickel-titanium (Ni-Ti) closed-coil spring, and the tooth movement was measured after 12 days. Silicone imprinting was used to estimate the OTM distance. Osteoclast activity was assessed using tartrate-resistant acid phosphatase (TRAP) staining of decalcified maxillary sections. ResultsSSHTN mice exhibited significantly increased tooth movement compared to normal mice. This enhanced movement was associated with more osteoclasts in the SSHTN group than in the control group. These findings suggest that SSHTN increases OTM levels by promoting bone resorption. ConclusionSSHTN significantly affected OTM by enhancing osteoclast activity and increasing tooth movement. These results underscore the importance of considering hypertensive conditions in orthodontic treatment planning as they may require adjustments in force application to prevent potential adverse effects.

On the influence of structural and chemical properties on the elastic modulus of woven bone under healing.

Woven bone, a heterogeneous and temporary tissue in bone regeneration, is remodeled by osteoblastic and osteoclastic activity and shaped by mechanical stress to restore healthy tissue properties. Characterizing this tissue at different length scales is crucial for developing micromechanical models that optimize mechanical parameters, thereby controlling regeneration and preventing non-unions. This study examines the temporal evolution of the mechanical properties of bone distraction callus using nanoindentation, ash analysis, micro-CT for trabecular microarchitecture, and Raman spectroscopy for mineral quality. It also establishes single- and two-parameter power laws based on experimental data to predict tissue-level and bulk mechanical properties. At the macro-scale, the tissue exhibited a considerable increase in bone fraction, controlled by the widening of trabeculae. The Raman mineral-to-matrix ratios increased to cortical levels during regeneration, but the local elastic modulus remained lower. During healing, the tissue underwent changes in ash fraction and in the percentages of Calcium and Phosphorus. Six statistically significant power laws were identified based on the ash fraction, bone fraction, and chemical and Raman parameters. The microarchitecture of woven bone plays a more significant role than its chemical composition in determining the apparent elastic modulus of the tissue. Raman parameters were demonstrated to provide more significant power laws correlations with the micro-scale elastic modulus than mineral content from ash analysis.

MicroRNA-324 mediates bone homeostasis and the regulation of osteoblast and osteoclast differentiation and activity

MicroRNAs (miRNAs) modulate the expression of other RNA molecules. One miRNA can target many transcripts, allowing each miRNA to play key roles in many biological pathways. Defects in bone homeostasis result in common age-related diseases including osteoporosis. Serum levels of miR-324-3p positively correlate with several features of bone maintenance. In contrast here, using in vivo micro-computed tomography and histology, global miR-324-null mice demonstrated increased bone mineral density and both trabecular and cortical thickness, with effect magnitudes increasing with age. The bone marrow of miR-324-null mice had reduced lipid content while TRAP staining revealed a decrease in osteoclasts, with histomorphometry demonstrating an increased rate of bone formation. Ex vivo assays showed that the high bone mass phenotype of miR-324-null mice resulted from both increased osteoblast activity and decreased osteoclastogenesis. RNA-seq analysis of osteoblasts, osteoclasts and bone marrow macrophages and target validation assays identified that the osteoclast fusion regulator Pin1 and the master osteogenic regulator Runx2 were targets of miR-324-5p in osteoclast lineage cells and osteoblasts, respectively. Indeed, in vitro Runx2 overexpression recapitulated the increased osteogenesis and decreased adipogenesis phenotype observed in vivo by the loss of miR-324. Overall, these data demonstrate the importance of miR-324 in bone homeostasis by regulating aspects of both bone formation and remodelling. Elucidation of pathways regulated by miR-324 offer promise for the treatment of bone diseases such as osteoporosis.

