Role In Bone Resorption Research Articles

Bone resorption as a marker for delayed esophageal perforation post anterior cervical spine surgery: a retrospective analysis and call for increased vigilance.

Delayed esophageal perforation following anterior cervical spine surgery (ACSS) is a rare but serious complication. This study is to investigate the clinical characteristics, diagnostic approaches, and treatment outcomes of delayed esophageal perforation following ACSS, with a focus on the role of bone resorption around internal fixations as a potential diagnostic indicator. We retrospectively analyzed patients diagnosed with delayed esophageal perforation after ACSS from January 2010 to December 2023 and described their clinical characteristics, diagnostic approaches, and treatment outcomes. Through the analysis of the differences in the radiomics of patients, we identified the possible clinical signs of esophageal perforation and shared our experience in treating esophageal perforation. A total of five patients met our criteria. All five patients exhibited bone resorption around their internal fixations on radiography. Although bone resorption typically suggests local infection, none of the patients showed clear signs of neck skin infection, leading us to suspect esophageal perforation as the underlying cause. Further diagnostic procedures including CT, MRI, esophagography, and endoscopy were crucial for confirming the diagnosis of delayed esophageal perforation and assessing its severity. All patients underwent surgical intervention involving implant removal and esophageal repair using a sternocleidomastoid muscle flap transfer. All patients recovered and were discharged after treatment, with no recurrence of symptoms during follow-up. Delayed esophageal perforation should be considered in patients with neck pain or nonspecific symptoms after ACSS, especially with bone resorption around internal fixations. Clinicians should maintain high vigilance and use multimodal imaging and endoscopy for timely diagnosis. Our study indicates a significant link between bone resorption and delayed esophageal perforation despite the limited number of cases. Highlighting this association aims to raise awareness and encourage further research. Larger studies are needed to validate our findings, improve clinical guidelines, and ultimately enhance patient outcomes in orthopedics.

Long-Term Follow-up After Ovariectomy Reveals Correlations Between Bone Marrow Adiposity and Trabecular Bone Quality in the Proximal Metaphysis of Tibiae in Rats.

This study aimed to evaluate the correlation between BMAT and bone quality, describe the long-term effects of ovariectomy on bone, and investigate BMAT's spatial distribution. Fifteen-months-old female Sprague‒Dawley rats were studied, comparing ovariectomized (OVX, n = 22) and sham-operated (SHAM, n = 11) groups at 6 months. Tibias were analyzed for bone microarchitecture, BMAT (microcomputed tomography), mineral parameters (quantitative backscattered electron imaging), and bone composition (Raman microspectroscopy). The OVX tibias showed severe trabecular bone loss (lower bone volume/total volume, p < 0.001) with increased BMAT (higher adipose volume per marrow volume, p < 0.001), decreased mineral content (lower calcium concentration, p < 0.001), and altered organic components (lower mineral/matrix ratio in new bone, p = 0.03 trabecular surface, p < 0.001 trabecular core). When the data are pooled over both groups (SHAM and OVX), the adipose volume/marrow volume ratio was negatively correlated with bone volume/total volume (r = - 0.79, p < 0.001) and mineral/matrix ratio (r = - 0.37, p = 0.04 trabecular surface; r = - 0.65, p < 0.001 trabecular core) and positively correlated with crystallinity (r = 0.55, p = 0.001 trabecular surface; r = 0.49, p = 0.006 trabecular core). The mineral/matrix ratio of trabecular surface new bone was strongly negatively correlated with the adipose compartment nearest to the bone surface. These findings suggest mechanisms underlying BMAT's role in bone resorption.

MMP13 Expression and Activity Suggest Its Role in Bone Resorption in Ameloblastomas.

