Loss Of Bone Mass Research Articles

Effect of Luteolin on cadmium-inhibited bone growth via suppressing osteoclastogenesis in laying chickens.

Luteolin (Lut) is a flavonoid derived from several plant sources. Cadmium (Cd) is a widespread environmental contaminant and potential toxin with detrimental effects on animal health. However, the effect of Lut on Cd-induced inhibition of bone growth in laying chickens remains unclear. This study investigates the effects of Lut on Cd-induced inhibition of bone growth in the femur and tibia of laying chickens. A total of sixty 1-day-old green-eggshell yellow feather laying chickens were randomly assigned to four groups after a 5-day of acclimation period: basal diet (Con), cadmium chloride (CdCl2, Cd), Lut, and Lut + Cd. Bone microstructure, serum biomarkers of bone remodeling, the levels of Cd, calcium (Ca), phosphorus (P), and trace metal elements were assessed using the micro-computed tomography (Micro-CT), enzyme-linked immunosorbent assay (ELISA), and microwave digestion, respectively. Bone remodeling biomarkers, late endosomal/lysosomal adaptor and MAPK and mTOR activator 1 (LAMTOR1), as well as the phosphorylation of AMP-activated protein kinase α (AMPKα) and protein kinase B (Akt), were quantified using the qRT-PCR and western blot. The results indicated that Lut effectively mitigated Cd-induced bone mass loss compared to the Cd group, resulting in increased bone volume (BV), bone surface/bone volume (BS/BV), connectivity density (Conn.Dn), and the length and weight of the femur and tibia in laying chickens. Mechanistically, compared to Cd group, Lut restored the ratio of osteoprotegerin (OPG)/receptor activator of NF-κB ligand (RANKL) in serum and bone tissue, enhanced the expression of bone morphogenetic protein-2 (BMP-2), runt-related transcription factor 2 (Runx2), osteocalcin (OCN), and Osterix (OSX), while reducing the levels of Ca, Cd, and alkaline phosphatase (ALP) activity, as well as the expression of osteopontin (OPN), c-Fos, osteoclast stimulatory-transmembrane protein (OC-STAMP), tartrate-resistant acid phosphatase (TRAP), cathepsin K (CTSK), matrix metalloprotein-9 (MMP-9), LAMTOR1, and the phosphorylation of AMPKα and Akt. Therefore, Lut alleviates Cd-induced damage to the femur and tibia of chickens by promoting osteogenesis and inhibiting osteoclastogenesis, positioning Lut as a potential therapeutic plant extract for enhancing bone growth in laying chickens.

Jingui Shenqi Wan alleviates bone loss induced by primary osteoporosis by inhibiting osteoblast pyroptosis

ObjectiveThe primary objective of this study was to elucidate the underlying pharmacological mechanisms by which Jingui Shenqi Wan (JGSQW) alleviates postmenopausal osteoporosis (PMOP). Through a systematic investigation, we sought to identify the specific molecular pathways through which JGSQW modulates the progression of PMOP, thereby providing a scientific basis for its clinical application.MethodsWe established an ovariectomized (OVX) mouse model to simulate estrogen deficiency-induced PMOP. Initially, micro-CT imaging and Alcian blue hematoxylin/orange G (ABH/OG) staining were employed to assess the effects of JGSQW on bone microarchitecture and bone mass preservation. Immunohistochemistry (IHC) was then utilized to evaluate the expression of osteogenic markers, including Osterix (OSX), Runx2, and Osteopontin (OPN). Additionally, Tartrate - Resistant Acid Phosphatase (TRAP) staining was performed to visualize and quantify osteoclasts. We further investigated the potential role of JGSQW in modulating the pyroptosis pathway.ResultsJGSQW effectively alleviates the destruction of bone microstructure and the loss of bone mass caused by estrogen deficiency, an effect that appears to be mediated by promoting osteogenesis. Additionally, JGSQW significantly downregulates the expression of GSDMD in osteoblasts and mitigates the abnormal release of inflammatory factors, thereby maintaining the normal functional activities of osteoblasts.ConclusionJGSQW may effectively mitigate the progression of estrogen deficiency-induced PMOP by inhibiting the dysregulated activation of osteoblast pyroptosis.