Herbal medicine Ninjinyoeito inhibits RANKL-induced osteoclast differentiation and bone resorption activity by regulating NF-κB and MAPK pathway

ObjectivesOsteoporosis is a systemic bone metabolism disorder characterized by decreased bone mass and strength. Osteoclasts (OCs) are giant multinucleated cells that regulate bone homeostasis by degrading bone matrix. Excessive OC differentiation and activity can lead to serious bone metabolic disorders including osteoporosis. Current treatments, including antiresorptive drugs, exert considerable adverse effects, including jaw osteonecrosis. Herbal medicines, such as Ninjinyoeito (NYT), may also offer efficacy, but with fewer adverse effects. In this study, we investigated NYT's effects on osteoclastogenesis. MethodsTartrate-resistant acid phosphatase (TRAP) staining and bone resorption assays were performed to examine NYT's effects on OC differentiation and function. OC-related gene expression at mRNA and protein levels was investigated to confirm NYT's inhibitory action against osteoclastogenesis. We also demonstrated involvement of signaling pathways mediated by IκBα and mitogen-activated protein kinases (MAPK) [extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38] and showed nuclear translocation of nuclear factor of activated T-cell cytoplasmic 1 (NFATc1) and nuclear factor kappa B (NF-κB) p65 during osteoclastogenesis. ResultsTRAP staining and bone resorption assays confirmed that NYT significantly inhibited OC differentiation and function. Western blot and RT-PCR results showed that NYT ameliorated osteoclastogenesis by suppressing mRNA and protein level expression of OC-related genes. Moreover, blots and immunocytochemistry (ICC) data clarified that NYT abrogates signaling pathways mediated by IκBα and MAPK (ERK, JNK, p38), and demonstrated nuclear translocation of NFATc1 and NF-κB p65 during OC differentiation. ConclusionsThese findings suggest NYT is an alternative therapeutic candidate for treating osteoporosis.

Cellular senescence by loss of Men1 in osteoblasts is critical for age-related osteoporosis.

Recent evidence suggests an association between age-related osteoporosis and cellular senescence in the bone; however, the specific bone cells that play a critical role in age-related osteoporosis and the mechanism remain unknown. Results revealed that age-related osteoporosis is characterized by the loss of osteoblast Men1. Osteoblast-specific inducible knockout of Men1 caused structural changes in the mice bones, matching the phenotypes in patients with age-related osteoporosis. Histomorphometrically, Men1-knockout mice femurs decreased osteoblastic activity and increased osteoclastic activity, hallmarks of age-related osteoporosis. Loss of Men1 induces cellular senescence via mTORC1 activation and AMPK suppression, rescued by metformin treatment. In bone morphogenetic protein-indued bone model, loss of Men1 leads to accumulation of senescent cells and osteoporotic bone formation, which are ameliorated by metformin. Our results indicate that cellular senescence in osteoblasts plays a critical role in age-related osteoporosis and that osteoblast-specific inducible Men1-knockout mice offer a promising model for developing therapeutics for age-related osteoporosis.

A size-switchable microsphere loaded with salmon calcitonin as two-weekly dosing for osteoporosis therapy

Osteoporosis is a disease with an increased incidence of fractures due to decreased bone mass and destruction of the microstructure of bone tissue. Salmon calcitonin (sCT), as a peptide, possesses the ability to inhibit osteoclast activity and thus regulate bone metabolism in clinical. However, short half-life and unstable physicochemical properties leading to rapid degradation of sCT have severely limited its clinical application. In this study, a size-switchable microsphere was developed to solve the problem of frequent administration and poor stability of sCT. sCT was encapsulated into Egg PC to form anhydrous reverse micelles (ARM) and then ARM was encapsulated into microspheres (MS@ARM). The degradable composite microspheres were utilized to provide a drug reservoir for sustained release of ARM encapsulated with sCT to reduce the frequency of drug administration, while the released ARM encapsulated with sCT entered the blood circulation to further protect sCT. In vitro release experiments demonstrated that the microspheres could sustain the release of sCT for at least 16 days. The microspheres MS@ARM showed the advanced therapeutic effect on the mouse model of glucocorticoid-induced osteoporosis (GIOP) at a low dosing frequency. The size-switchable microsphere is expected to be a new strategy for delivering sCT for osteoporosis treatment.

Myoblast-Derived Galectin 3 Impairs the Early Phases of Osteogenesis Affecting Notch and Akt Activity.