Ameloblastoma is a locally destructive benign odontogenic tumor. While the neoplastic cells of conventional ameloblastoma can infiltrate the connective tissue and bone, in unicystic ameloblastoma the epithelium is encapsulated. The mechanisms driving ameloblastoma's bone resorption remains unclear. RNA sequencing (RNA-seq) was performed in a discovery cohort of conventional ameloblastoma, and pathway enrichment analysis was carried out. mRNA levels of MMP13, a gene associated with bone resorption, were assessed using RT-qPCR in a larger cohort of conventional ameloblastoma and in unicystic ameloblastoma. Zymogram gels and the immunoexpression profile of collagenase 3 (encoded by MMP13 gene) were evaluated as well. Enriched pathways related to bone mineralization and upregulation of MMP13 were observed in ameloblastomas. Collagenolytic activity of collagenase 3 was detected in the tumor lysates. Collagenase 3 immunopositivity was observed in ameloblastomatous epithelium infiltrating the fibrous capsule of unicystic ameloblastoma. At the tumor-bone interface, collagenase 3 expression was detected in stromal cells, osteoblasts, and osteocytes. The results indicate a potential involvement of MMP13 in ameloblastoma-related bone resorption and progression.

Identification of microRNAs expressed in an animal model of periodontal disease and their impact on pathological processes

MicroRNAs represent a class of small RNAs that act to silence genes post-transcriptionally by inhibiting the translation of target messenger RNAs, and this study aimed to understand how miRNAs influence the set-up of periodontal disease. Periodontitis was induced by inserting a ligature into the left first mandibular molar in a rat model, which was kept for the entire 56 days-time of experiment. After 56 days post-periodontitis induction, the histopathological analysis showed an apical extension of the junctional epithelium, with areas of hyperplasia, exocytosis, and a mixed inflammatory infiltrate with a predominance of neutrophils, lymphocytes, and eventual plasma cells in the deeper layers. The cement surface showed areas of irregularity, covered by cementoblasts and irregular surfaces, confirming the set-up of periodontitis. In the sequencing analysis, 26,404 genes were identified, with 132 reaching statistical significance. Among genes with a statistical difference, 18 were found to encode for microRNAs. The identified microRNAs are primarily involved in bone remodeling by acting on fibroblast growth factors, and collagen production. These outcomes demonstrate a signaling role in bone resorption, which is consistent with the histopathological observations that show the installation of inflammation with epithelial migration and the beginning of the repair process, with cementum resorption. The disclosure of how miRNAs may influence the maintaining of periodontal disease will help the development of new dental materials for the prophylaxis and treatment of alveolar bone resorption.

Changes in Dickkopf-1, but Not Sclerostin, in Gingival Crevicular Fluid Are Associated with Peroral Statin Treatment in Patients with Periodontitis.

Background and Objectives: Periodontitis is marked by the destruction of alveolar bone. Sclerostin (SOST) and dickkopf-1 (DKK-1) act as inhibitors of the Wingless-type (Wnt) signaling pathway, a key regulator of bone metabolism. Recent studies have suggested that statins play a role in bone resorption and formation by influencing Wnt signaling. The aim of this study was to determine the levels of SOST and DKK-1 in periodontal patients with and without peroral statins treatment in their therapy. Materials and Methods: A total of 79 patients with diagnosed periodontitis were divided into two groups: 39 patients on statin therapy (SP group) and 40 patients without statin therapy as a control group (P group). The periodontal clinical examination probing (pocket) depth (PD) and gingival recession (GR) were measured, and approximal plaque was detected, while vertical and horizontal bone resorption was measured using a panoramic radiograph image. Clinical attachment loss (CAL) values were calculated using PD and GR values. Gingival crevicular fluid (GCF) was collected and used for measuring SOST and DKK-1 levels. A questionnaire was used to assess lifestyle habits and statin intake. Patients' medical records were used to obtain biochemical parameters. Results: There was no significant difference in sclerostin concentration between the SP and P group. DKK-1 values were significantly higher in the SP group compared to the control group (p = 0.04). Also, PD (p = 0.001) and GR (p = 0.03) were significantly higher in the SP group. The level of DKK-1 had a positive relationship with the PD, the greater the PD, the higher the level of DKK-1 (Rho = 0.350), while there was no significant association with other parameters. Conclusions: Peroral statins in periodontal patients are associated with GCF levels of DKK-1 but not with sclerostin levels.