The diagnostic value of the combined application of blood lipid metabolism markers and interleukin-6 in osteoporosis and osteopenia

BackgroundThis study aimed to analyse the relationship of the blood lipid profile and interleukin-6 (IL-6) with osteoporosis and osteopenia and to explore the predictive value of the combined application of these biomarkers in osteoporosis and osteopenia.MethodsData from 276 patients treated in the orthopaedics department were retrospectively analysed. Their general information was collected, and the relationships among the blood lipid profile, IL-6 with bone turnover markers, and bone mineral density (BMD) were analysed. Patients were categorized based on their T scores for intergroup comparisons. Finally, the diagnostic efficiency of lipid metabolism markers and IL-6 for osteoporosis and osteopenia was assessed using receiver operating characteristic (ROC) curves.Results(1) In both males and females, a negative relationship was observed between BMD and several biomarkers, including total cholesterol (TC), apolipoprotein B (ApoB), low-density lipoprotein cholesterol (LDL-C), free fatty acids (FFAs), and IL-6. Additionally, apolipoprotein A1 (ApoA1) was negatively correlated with BMD only in females, and the ApoA1/ApoB ratio was positively correlated with BMD only in males. (2) FFAs and IL-6 were positively correlated with β-CrossLaps peptide in males. However, for females, TC, ApoB, LDL-C, and IL-6 were negatively correlated with 25-hydroxyvitamin D. FFAs, IL-6, and age were negatively correlated with osteocalcin in males and females. (3) According to the T scores for the lumbar spine, the TC, ApoA1, ApoB, HDL-C, LDL-C, FFA, and IL-6 levels in the osteoporosis group and the TC, ApoB, LDL-C, and FFA levels in the osteopenia group were significantly greater than those in the normal bone mass group. Additionally, the osteoporosis group presented substantially higher levels of ApoA1, FFAs, and IL-6 than the osteopenia group. (4) IL-6 was positively correlated with FFAs, while a negative correlation was observed with TC, ApoA1, ApoB, HDL-C, and LDL-C. (5) The ROC curve revealed that the areas under the curve (AUCs) of TC, FFAs, IL-6, ApoA1, and the ApoA1/ApoB ratio for predicting osteoporosis or osteopenia were 0.634, 0.713, 0.670, 0.628, and 0.516, respectively, whereas the AUC of the combination of TC, FFAs, IL-6, and ApoA1 was 0.846, and the AUC of the combination of TC, FFAs, IL-6, and the ApoA1/ApoB ratio was 0.842. In the sex stratification analysis, in males, the AUCs of TC, FFAs, IL-6, and the ApoA1/ApoB ratio for the prediction of osteoporosis or osteopenia were 0.596, 0.688, 0.739, and 0.539, respectively. In contrast, the AUC of the combination of TC, FFAs, IL-6, and the ApoA1/ApoB ratio was 0.838. In females, the AUCs of TC, FFAs, IL-6, ApoA1, and the ApoA1/ApoB ratio for predicting osteoporosis or osteopenia were 0.620, 0.728, 0.653, 0.611, and 0.502, respectively, whereas the AUC of the combination of TC, FFAs, IL-6, and ApoA1 was 0.841, and the AUC of the combination of TC, FFAs, IL-6, and the ApoA1/ApoB ratio was 0.828.ConclusionThe levels of TC, FFAs, IL-6, ApoA1, and ApoB could contribute to changes in bone metabolism, moreover, FFAs could induce an increase in IL-6 further aggravating bone mass loss and leading to osteoporosis. Based on the comparison of the AUC results, the combination of TC, FFAs, and IL-6 with ApoA1 or the ApoA1/ApoB ratio can better predict osteoporosis or osteopenia in patients, and the diagnostic efficiency is significantly better than that of any individual indicator. The regulation of blood lipid levels should become a new target for clinicians to treat osteoporosis and osteopenia.

Exploring the relationship between periodontal diseases and osteoporosis: Potential role of butyrate.