Galectin-3 (Gal-3) is a pleiotropic lectin produced by most cell types, which regulates multiple cellular processes in various tissues. In bone, depending on its cellular localization, Gal-3 has a dual and opposite role. If, on the one hand, intracellular Gal-3 promotes bone formation, on the other, its circulating form affects bone remodeling, antagonizing osteoblast differentiation and increasing osteoclast activity. From an analysis of the secretome of cultured differentiating myoblasts, we interestingly found the presence of Gal-3. After that, we confirmed that Gal-3 was expressed and released in the extracellular environment from myoblast cells during their differentiation into myotubes, as well as after mechanical strain. An in vivo analysis revealed that Gal-3 was triggered by trained exercise and was specifically produced by fast muscle fibers. Speculating a role for this peptide in the muscle-to-bone cross talk, a direct co-culture in vitro system, simultaneously combining media that were obtained from differentiated myoblasts and osteoblast cells, confirmed that Gal-3 is a mediator of osteoblast differentiation. Molecular and proteomic analyses revealed that the secreted Gal-3 modulated the biochemical processes occurring in the early phases of bone formation, in particular impairing the activity of the STAT3 and PDK1/Akt signaling pathways and, at the same time, triggering that one of Notch. Circulating Gal-3 also affected the expression of the most common factors involved in osteogenetic processes, including BMP-2, -6, and -7. Intriguingly, Gal-3 was able to interfere with the ability of differentiating osteoblasts to interact with the components of the extracellular bone matrix, a crucial condition required for a proper osteoblast differentiation. All in all, our evidence lays the foundation for further studies to present this lectin as a novel myokine involved in muscle-to-bone crosstalk.

Effectiveness of Short-Term Use Denosumab and Risedronate Using β-Crosslaps and Histopathology as a Parameter in Osteoporotic Rat Model

Osteoporosis is a condition of decreased bone mass density. Pharmacological management uses drugs that decrease bone resorption or increase bone formation. The most commonly used drugs are bisphosphonates. Risedronate is one of these bisphosphonates. It inhibits osteoclasts, resulting in osteoclast apoptosis. Denosumab is a human monoclonal antibody that inhibits receptor activator kappa-B ligand, inhibiting osteoclast activation. Both drugs are widely used. Research on the efficacy of these two mechanisms has yet to obtain conclusive results. β-cross-laps is a parameter that can be used to evaluate the effectiveness of therapy through monitoring the bone resorption process. This experimental study used female rats &gt;9 weeks old and was conducted at the Pharmacology and Therapeutic Laboratory, Universitas Padjadjaran Bandung, Indonesia, from June to September 2021. This study utilized a simple random sampling to allocate 24 experimental animals into three groups: control, risedronate, and denosumab. β-Crosslaps expression values before ovariectomy, post ovariectomy before receiving medication, and post ovariectomy and receiving medication was recorded and statistically analyzed using the SPSS version 24.0. The analysis of 24 samples revealed a statistically significant decrease in the median value of β-Crosslaps after ovariectomy in the denosumab group (p=0.036) when compared to the control group, whereas the decrease in the risedronate group was not significant (p=0.687). Administration of denosumab in rat models is more effective in reducing bone resorption compared to risedronate.

Angiotensin Receptor Blockers, But Not Angiotensin Converting Enzyme Inhibitors, Improve Bone Mineral Density: Results From The TUDA study

Abstract Background Both hypertension and osteoporosis are common in older adults and frequently co-exist. The renin angiotensin system has been implicated in osteoclast activation and bone loss. Several studies have previously examined the relationship between various inhibitors of RAS and bone mineral density (BMD). In this study we examined the relationship between angiotensin receptor blockers (ARBs) and angiotensin converting enzyme ACE inhibitors and BMD. Methods Study participants were from a cross-sectional study of adults aged &amp;gt;60 years; Trinity Ulster University Department of Agriculture (TUDA) study. We excluded participants on treatments for osteoporosis. In users and non-users of ARBs and ACE inhibitors, we compared least squares means BMD measured by densitometry at the neck of femur, hip, and lumbar spine adjusted for age, sex, body mass index, timed up and go, vitamin D, parathyroid hormone, eGFR, diabetes mellitus, smoking, alcohol consumption, dairy intake, glucocorticoid exposure, thiazide, and loop diuretic use. Results There were 2218 participants (mean age 70.1±6.5 years, 58.3% female, 23.4% (n=519) on ARBs and 30.9% (n=686) on ACE inhibitors). In both univariate and multivariate analysis, ARB users had higher BMD than non-users were associated with higher BMD at the neck of femur (0.860 g/cm² vs. 0.846 g/cm², p=0.016); at the total hip, (0.938 g/cm² vs. 0.919 g/cm², p=0.004); at the lumbar spine, BMD was 1.106 g/cm² vs. 1.074 g/cm² p&amp;lt; 0.001). No significant relationship between ACE inhibitors and BMD at any site was observed after multivariate adjustment. Conclusion ARBs were associated with improved BMD while ACE inhibitors were not. Similar results have been found in other studies but the mechanisms but there is substantial uncertainty regarding the mechanisms underlying these relationships. These findings could be important in the choice of antihypertensive agent in older patients at risk of fracture and further research is warranted.