PTH and the Regulation of Mesenchymal Cells within the Bone Marrow Niche.

Parathyroid hormone (PTH) plays a pivotal role in maintaining calcium homeostasis, largely by modulating bone remodeling processes. Its effects on bone are notably dependent on the duration and frequency of exposure. Specifically, PTH can initiate both bone formation and resorption, with the outcome being influenced by the manner of PTH administration: continuous or intermittent. In continuous administration, PTH tends to promote bone resorption, possibly by regulating certain genes within bone cells. Conversely, intermittent exposure generally favors bone formation, possibly through transient gene activation. PTH's role extends to various aspects of bone cell activity. It directly influences skeletal stem cells, osteoblastic lineage cells, osteocytes, and T cells, playing a critical role in bone generation. Simultaneously, it indirectly affects osteoclast precursor cells and osteoclasts, and has a direct impact on T cells, contributing to its role in bone resorption. Despite these insights, the intricate mechanisms through which PTH acts within the bone marrow niche are not entirely understood. This article reviews the dual roles of PTH-catabolic and anabolic-on bone cells, highlighting the cellular and molecular pathways involved in these processes. The complex interplay of these factors in bone remodeling underscores the need for further investigation to fully comprehend PTH's multifaceted influence on bone health.

Galectin-8 modulates human osteoclast activity partly through isoform-specific interactions.

In overactive human osteoclasts, we previously identified an alternative splicing event in LGALS8, encoding galectin-8, resulting in decreased expression of the long isoform. Galectin-8, which modulates cell-matrix interactions and functions intracellularly as a danger recognition receptor, has never been associated with osteoclast biology. In human osteoclasts, inhibition of galectin-8 expression revealed its roles in bone resorption, osteoclast nuclearity, and mTORC1 signaling regulation. Galectin-8 isoform-specific inhibition asserted a predominant role for the short isoform in bone resorption. Moreover, a liquid chromatography with tandem mass spectrometry (LC-MS/MS) proteomic analysis of galectin-8 isoforms performed in HEK293T cells identified 22 proteins shared by both isoforms. Meanwhile, nine interacting partners were specific for the short isoform, and none were unique to the long isoform. Interactors specific for the galectin-8 short isoform included cell adhesion proteins and lysosomal proteins. We confirmed the interactions of galectin-8 with CLCN3, CLCN7, LAMP1, and LAMP2, all known to localize to secretory vesicles, in human osteoclasts. Altogether, our study reveals direct roles of galectin-8 in osteoclast activity, mostly attributable to the short isoform.

Zoledronic acid enhances tumor growth and metastatic spread in a mouse model of jaw osteosarcoma.

Investigation of the therapeutic effect of zoledronic acid (ZA) in a preclinical model of jaw osteosarcoma (JO). The effect of 100 μg/kg ZA administered twice a week was assessed in a xenogenic mouse model of JO. The clinical (tumor growth, development of lung metastasis), radiological (bone microarchitecture by micro-CT analysis), and molecular and immunohistochemical (TRAP, RANK/RANKL, VEGF, and CD146) parameters were investigated. Animals receiving ZA exhibited an increased tumor volume compared with nontreated animals (71.3 ± 14.3 mm3 vs. 51.9 ± 19.9 mm3 at D14, respectively; p = 0.06) as well as increased numbers of lung metastases (mean 4.88 ± 4.45 vs. 0.50 ± 1.07 metastases, respectively; p = 0.02). ZA protected mandibular bone against tumor osteolysis (mean bone volume of 12.81 ± 0.53 mm3 in the ZA group vs. 11.55 ± 1.18 mm3 in the control group; p = 0.01). ZA induced a nonsignificant decrease in mRNA expression of the osteoclastic marker TRAP and an increase in RANK/RANKL bone remodeling markers. The use of bisphosphonates in the therapeutic strategy for JO should be further explored, as should the role of bone resorption in the pathophysiology of the disease.