Osteoporosis, a condition marked by the loss of bone density and mass, affects individuals of all ages. However, it becomes more prevalent and severe with aging, increasing the risk of fractures and other health complications. Recent research has highlighted a link between osteoporosis and periodontitis, a chronic gum disease, as both conditions involve excessive bone loss that can lead to significant oral health problems if untreated. The growing interest in strategies to prevent bone loss has brought attention to butyrate, a short-chain fatty acid produced by gut bacteria during fiber fermentation. Butyrate has demonstrated protective effects against systemic bone loss, particularly in the context of osteoporosis. Notably, oral bacteria also produce butyrate, suggesting its potential as a therapeutic tool for preventing periodontal bone loss. Given the connection between systemic and oral health, understanding the role of butyrate in bone metabolism could offer new avenues for treating osteoporosis and periodontitis. This review will explore the biological mechanisms through which butyrate influences bone health, aiming to highlight its potential therapeutic applications in preventing bone loss across these conditions.

Bone Density Among Punjabi Population

Bone density and the phenomens of bone loss with advanced age vary significantly across various populations. Collating data from various studies, including radiography of metacarpal bones, has revealed that Indians typically rank lower than other populations due to several factors, such as malnutrition, hormone related issues like hypothyroidism, genetic factors affecting bone growth and height, as well as malfunction in Vitamin D and calcium metabolism, along with diabetes. Thus, a study was conducted on the Punjabi population across all age groups, starting from the time of bone maturity. The findings clearly demonstrate poor acquisition of bone mass and pronounced bone loss in the elderly, with women exhibiting greater vulnerability compared to men in terms of poor bone strength and bone loss. This data holds significance for the development of public policies and healthcare initiatives aimed at addressing malnutrition, Vitamin D deficiency, and calcium issues from childhood to old age. Implementation of such measures could mitigate prevalent physical and mental health challenges in underdeveloped third-world countries like India. Despite facing similar challenges of poverty and malnutrition, the charts indicate that African populations exhibit higher bone density levels than Indian populations.

Evaluation of Human β-defensin-3 Diagnostic Role in a Group of Iraqi Patients with Osteoporosis

Background: Osteoporosis (OP) is a prevalent age-related condition that increases the risk of fracture and bone fragility, as result loss of bone mass as well as micro-architectural degradation of the bone, thereby reducing the mass and strength of bone. Human β-defensin (HBD-3) is ananti-inflammatory peptide andcrucial part of the human innate immune system. Giving early therapeutic intervention for OP requires an early diagnosis. Objectives: To evaluate the serum HBD-3 accuracy of diagnosis in patients with osteoporosis. Methods: The study was conducted in the National Joint Center at Yarmouk Teaching Hospital in Baghdad during September - October 2023. Eighty participants were recruited, all of whom had clinical examinations and had their bone status measured by dual-energy X-ray absorptiometry (DXA). Levels of serum HBD-3 and vitamin D3 (Vit D3) were determined by the ELISA technique. Calcium level (Ca+2) was measured using a spectrophotometer. A comparative study was conducted between forty patients with OP and 40 controls. The study included females and males with an age range between (40-60) years. Results: The serum level of HBD-3 in the OP group was significantly higher (p < 0.001) than that of the healthy controls. The area under the curve (AUC) was found to be (1.000) in the ROC curve analysis for serum HBD-3 level. Conclusion: Serum HBD-3 can be a valuable indicator of OP in middle-aged individuals, and may be a helpful biological marker for OP diagnosis.

Osteogenesis and Embryogenesis in Zebrafish Embryo Is Differentially Modulated by Solvents and Prednisolone

Several molecules and extracts are known to have bone-specific effects. For example, the long-term use of glucocorticoids like prednisolone causes several negative effects including a loss of bone mass. Molecules like prednisolone are usually dissolved in organic solvent which are known to be toxic for zebrafish embryo in certain concentrations. Nevertheless, solvents like dimethyl sulfoxide (DMSO), ethanol and methanol have never been tested for specific skeletal effects during development in dose-dependency. Vitality assay, live fluorescence and bone-specific staining were used to evaluate solvents effects compared to prednisolone. DMSO, ethanol and methanol perturb osteogenesis starting from 1%, 1.5% and 3% respectively, concentrations in which vasculature, length and survival rate appear unaffected. This effect may be due to high sensitivity of the osteogenesis process to external chemical stimuli, especially in the trunk. On the contrary, the negative effect of prednisolone on skeletal development appears more specific since it is found at very low concentrations, far from any other developmental defects. The recommended solvent concentration to be used in zebrafish embryos osteogenesis assay was established in 0.5% for DMSO, 2% for methanol and 0.5% for ethanol. We recommend analyzing both head and trunk mineralization in zebrafish embryo osteogenesis assay.