The effects of fulvic acids and low-level laser therapy on orthodontic retention in rats

BackgroundShortening retention time and minimizing relapse rates are ongoing challenges in orthodontics. This study investigated the effects of natural fulvic acids (FAs) and low-level laser therapy (LLLT) on orthodontic retention in rats.MethodsSeventy-two male Sprague-Dawley rats underwent mesial movement of the left maxillary first molar using a 50 g force via a nickel-titanium tension spring. After three weeks of movement, the rats entered the retention phase with retainer wires and were divided into four groups: Control (no intervention), FAs (80 mg/kg orally daily), LLLT (808 nm laser twice weekly), and FAs + LLLT (both treatments). Retainers were removed on days 7, 14, and 21 for a 3-day relapse assessment. Maxillary impressions were analyzed for relapse rates using 3Shape software, alongside histological and immunohistochemical evaluations of bone morphogenetic protein-2 (BMP-2) expression in periodontal tissues, with differences among groups analyzed using an ordinary two-way analysis of variance (ANOVA).ResultsThe relapse rate decreased over time, particularly at 10, 17, and 24 days (p < 0.001). The FAs group did not significantly affect relapse rates compared to the control group (p = 0.084). In contrast, both the LLLT and FAs + LLLT groups significantly reduced relapse rate (p < 0.001), with no significant difference between these groups (p = 0.555). Histological examination revealed active osteoclasts on day 10, decreasing by days 17 and 24. The LLLT and FAs + LLLT groups showed less local cementum resorption and better periodontal fiber arrangement. All treatment groups significantly increased BMP-2 expression (P < 0.05) compared to controls. with LLLT and FAs + LLLT differing significantly from FAs (P < 0.001), though no difference was observed between LLLT and FAs + LLLT (P = 0.578).ConclusionsFAs did not significantly reduce relapse rate with retainers, while LLLT effectively reduced relapse rates, showing no additional benefit from combining FAs with LLLT. Both FAs and LLLT increased BMP-2 expression in PDL fibroblasts but with no synergistic effect.

Increased bone mass but delayed mineralization: in vivo and in vitro study for zoledronate in bone regeneration

BackgroundBisphosphonates (BPs) are widely used to inhibit excessive osteoclast activity. However, the potential to compromise bone defect healing has limited their broader application. To better understand the influence of BPs on bone regeneration, we established a bone grafting model with Zoledronate administration, aiming to deepen the understanding of bone remodeling and mineralization processes.MethodsA bone grafting model was established in the distal femurs of male Sprague–Dawley rats. The experimental group received systemic administration of Zoledronate (ZOL, 0.2 mg/kg, administered twice). Histological analysis and immunohistochemistry (IHC) were employed to assess osteoblastic and macrophage activity, tartrate-resistant acid phosphatase (TRAP) staining was used to evaluate osteoclastogenesis. Mineralization was assessed through Micro-CT analysis, Raman spectroscopy, and back-scatter scanning electron microscopy (BSE-SEM). Additionally, the in vitro effects of ZOL on osteoblast and osteoclast activity were investigated to further elucidate its impact on bone regeneration.ResultsIn vivo, the ZOL group showed increased bone mass, as observed in histological and radiological assessments. However, Micro-CT, Raman spectroscopy, and BSE-SEM detection revealed lower mineralization levels in ZOL group's regenerated bone. Acid-etched SEM analysis showed abnormal osteocyte characteristics in ZOL-group’s regenerated bone. Simultaneously, elevated osteopontin (OPN), F4/80 expression along with reduced TRAP expressing was found in the grafting region of ZOL group. In vitro, ZOL did not negatively impact osteogenetic activity (ALP, BMP4, OCN expression) at the tested concentrations (0.02–0.5 g/ml) but significantly impaired mineralization and inhibited osteoclast formation, even at the lowest concentration.ConclusionsThis study highlights a less recognized negative effect of ZOL on bone mineralization during bone regeneration. More research is needed to elucidate the underlying mechanism.