Comparative interactome analysis of α-arrestin families in human and Drosophila

The α-arrestins form a large family of evolutionally conserved modulators that control diverse signaling pathways, including both G-protein-coupled receptor (GPCR)-mediated and non-GPCR-mediated pathways, across eukaryotes. However, unlike β-arrestins, only a few α-arrestin targets and functions have been characterized. Here, using affinity purification and mass spectrometry, we constructed interactomes for 6 human and 12 Drosophila α-arrestins. The resulting high-confidence interactomes comprised 307 and 467 prey proteins in human and Drosophila, respectively. A comparative analysis of these interactomes predicted not only conserved binding partners, such as motor proteins, proteases, ubiquitin ligases, RNA splicing factors, and GTPase-activating proteins, but also those specific to mammals, such as histone modifiers and the subunits of V-type ATPase. Given the manifestation of the interaction between the human α-arrestin, TXNIP, and the histone-modifying enzymes, including HDAC2, we undertook a global analysis of transcription signals and chromatin structures that were affected by TXNIP knockdown. We found that TXNIP activated targets by blocking HDAC2 recruitment to targets, a result that was validated by chromatin immunoprecipitation assays. Additionally, the interactome for an uncharacterized human α-arrestin ARRDC5 uncovered multiple components in the V-type ATPase, which plays a key role in bone resorption by osteoclasts. Our study presents conserved and species-specific protein–protein interaction maps for α-arrestins, which provide a valuable resource for interrogating their cellular functions for both basic and clinical research.

Comparative interactome analysis of α-arrestin families in human and Drosophila.

The α-arrestins form a large family of evolutionally conserved modulators that control diverse signaling pathways, including both G-protein-coupled receptor (GPCR)-mediated and non-GPCR-mediated pathways, across eukaryotes. However, unlike β-arrestins, only a few α-arrestin targets and functions have been characterized. Here, using affinity purification and mass spectrometry, we constructed interactomes for 6 human and 12 Drosophila α-arrestins. The resulting high-confidence interactomes comprised 307 and 467 prey proteins in human and Drosophila, respectively. A comparative analysis of these interactomes predicted not only conserved binding partners, such as motor proteins, proteases, ubiquitin ligases, RNA splicing factors, and GTPase-activating proteins, but also those specific to mammals, such as histone modifiers and the subunits of V-type ATPase. Given the manifestation of the interaction between the human α-arrestin, TXNIP, and the histone-modifying enzymes, including HDAC2, we undertook a global analysis of transcription signals and chromatin structures that were affected by TXNIP knockdown. We found that TXNIP activated targets by blocking HDAC2 recruitment to targets, a result that was validated by chromatin immunoprecipitation assays. Additionally, the interactome for an uncharacterized human α-arrestin ARRDC5 uncovered multiple components in the V-type ATPase, which plays a key role in bone resorption by osteoclasts. Our study presents conserved and species-specific protein-protein interaction maps for α-arrestins, which provide a valuable resource for interrogating their cellular functions for both basic and clinical research.

Single-Cell Spatial-Temporal Analysis of ZNF451 in Mediating Drug Resistance and CD8+ T Cell Dysfunction.