Lead (Pb) Induces Osteotoxicity Through the Activation of Mutually Reinforced ER Stress and ROS in MC3T3-E1 Cells.

Lead (Pb) is the most common contaminant of heavy metals and is widely present in the environment. Destruction of bone structure, malformation of bone development, and loss of bone mass are important pathological features of lead-exposed individuals. However, the exact molecular mechanisms associated with lead exposure and osteogenic injury are still not fully understood. MC3T3-E1 mouse embryonic osteoblast is a cell line widely used in osteoblast cytology. It can differentiate into mature osteoblasts and express bone-specific genes in cell culture. The doses of 1, 2, and 4 mM Pb were adopted to study the toxicity of Pb on MC3T3-E1 proliferation and differentiation. In this study, the results show that Pb increases the expression of apoptosis-related proteins, including PARP1, cleaved caspase-3, Bax, and cleaved caspase-9. More importantly, Pb activated endoplasmic reticulum stress and oxidative stress, as evident by elevated PERK/ATF4/CHOP and ROS/NRF2 signaling pathway. Pb induced ROS production in MC3T3-E1 cells through endoplasmic reticulum stress and produced a lethal effect. NAC mitigated these effects. Endoplasmic reticulum stress inhibitor 4-PBA can block the ER stress pathway, reduce ROS production, and enhance cell viability. In addition, studies have shown that ERO1 activation in the ER stress pathway is responsible for inducing ROS production. ROS produced by the mitochondrial pathway also aggravates ER stress. This study suggests that Pb induces MC3T3-E1 cell apoptosis by inducing PERK-mediated ER stress and NRF2-mediated oxidative stress via mutual enhancement, which may be an important mechanism leading to skeletal toxicity.

Fecal microbiota transplantation from postmenopausal osteoporosis human donors accelerated bone mass loss in mice.

To investigate the effect of gut microbiota from postmenopausal osteoporosis patients on bone mass in mice. Fecal samples were collected from postmenopausal women with normal bone mass (Con, n=5) and postmenopausal women with osteoporosis (Op, n=5). Microbial composition was identified by shallow shotgun sequencing. Then fecal samples were transplanted into pseudo-sterile mice previously treated with antibiotics for 4 weeks. These mice were categorized into two groups: the Vehicle group (n=7) received fecal samples from individuals with normal bone mass, and the FMT group (n=7) received fecal samples from individuals with osteoporosis. After 8 weeks, bone mass, intestinal microbial composition, intestinal permeability and inflammation were assessed, followed by a correlation analysis. The bone mass was significantly reduced in the FMT group. Microbiota sequencing showed that Shannon index (p < 0.05) and Simpson index (p < 0.05) were significantly increased in Op groups, and β diversity showed significant differences. the recipient mice were similar. linear discriminant analysis effect size (LEfSe) analysis of mice showed that Halobiforma, Enterorhabdus, Alistipes, and Butyricimonas were significantly enriched in the FMT group. Lachnospiraceae and Oscillibacter were significantly enriched in the Vehicle group. H&E staining of intestinal tissues showed obvious intestinal mucosal injury in mice. Intestinal immunohistochemistry showed that the expression of Claudin and ZO-1 in the intestinal tissue of the FMT group mice was decreased. The FITC-Dextran (FD-4) absorption rate and serum soluble CD14 (sCD14) content were increased in FMT mice. Correlation analysis showed that these dominant genera were significantly associated with bone metabolism and intestinal permeability, and were associated with the enrichment of specific enzymes. Serum and bone tissue inflammatory cytokines detection showed that the expression of TNF-α and IL-17A in the FMT group were significantly increased. Overall, our findings suggested gut microbiota from postmenopausal osteoporosis patients accelerate bone mass loss in mice. Aberrant gut microbiota might play a causal role in the process of bone mass loss mediated by inflammation after the destruction of the intestinal barrier.