The Effect of Corticotomy-Assisted Orthodontic Therapy (CAOT) or Periodontally Accelerated Osteogenic Orthodontics (PAOO) on Bone Remodeling and the Health of Periodontium: A Systematic Review of Systematic Reviews.

Background: Orthodontic treatment involves moving teeth within the alveolar ridge. Bone remodeling is associated with the activity of osteoblasts and osteoclasts. Procedures such as corticotomy-assisted orthodontic therapy (CAOT) or periodontally accelerated osteogenic orthodontics (PAOO) are intended to reduce bone density and negative stress on the grip side and therefore limit bone resorption during orthodontic movement or add bone substitute material so that the tooth does not cross the vestibular plate. Methods: The study was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The study design was defined in the PICO format-Population (P): patients with full permanent dentition, both adolescents and adults; Intervention (I): orthodontic treatment with fixed appliances using additional supportive treatments such as CAOT or PAOO; Comparison (C): assessment of the impact of additional treatments during orthodontic treatment on the remodeling of the alveolar bone and the condition of the periodontium; Result (O): statistically significant/non-significant differences in the condition of the alveolar bone before and after orthodontic treatment. Search filters include the time of publication of the article, systematic reviews from the last five years, and publications that appeared in English. The information provided in the abstracts of systematic reviews that describe the effects of additional procedures during orthodontic treatment such as CAOT or PAOO on the health of periodontium was analyzed. Articles unrelated to the subject of the planned study and those in which tooth movement acceleration was analyzed were excluded. Results: Eight articles were selected in which a total number of 835 subjects took part. The changes in bone density and effects on periodontium were different after CAOT and PAOO. Conclusions: The validity of CAOT and PAOO procedures remains controversial. Better results are obtained when combined with tissue augmentation or thickening of the gingival phenotype rather than as stand-alone procedures, as their uses to protect periodontal tissues are limited.

Lycium barbarum glycopeptide reduces bone loss caused by exosomes derived from human gingival fibroblasts with radiation exposure

To explore the protective effect of Lycium barbanun glycopeptide (LbGP) against osteogenic inhibition induced by exosomes derived from human gingival fibroblasts (HGFs) exposed to radiation. Cultured HGFs with or without LbGP pretreatment were exposed to 8 Gy X-ray radiation, and the changes in cell apoptosis, senescence and α-SMA level were detected using RT-qPCR, Western blotting and β-galactosidase staining. The exosomes secreted by the treated cells were extracted, and after identification by electron microscopy, particle size analysis and Western blotting, the exosomes were added into primary cultured bone mesenchymal stem cells (BMSCs), and osteoclast activity and osteogenesis in the cell cultures were detected by Trap staining, Alizarin red staining, ALP staining, RT-qPCR and Western blotting. In cultured HGFs, X-ray radiation significantly increased the percentage of senescent cells, which was obviously lowered by LbGP treatment. X-ray radiation significantly reduced Bcl-2/Bax ratio and increased α -SMA expression in HGFs, and these changes were significantly suppressed by LbGP pretreatment. In rat BMSCs, incubation with the exosomes derived from HGFs with radiation exposure caused a significant increase of osteoclasts, reduced calcium nodules and lowered alkaline phosphatase expression in the cells; The opposite changes were observed in the cells treated with exosomes from LbGPpretreated HGFs, which also significantly increased the cellular expressions of the osteogenic genes (BMP2, ALP, and RUNX2) and proteins (ALP and RUNX2) as compared with the exosomes from irradiated HGFs. LbGP can effectively inhibit osteoclast activity and promote osteogenesis by acting on exosomes secreted by irradiated HGFs, suggesting its potential value for treatment of osteoradionecrosis of the jaw.