Cisplatin is widely used to treat osteosarcoma, but recurrent cases often develop resistance, allowing the disease to progress and complicating clinical management. This study aimed to elucidate the immune microenvironment of osteosarcoma, providing insights into the mechanisms of recurrence and identifying potential therapeutic strategies. By analyzing multiple single-cell and bulk RNA-sequencing datasets, we discovered that the SUMOylation-related gene ZNF451 promotes osteosarcoma recurrence and alters its immune microenvironment. ZNF451 was found to importantly enhance the growth, migration, and invasion of resistant cells while also reducing their sensitivity to cisplatin and lowering their apoptosis rate. Moreover, our data indicated that ZNF451 plays a crucial role in bone resorption and epithelial-mesenchymal transition. ZNF451 also regulates CD8+ T cell function, leading to their exhaustion and transition to the CD8T.EXH state. Additionally, β-cryptoxanthin has been identified as a potential therapeutic agent that inhibits osteosarcoma progression by targeting ZNF451. In summary, these findings highlight the critical role of ZNF451 in promoting osteosarcoma progression and underscore its potential as a therapeutic target and biomarker for osteosarcoma.

Extracellular Fe2+ and Fe3+ modulate osteocytic viability, expression of SOST, RANKL and FGF23, and fluid flow-induced YAP1 nuclear translocation

Iron overload negatively affects bone mass and strength. However, the impact of iron excess on osteocytes—important bone cells for mechanotransduction and remodeling—is poorly understood. Herein, we examined the effects of iron exposure on osteocytes during their maturation process. We discovered that iron overload caused apoptosis of osteocytes in early and late stages of differentiation. Notably, the expression of key proteins for iron entry was downregulated during differentiation, suggesting that mature osteocytes were less susceptible to iron toxicity due to limited iron uptake. Furthermore, iron overload also enriched a subpopulation of mature osteocytes, as indicated by increased expression of Dmp1, a gene encoding protein for bone mineralization. These iron-exposed osteocytes expressed high levels of Sost, Tnfsf11 and Fgf23 transcripts. Consistently, we demonstrated that exogenous FGF23 stimulated the formation and survival of osteoclasts, suggesting its regulatory role in bone resorption. In addition, iron overload downregulated the expression of Cx43, a gene encoding gap junction protein in the dendritic processes, and impaired YAP1 nuclear translocation in response to fluid flow in differentiated osteocytes. It can be concluded that iron overload induces cellular adaptation in differentiating osteocytes, resulting in insensitivity to mechanical stimulation and potential disruption of the balance in bone remodeling.

Anti-resorption role of low-intensity pulsed ultrasound (LIPUS) during large-scale bone reconstruction using porous titanium alloy scaffolds through inhibiting osteoclast differentiation

BackgroundTi6Al4V biomaterials combine with low-intensity pulsed ultrasound (LIPUS) has been reported with great bone regeneration capacity. It is important to better understand how LIPUS benefits bone microenvironment to seek for target of therapeutic medicine. Osteoclast differentiation plays a crucial role in bone resorption. Recent advances in molecular biology have revealed that N6-methyladenosine (m6A) RNA modifications can modulate biological processes, but their role in bone biology, particularly in osteoclast differentiation, remains unclear. We aim to understand how LIPUS regulates bone microenvironment especially osteoclast formation during bone regeneration to provide new therapeutic options for preventing and delaying bone resorption, thus with better bone regeneration efficiency. Results1. LIPUS promoted bone ingrowth and bone maturity while inhibiting osteoclast formation within Ti6Al4V scaffolds in large-scale bone defect model. 2. LIPUS was found to inhibit osteoclast differentiation by decreasing the overall expression of osteoclast markers in vitro. 3. LIPUS decreases RNA m6A-modification level through upregulating FTO expression during osteoclast differentiation during. 4. Inhibiting FTO expression and function leads to less inhibition during osteoclast differentiation. ConclusionLIPUS suppresses osteoclast differentiation during bone regeneration through reducing m6A modification of osteoclastic RNAs by up regulating FTO expression.