Host-specific effects of Eubacterium species on Rg3-mediated modulation of osteosarcopenia in a genetically diverse mouse population

BackgroundOsteosarcopenia, characterized by the simultaneous loss of bone and muscle mass, is a serious health problem in the aging population. This study investigated the interplay between host genetics, gut microbiota, and musculoskeletal health in a mouse model of osteosarcopenia, exploring the therapeutic potential of gut microbiota modulation.MethodsWe examined the effects of Rg3, a phytochemical, on osteosarcopenia and its interactions with host genetics and gut microbiota in six founder strains of the Collaborative Cross (CC) population. Subsequently, we evaluated the therapeutic potential of Eubacterium nodatum (EN) and Eubacterium ventriosum (EV), two gut microbes identified as significant correlates of Rg3-mediated osteosarcopenia improvement, in selected C57BL/6 J (B6) and 129S1/SvImJ (129S1) mouse strains.ResultsRg3 treatment altered gut microbiota composition aligned with osteosarcopenia phenotypes, which response varied depending on host genetics. This finding enabled the identification of two microbes in the Eubacterium genus, potential mediator of Rg3 effect on osteosarcopenia. Oral administration of EN and EV differentially impacted bone density, muscle mass, exercise performance, and related gene expression in a mouse strain-specific manner. In 129S1 mice, EN and EV significantly improved these parameters, effectively reversing osteosarcopenic phenotypes. Mechanistic investigations revealed that these effects were mediated through the modulation of osteoblast differentiation and protein degradation pathways. In contrast, EN and EV did not significantly improve osteosarcopenic phenotypes in B6 mice, although they did modulate mitochondrial biogenesis and microbial diversity.ConclusionsOur findings underscore the complex interplay between host genetics and the gut microbiota in osteosarcopenia and emphasize the need for personalized treatment strategies. EN and EV exhibit strain-specific therapeutic effects, suggesting that tailoring microbial interventions to individual genetic backgrounds may be crucial for optimizing treatment outcomes.9Nfyi13u2tifXMNNi2cAAqVideo Graphical

Characterization of Patients with Osteoporosis at UMHES San Blas According to Sociodemographic Factors and Fracture Site

The research titled "Characterization of Patients with Osteoporosis at UMHES San Blas According to Sociodemographic Factors and Fracture Site" aims to identify the sociodemographic and clinical risk factors in patients with osteoporosis, as well as to determine the most frequent fracture sites. This disease, characterized by the loss of bone mass, is often underdiagnosed, which increases the risk of fragility fractures and associated morbidity and mortality. It is essential to characterize these patients in order to implement effective prevention and treatment strategies, as recommended by the Colombian Association of Osteoporosis and Mineral Metabolism (ACOMM) [1]. This is a quantitative, descriptive study based on the review of medical records of patients over the age of 55 who sought orthopedic care at the Integrated Health Services Sub-network of Centro Oriente, specifically at UMHES San Blas in Bogotá, between January 2017 and November 2020. A total of 800 patients were included, 41% of whom presented with osteoporotic fractures. The results allow for the correlation of sociodemographic and clinical variables with fracture sites, identifying the most significant risk factors for the population under study. This information is crucial for the development of more effective interventions in the prevention and management of osteoporosis, ultimately improving the bone health of the patients.

REGγ is essential to maintain bone homeostasis by degrading TRAF6, preventing osteoporosis

Primary osteoporosis, manifesting as decreased bone mass and increased bone fragility, is a "silent disease" that is often ignored until a bone breaks. Accordingly, it is urgent to develop reliable biomarkers and novel therapeutic strategies for osteoporosis treatment. Here, we identified REGγ as a potential biomarker of osteoporotic populations through proteomics analysis. Next, we demonstrated that REGγ deficiency increased osteoclast activity and triggered bone mass loss in REGγ knockout (KO) and bone marrow-derive macrophage (BMM)-conditional REGγ KO mice. However, the osteoclast activity decreased in BMM-conditional REGγ overexpression mice. Mechanistically, we defined that REGγ-20S proteasome directly degraded TRAF6 to inhibit bone absorption in a ubiquitin-independent pathway. More importantly, BMM-conditional Traf6 KO with REGγ KO mice could "rescue" the osteoporosis phenotypes. Based on NIP30 (a REGγ "inhibitor") dephosphorylation by CKII inhibition activated the ubiquitin-independent degradation of TRAF6, we selected TTP22, an inhibitor of CKII, and defined that TTP22 could alleviate osteoporosis in vitro and in vivo. Overall, our study reveals a unique function of NIP30/REGγ/TRAF6 axis in osteoporosis and provides a potential therapeutic drug TTP22 for osteoporosis.