Chikungunya-Driven Gene Expression Linked to Osteoclast Survival and Chronic Arthralgia.

Chikungunya fever (CHIKF), caused by the Chikungunya virus (CHIKV), manifests as acute febrile illness often associated with polyarthritis and polyarthralgia. Although the acute symptoms resolve within two weeks, many patients experience prolonged joint pain and inflammation, resembling rheumatoid arthritis (RA). This study aimed to identify molecular markers related to joint pain and chronicity in CHIKV-infected individuals by analyzing blood transcriptomes using bulk RNA sequencing. B- and T-cell receptor (BCR and TCR) diversity was assessed through computational analysis of RNA-seq data, revealing a significant reduction in CDR3 diversity in CHIKV-infected individuals compared to healthy controls. This reduced diversity was associated with the upregulation of genes involved in osteoclast differentiation and activation, particularly through the RANK/RANKL signaling pathway. These findings suggest a potential link between immune dysregulation and enhanced osteoclast activity, which may contribute to the persistence of joint pain in chronic CHIKF. Targeting osteoclast-related pathways could offer therapeutic strategies for managing chronic symptoms in CHIKF patients.

Role of ginsenosides in bone remodelling: A narrative review on molecular mechanism

Osteoporosis (OP) is a metabolic bone disease that impacts a large number of humanity. Degeneration of the bone microstructure, loss of mass, and heightened fragility are symptoms. The primary reason is because the rates of bone formation and resorption are different. Extensive research on the effects of ginsenoside, a component of ginseng used in traditional Indian medicine, on osteoporosis has shown promising results. There were forty-four articles written about ginsenosides, osteoblasts, osteoclasts, osteoporosis, and bone mesenchymal cells. The effects of ginsenosides on osteoblast, osteoclast, and mesenchymal stem cell activity in bone remodelling and their potential role in preventing osteoporosis were the focus of these studies. This in-depth study sheds light on the several ginsenosides used to treat osteoporosis from different perspectives, paving the way for potential therapeutic applications in the future.

Peptides as modulators of FPPS enzyme: A multifaceted evaluation from the design to the mechanism of action

Bone diseases are medical conditions caused by the loss of bone homeostasis consecutive to increased osteoclast activity and diminished osteoblast activity. The mevalonate pathway (MVA) is crucial for maintaining this balance since it drives the post-translational prenylation of small guanosine triphosphatases (GTPases) proteins. Farnesyl pyrophosphate synthase (FPPS) plays a crucial role in the MVA pathway. Consequently, in the treatment of bone-related diseases, FPPS is the target of FDA-approved nitrogen-containing bisphosphonates (N-BPs), which have tropism mainly for bone tissue due to their poor penetration in soft tissues. The development of inhibitors targeting the FPPS enzyme has garnered significant interest in recent decades due to FPPS's role in the biosynthesis of cholesterol and other isoprenoids, which are implicated in cancer, bone diseases, and other conditions. In this study, we describe a multidisciplinary approach to designing novel FPPS inhibitors, combining computational modeling, biochemical assays, and biophysical techniques. A series of peptides and phosphopeptides were designed, synthesized, and evaluated for their ability to inhibit FPPS activity. Molecular docking was employed to predict the binding modes of these compounds to FPPS, while Surface Plasmon Resonance (SPR) and Nuclear Magnetic Resonance (NMR) spectroscopy experiments – based on Saturation Transfer Difference (STD) and an enzymatic NMR assay – were used to measure their binding affinities and kinetics. The biological activity of the most promising compounds was further assessed in cellular assays using murine colorectal cancer (CRC) cells. Additionally, genomics and metabolomics profiling allowed to unravel the possible mechanisms underlying the activity of the peptides, confirming their involvement in the modulation of the MVA pathway. Our findings demonstrate that the designed peptides and phosphopeptides exhibit significant inhibitory activity against FPPS and possess antiproliferative effects on CRC cells, suggesting their potential as therapeutic agents for cancer.