Role of chemical mediators and biological factors in tooth movement

In recent years, there have been various theories proposed to describe the mechanism causing tooth movement. These theories can be broadly categorized into two perspectives: one focusing on bone as the direct target of mechanical force, and the other highlighting the periodontal ligament (PDL) as the key target. While the direct view suggests that osteoclasts and osteoblasts are directly stimulated by compression and tension stresses, respectively, the indirect view suggests that the PDL responds to orthodontic forces. However, evidence challenges the direct view, as bone does not respond to static forces and implants/ankylosed teeth do not move. The indirect view proposes that orthodontic forces lead to areas of compression and tension within the PDL, causing various cellular responses and inflammatory reactions. Osteoclasts play a crucial role in bone resorption, influencing the rate of tooth movement. Inflammatory mediators, including chemokines, cytokines, prostaglandins, and neuropeptides, are released during orthodontic tooth movement, facilitating osteoclast recruitment and activation. Osteoclast genesis is influenced by factors such as TNF-α, IL-1, IL-6, and prostaglandins. Chemical mediators, including parathyroid hormone, vitamin D3, corticosteroids, and thyroxin, have been explored for their potential to accelerate tooth movement, but their systemic effects and practical application present challenges. Overall, understanding the biology of tooth movement involves considering the interactions among osteocytes, osteoclasts, and osteoblasts, as well as immune cells and inflammatory cytokines. Expediting tooth movement requires further research and the development of effective and safe strategies.

Massively HIV-1-infected macrophages exhibit a severely hampered ability to differentiate into osteoclasts.

Osteoclasts play a crucial role in bone resorption, and impairment of their differentiation can have significant implications for bone density, especially in individuals with HIV who may be at risk of altered bone health. The present study aimed to investigate the effects of HIV infection on osteoclast differentiation using primary human monocyte-derived macrophages as precursors. The study focused on assessing the impact of HIV infection on cellular adhesion, cathepsin K expression, resorptive activity, cytokine production, expression of co-receptors, and transcriptional regulation of key factors involved in osteoclastogenesis. Primary human monocyte-derived macrophages were utilized as precursors for osteoclast differentiation. These precursors were infected with HIV, and the effects of different inoculum sizes and kinetics of viral replication were analyzed. Subsequently, osteoclastogenesis was evaluated by measuring cellular adhesion, cathepsin K expression, and resorptive activity. Furthermore, cytokine production was assessed by monitoring the production of IL-1β, RANK-L, and osteoclasts. The expression levels of co-receptors CCR5, CD9, and CD81 were measured before and after infection with HIV. The transcriptional levels of key factors for osteoclastogenesis (RANK, NFATc1, and DC-STAMP) were examined following HIV infection. Rapid, massive, and productive HIV infection severely impaired osteoclast differentiation, leading to compromised cellular adhesion, cathepsin K expression, and resorptive activity. HIV infection resulted in an earlier production of IL-1β concurrent with RANK-L, thereby suppressing osteoclast production. Infection with a high inoculum of HIV increased the expression of the co-receptor CCR5, as well as the tetraspanins CD9 and CD81, which correlated with deficient osteoclastogenesis. Massive HIV infection of osteoclast precursors affected the transcriptional levels of key factors involved in osteoclastogenesis, including RANK, NFATc1, and DC-STAMP. The effects of HIV infection on osteoclast precursors were found to be dependent on the size of the inoculum and the kinetics of viral replication. These findings underscore the importance of understanding the underlying mechanisms to develop novel strategies for the prevention and treatment of bone disorders in individuals with HIV.

MMPs/TIMPs ratio: A Biomarker of Bone Resorption in Geriatric Osteoporosis?