Accumulation of Advanced Oxidation Protein Products Promotes Age-Related Decline of Type H Vessels in Bone.

Type H vessels have been proven to couple angiogenesis and osteogenesis. The decline of type H vessels contributes to bone loss in the aging process. Aging is accompanied by the accumulation of advanced oxidation protein products (AOPPs). However, whether AOPP accumulation is involved in age-related decline of type H vessels is unclear. Here, we show that the increase of AOPP levels in plasma and bone was correlated with the decline of type H vessels and loss of bone mass in old mice. Exposure of microvascular endothelial cells to AOPPs significantly inhibited cell proliferation, migration, and tube formation; increased NADPH oxidase activity and excessive reactive oxygen species generation; upregulated the expression of vascular cell adhesion molecule-1 and intercellular cell adhesion molecule-1; and eventually impaired angiogenesis, which was alleviated by redox modulator N-acetylcysteine and NADPH oxidase inhibitor apocynin. Furthermore, reduced AOPP accumulation by NAC treatment was able to alleviate significantly the decline of type H vessels, bone mass loss, and deterioration of bone microstructure in old mice. Collectively, these findings suggest that AOPPs accumulation contributes to the decline of type H vessels in the aging process, and illuminate a novel potential mechanism underlying age-related bone loss.

Calcium plus vitamin D supplementation during pregnancy has no impact on postpartum transient longitudinal changes in hip geometry in adolescent mothers: a secondary analysis of a randomised controlled trial.

We have previously demonstrated that calcium plus vitamin D supplementation during adolescent pregnancy reduces the magnitude of transient postpartum bone mass loss. In the present post hoc analysis, we further investigated the effect of calcium plus vitamin D supplementation during pregnancy in hip geometry throughout one year postpartum in Brazilian adolescents with low daily calcium intake (∼600 mg/d). Pregnant adolescents (14-19 years) were randomly assigned to receive calcium (600 mg/d) plus vitamin D3 (200 μg/d) or a placebo from 26 weeks of gestation until parturition. Dual-energy X-ray absorptiometry images were obtained at 5 (n 30 and 26 for calcium plus vitamin D and placebo, respectively), 20 (n 26 and 21) and 56 (n 18 and 12) weeks postpartum, and hip geometry parameters were analysed by Advanced Hip Assessment software. The effects of the intervention, time point and their interaction were assessed using repeated-measures mixed-effects models. No significant intervention effects or intervention × time interactions were observed on hip geometry parameters (P > 0·05). Time effects were observed in cross-sectional area, cross-sectional moment of inertia and section modulus parameters with decreases from the 5th to the 20th week postpartum followed by recovery from the 20th to the 56th week (P < 0·05). Our findings indicate that the postpartum period is associated with transient changes in the hip geometry of lactating adolescent mothers, regardless of the low calcium intake and the supplementation offered during pregnancy, suggesting that a physiological adaptation of these adolescents to low calcium intake is at play.

Acetyl-11-keto-β-boswellia acid attenuates Ti particle-induced osteoblastic oxidative stress and osteolysis through the Foxo3 signaling pathway

Oxidative stress injury in osteoblasts is one of the leading causes of periprosthetic osteolysis (PPOL). Acetyl-11-keto-β-boswellia acid (AKBA) has been used as an antioxidant in the treatment of various diseases, but its antioxidant mechanism in osteolysis has yet to be elucidated. In this study, a mouse cranial osteolysis model was constructed, and MC3T3-E1 cells and bone marrow mesenchymal stem cells (BMSCs) were cultured in vitro. Western blotting and immunofluorescence staining revealed that titanium (Ti) particles aggravated osteoblast oxidative stress injury and apoptosis. Ti particles and hydrogen peroxide reduced the osteogenic ability of BMSCs. At a certain concentration, AKBA alleviated the oxidative stress injury of MC3T3-E1 cells induced by Ti particles and enhanced the osteogenic ability of BMSCs, and the expression of Forkhead box O3 (Foxo3) increased with increasing AKBA concentration. To verify the antioxidant mechanism of AKBA, we designed and synthesized Foxo3-targeting siRNAs. We found that after Foxo3 expression was inhibited, the protective effect of AKBA on osteoblasts decreased significantly. Moreover, AKBA treatment suppressed bone mass loss in the skull mediated by Ti particles in mice. Therefore, we suggest that AKBA alleviates the oxidative stress injury in osteoblasts induced by Ti particles, at least in part, by regulating the expression of Foxo3. In this study, the mechanism and biosafety of AKBA in treating PPOL were demonstrated to some extent.

Loss of Runx2 in Gli1+ osteogenic progenitors prevents bone loss following ovariectomy

Abstract Osteoporosis is a metabolic bone disorder characterized by low bone mass and bone mineral density. It is the most prevalent bone disease and a common cause of fracture in aging adults. Low bone mass, as seen in osteoporosis, results from an imbalance between osteoblast and osteoclast activity. Gli1+ cells are indispensable to the maintenance of bone tissue homeostasis. These cells give rise to osteoprogenitors and are present at the osteogenic fronts of long bones in adult mice. Runx2 is a key regulator of osteogenesis and plays a crucial role in osteoblastic differentiation and maturation during development. However, its function in maintaining adult bone tissue homeostasis remains unclear. In this study, we investigated the role of Runx2 in maintaining adult bone homeostasis in the context of ovariectomy-induced estrogen deficiency, a model for postmenopausal osteoporosis. Our results show that deletion of Runx2 in the Gli1+ osteogenic progenitor population prevents loss of both cortical and trabecular bone mass and mineralization after ovariectomy. At the cellular level, loss of Runx2 leads to a decrease in osteoclast activity. Our study indicates that Runx2 is essential for maintaining adult bone tissue homeostasis by regulating osteoclast differentiation.

SFRP1-Silencing GapmeR-Loaded Lipid-Polymer Hybrid Nanoparticles for Bone Regeneration in Osteoporosis: Effect of Dosing and Targeting Strategy.

Osteoporosis is a metabolic disorder characterized by the loss of bone mass and density. Nucleic acid-based therapies are among the most innovative approaches for osteoporosis management, although their effective delivery to bone tissue remains a challenge. In this work, SFRP1-silencing GampeR loaded-nanoparticles were prepared and functionalized with specific moieties to improve bone targeting and, consequently, therapeutic efficacy. SFRP1-silencing would promote osteoblastic differentiation by enhancing the WNT/β-catenin pathway and thus diminishing the progression of osteoporosis. A nucleic acid-based delivery system consisting of lipid-polymer hybrid nanoparticles (LPNPs) loading a GapmeR for SFRP1 silencing was developed and further functionalized with two bone-targeting moieties: a specific aptamer (Apt) for murine mesenchymal stem cells and an antiresorptive drug, namely alendronate (ALD). These systems were tested in vivo in osteoporotic mice at different dosage regimens to analyze dose dependence in bone-forming activity and potential toxicity. The quality of trabecular and cortical bone was assessed by both micro computed tomography (micro-CT) and histological and histomorphometric analyses. Early and late osteogenesis were quantified by immunohistochemistry. Results showed that functionalizing LPNPs loaded with an SFRP1-silencing GapmeR using both Apt and ALD improved bone quality and enhanced osteogenesis following a dose-effect relationship, as revealed by micro-CT, histological and immunohistochemical analyses. In contrast, non-functionalized LPNPs did not produce these effects. These findings highlight the relevance of proper targeting and dosage in nucleic acid-based therapeutics, proving to be crucial for exerting their therapeutic effect: a deficient targeting strategy and/or dosage may result in the therapeutic failure of an adequate gene therapy agent.

The miR-665/SOST Axis Regulates the Phenotypes of Bone Marrow Mesenchymal Stem Cells and Osteoporotic Symptoms in Female Mice