Matrix metalloproteinases (MMPs) play an important role in bone resorption and are regulated by tissue inhibitors of metalloproteinases (TIMPs). We investigated the use of MMP2/TIMP2 and MMP9/TIMP1 ratios as biomarkers of bone resorption in geriatric osteoporosis and evaluated the relationship between osteoporosis and geriatric syndromes. This analytical cross-sectional study involved 87 patients (41 with osteoporosis) treated at the geriatric outpatient clinic of a university hospital. The demographic characteristics, comprehensive geriatric assessment scores, laboratory findings, and bone mineral density of the patients were recorded. Serum MMP9, TIMP1, MMP2, and TIMP2 levels were analyzed by enzyme-linked immunosorbent assay (ELISA). We enrolled 41 and 46 patients with and without osteoporosis, respectively. The groups showed no significant differences in MMP2/TIMP2 and MMP9/TIMP1 ratios (p=0.569 and p=0125, respectively). While the basic activities of daily life (BADL) scores in the osteoporosis group were higher than those in the group without osteoporosis, the instrumental activities of daily life (IADL) scores were significantly lower (p=0.001 and p=0.007, respectively). No significant differences were observed in Mini-Nutritional Assessment (MNA), Mini-Mental State Examination (MMSE), and Geriatric Depression Scale (GDS) scores (p=0.598, p=0.898, and p=0.287, respectively). This is the first study to examine the relationship between osteoporosis and several geriatric syndromes, as well as the relationship between osteoporosis and serum MMP, TIMP values, and MMP/TIMP ratios in geriatric patients. Our results showed that osteoporosis causes dependency in both BADLs and IADLs, and that the MMP2/TIMP2 and MMP9/TIMP1 ratios provided no additional benefit in demonstrating bone resorption in geriatric osteoporosis.

THE THREE KEY PLAYERS IN OSTEOIMMUNOLOGY: RANK, RANKL AND OSTEOPROTEGERIN

The RANK, RANKL and OPG interaction plays a major role in bone resorption and remodelling. The history dates back to mid 1990s when the RANK/ RANKL interaction was found to mediate osteoblastic stromal cells to stimulate osteoclastic bone resorption. This interaction was found to induce several cytokines including the TNF superfamily, thereby activating the pathways of bone remodelling. The Osteoprotegerin (OPG) prevents the binding of RANKL to RANK, thereby preventing the excessive bone resorption. When there is an imbalance in the levels of RANK/RANKL/OPG, the metabolic activity of the bone cells gets altered and thus there is loss of balance between bone formation and resorption. Thus, studying the inter – relationship between RANK, RANKL and OPG becomes critical for assessing the osteoblastic and osteoclastic activity.

Anti-Arthritic Effect of Edaravone Against Complete Freund Adjuvant Induced Arthritis via Osteoclast Differentiation and HIF-1α-VEGF-ANG-1 Axis.

Bone dysfunction is a crucial problem that occurs during rheumatoid arthritis (RA) disease. Osteoclast plays a significant role in bone resorption and osteoclast differentiation and its enhancement of bone destruction. Edaravone remarkably exhibited free radical scavenging and anti-inflammatory effects. The objective of the current investigation is to comfort the inhibitory effect of Edaravone (ED) against complete Freund adjuvant (CFA) rat model via inhibition of angiogenesis and inflammation. Subcutaneous injection of CFA (1%) was used to induce arthritis; the rats were divided into different groups and received the oral administration of ED. Paw edema, body weight, and arthritis score were regularly estimated. Biochemical parameters were estimated, respectively. We also estimate the level of hypoxia-inducible factor-1α (HIF-1α), angiopoietin 1 (ANG-1), and vascular endothelial growth factor (VEGF). We also checked into how ED affected the differentiation of osteoclasts utilising a co-culture system with monocytes and synovial fibroblasts in arthritis rats. ED treatment significantly (P<0.001) suppressed the arthritis score and paw edema and improved the body weight. ED treatment significantly (P<0.001) altered the antioxidant parameters and pro-inflammatory cytokines: inflammatory mediator nuclear kappa B factor (NF-κB), cyclooxygenase-2 (COX-2), and prostaglandin E2 (PGE2), respectively. Furthermore, ED treatment significantly (P<0.001) suppressed the level of ANG-1, HIF-1α, and VEGF, respectively. The results suggest that ED suppressed osteoclast differentiation and also decreased the level of cytokines and osteopontin (OPN), receptor activator for nuclear factor-κ B Ligand (RANKL) and macrophage colony stimulating factor (M-CSF) in the co-culture supernatant of monocytes and synovial fibroblasts. Edaravone could mitigate CFA via inhibiting angiogenesis and inflammatory reactions, which may be linked with the HIF-1α-VEGF-ANG-1 axis and also enhance the bone destruction of murine arthritis via suppression of osteoclast differentiation and inflammatory reaction.

Soy Isoflavones and Bone Health: Focus on the RANKL/RANK/OPG Pathway.

Bone remodels via resorption and formation, two phenomena that continuously occur in bone turnover. The RANKL/RANK/OPG pathway is one of the several mechanisms that affect bone turnover. The RANKL/OPG ratio has a substantial role in bone resorption. An imbalance between formation and resorption is related to an increased RANKL/OPG balance. OPG, a member of this system, can bind to RANKL and suppress RANK-RANKL interaction, and subsequently, inhibit further osteoclastogenesis. The serum levels of RANKL and OPG in the bone microenvironment are vital for osteoclasts formation. The RANK/RANKL/OPG system plays a role in the pathogenesis of bone disorders. This system can be considered a new treatment target for bone disorders. Soy isoflavones affect the RANK/RANKL/OPG system through numerous mechanisms. Soy isoflavones decrease RANKL levels and increase OPG levels. Therefore, isoflavones improve bone metabolism and decrease bone resorption. Soy isoflavones decrease serum markers of bone resorption and improve bone metabolism. However, while the available data are promising, the results of several studies reported no change in RANKL and OPG levels with isoflavones supplementation. In this regard, current evidence is insufficient for conclusive approval of the efficacy of isoflavones on RANKL/RANK/OPG and further research, including animal and human studies, are needed to confirm the effect of soy isoflavones on the RANKL/RANK/OPG pathway. This study was a review of available evidence to determine the role of isoflavones in bone hemostasis and the RANK/RANKL/OPG pathway. The identification of the effects of isoflavones on the RANKL/RANK/OPG pathway directs future studies and leads to the development of effective treatment strategies for bone disorders.

Gut microbiome and human health: Exploring how the probiotic genus Lactobacillus modulate immune responses.

The highest density of microbes resides in human gastrointestinal tract, known as "Gut microbiome". Of note, the members of the genus Lactobacillus that belong to phyla Firmicutes are the most important probiotic bacteria of the gut microbiome. These gut-residing Lactobacillus species not only communicate with each other but also with the gut epithelial lining to balance the gut barrier integrity, mucosal barrier defence and ameliorate the host immune responses. The human body suffers from several inflammatory diseases affecting the gut, lungs, heart, bone or neural tissues. Mounting evidence supports the significant role of Lactobacillus spp. and their components (such as metabolites, peptidoglycans, and/or surface proteins) in modulatingimmune responses, primarily through exchange of immunological signals between gastrointestinal tract and distant organs. This bidirectional crosstalk which is mediated by Lactobacillus spp. promotes anti-inflammatory response, thereby supporting the improvement of symptoms pertaining to asthma, chronic obstructive pulmonary disease (COPD), neuroinflammatory diseases (such as multiple sclerosis, alzheimer's disease, parkinson's disease), cardiovascular diseases, inflammatory bowel disease (IBD) and chronic infections in patients. The metabolic disorders, obesity and diabetes are characterized by a low-grade inflammation. Genus Lactobacillus alleviates metabolic disorders by regulating the oxidative stress response and inflammatory pathways. Osteoporosis is also associated with bone inflammation and resorption. The Lactobacillus spp. and their metabolites act as powerful immune cell controllers and exhibit a regulatory role in bone resorption and formation, supporting bone health. Thus, this review demonstrated the mechanisms and summarized the evidence of the benefit of Lactobacillus spp. in alleviating inflammatory diseases pertaining to different organs from animal and clinical trials. The present narrative review explores in detail the complex interactions between the gut-dwelling Lactobacillus spp. and the immune components in distant organs to promote host's health.