Osteoporosis is a common degenerative skeletal disease among older people, especially postmenopausal women. Bone marrow mesenchymal stem cells (BMSCs), the progenitors of osteoblasts, are essential to the pathophysiology of osteoporosis. Herein, targeting miRNAs with differential expression in dysfunctional BMSCs was accomplished by bioinformatics analysis based on public databases. Target mRNAs were predicted and applied for signaling pathway and function enrichment annotations. Invitro and invivo effects of selected miRNA on BMSC proliferation and osteogenesis were investigated, the putative binding between selected miRNA and predicted target mRNA was verified, and the co-effects of the miRNA/mRNA axis on BMSCs were determined. miRNA 665 (miR-665) was down-regulated in osteoporotic BMSCs compared with normal BMSCs and elevated in BMSCs experiencing osteogenic differentiation. In BMSCs, miR-665 overexpression promoted cell proliferation and osteogenic differentiation. miR-665 targeted the Wnt signaling inhibitor sclerostin (SOST) and inhibited SOST mRNA and protein expression. SOST overexpression inhibited BMSC cell proliferation and osteogenic differentiation. When co-transduced to BMSCs, SOST knockdown significantly reversed the effects of miR-665 on BMSCs. In ovariectomy (OVX)-induced osteoporosis model mice, OVX remarkably decreased bone mass, whereas miR-665 overexpression partially improved OVX-induced bone mass loss. miR-665 was down-regulated in osteoporotic BMSCs and up-regulated in osteogenically differentiated BMSCs. In conclusion, the miR-665/SOST axis modulates BMSC proliferation, osteogenic differentiation, and OVX-induced osteoporosis in mice, possibly through Wnt signaling.

Bone Regeneration with Dental Pulp Stem Cells in an Experimental Model.

The therapeutic approach to bone mass loss and bone's limited self-regeneration is a major focus of research, emphasizing new biomaterials and cell therapy. Tissue bioengineering emerges as a potential alternative to conventional treatments. In this study, an experimental model of a critical bone lesion in rats was used to investigate bone regeneration by treating the defect with biomaterials Evolution® and Gen-Os® (OsteoBiol®, Turín, Italy), with or without mesenchymal stromal cells from dental pulp (DP-MSCs). Forty-six adult male Wistar rats were subjected to a 5-mm critical bone defect in the right mandible, which does not regenerate without intervention. The rats were randomly assigned to a Simulated Group, Control Group, or two Study Groups (using Evolution®, Gen-Os®, and DP-MSCs). The specimens were euthanized at three or six months, and radiological, histological, and ELISA tests were conducted to assess bone regeneration. The radiological results showed that the DP-MSC group achieved uniform radiopacity and continuity in the bone edge, with near-complete structural defect restitution. Histologically, full bone regeneration was observed, with well-organized, vascularized lamellar bone and no lesion edges. These findings were supported by increases in endoglin, transforming growth factor-beta 1 (TGF-β1), protocollagen, parathormone, and calcitonin, indicating a conducive environment for bone regeneration. The use of DP-MSCs combined with biomaterials with appropriate three-dimensional matrices is a promising therapeutic option for further exploration.

In-silico analysis predicts disruption of normal angiogenesis as a causative factor in osteoporosis pathogenesis

Angiogenesis-osteogenesis coupling is critical for proper functioning and maintaining the health of bones. Any disruption in this coupling, associated with aging and disease, might lead to loss of bone mass. Osteoporosis (OP) is a debilitating bone metabolic disorder that affects the microarchitecture of bones, gradually leading to fracture. Computational analysis revealed that normal angiogenesis is disrupted during the progression of OP, especially postmenopausal osteoporosis (PMOP). The genes associated with OP and PMOP were retrieved from the DisGeNET database. Hub gene analysis and molecular pathway enrichment were performed via the Cytoscape plugins STRING, MCODE, CytoHubba, ClueGO and the web-based tool Enrichr. Twenty-eight (28) hub genes were identified, eight of which were transcription factors (HIF1A, JUN, TP53, ESR1, MYC, PPARG, RUNX2 and SOX9). Analysis of SNPs associated with hub genes via the gnomAD, I-Mutant2.0, MUpro, ConSurf and COACH servers revealed the substitution F201L in IL6 as the most deleterious. The IL6 protein was modeled in the SWISS-MODEL server and the substitution was analyzed via the YASARA FoldX plugin. A positive ΔΔG (1.936) of the F201L mutant indicates that the mutated structure is less stable than the wild-type structure is. Thirteen hub genes, including IL6 and the enriched molecular pathways were found to be profoundly involved in angiogenesis/endothelial function and immune signaling. Mechanical loading of bones through weight-bearing exercises can activate osteoblasts via mechanotransduction leading to increased bone formation. The present study suggests proper mechanical loading of bone as a preventive strategy for PMOP, by which angiogenesis and the immune status of the bone can be maintained. This in silico analysis could be used to understand the molecular etiology of OP and to develop novel therapeutic approaches.