BACKGROUND:Osteosarcoma is a rare malignant tumor originating from bone tissue. Despite advancements in neoadjuvant chemotherapy, the 5-year survival rate for osteosarcoma patients has plateaued around 60 % for the past fifty years, primarily due to the development of chemo-insensitivity. Cisplatin, a cornerstone in current treatment regimens, still has a low response rate in osteosarcoma patients, highlighting the need for strategies to enhance cisplatin sensitivity. PURPOSE:The purpose of this study is to explore the effects of formononetin, a bioactive compound, in sensitizing osteosarcoma cells to cisplatin. STUDY DESIGN:We utilized PDX models of osteosarcoma to evaluate the combined therapeutic effect of formononetin and cisplatin. Single-cell RNA sequencing and single-cell ATAC sequencing were performed on tumor tissues from these models to provide a detailed molecular profile of the treatment effects. METHODS:PDX models of osteosarcoma were established, followed by treatment with formononetin and cisplatin. A total of 7216 human-derived osteosarcoma cells and 89,558 mouse-derived cells were analyzed to assess their role in cisplatin sensitivity and tumor immune microenvironment changes. RESULTS:Our findings demonstrated that cisplatin insensitivity in osteosarcoma is strongly linked to ferroptosis. Formononetin sensitized osteosarcoma cells to cisplatin by inhibiting MAZ/GPX4 axis and inducing ferroptosis. Additionally, formononetin increased NK cell infiltration and immune activity, while reducing the infiltration of exhausted Cd8+ T cells and tumor-associated neutrophils, thereby reprogramming the tumor immune microenvironment and further enhancing cisplatin sensitivity. CONCLUSION:This study is the first to demonstrate that formononetin can enhance cisplatin sensitivity in osteosarcoma. By using osteosarcoma PDX models and performing comprehensive single-cell sequencing analyses, we identified formononetin as a promising sensitizer for cisplatin treatment. Our findings offer new therapeutic insights and mechanistic understanding that could help overcome cisplatin insensitivity in osteosarcoma and potentially improve patient outcomes.

Osteosarcoma, the most common primary malignant bone tumor in children and adolescents, is highly aggressive and prone to metastasis. Endothelial cells (ECs) are involved in angiogenesis and play a key role in promoting the metastasis of tumor. However, research on tip-like ECs within osteosarcoma was extremely rare. In this study, a single-cell atlas of ECs was constructed using single-cell transcriptomic data. It was found that tip-like ECs were abundant in the primary tumors and metastatic foci. Gene sets score analysis indicated their enrichment in pathways associated with angiogenesis and metastasis. What’s more, MCAM was highly expressed in tip-like ECs and was likely to promote the metastasis of osteosarcoma. MCAM was also found to be highly expressed in the ECs of metastatic lymph nodes when compared to normal lymph node samples. Meanwhile, spatial transcriptomics data confirmed the presence of MCAM-positive ECs in metastatic lymph node, closely localized to osteoblasts. In vitro assays, including qRT-PCR, tube formation, and immunofluorescence, validated the role of the MCAM gene in promoting angiogenesis. In conclusion, tip-like ECs may promote tumor metastasis by enhancing angiogenesis. MCAM was a functional gene for tip-like ECs and could serve as a target for the treatment of osteosarcoma.

Resistance to and associated toxic side effects of neoadjuvant chemotherapy remain major obstacles to improving the prognosis of osteosarcoma patients. Consequently, there is an urgent need to discover effective therapeutic agents with lower toxicity. In this study, the patient-derived xenograft (PDX) model was established and single-cell multi-omics sequencing was performed to comprehensively analyze changes in cellular heterogeneity and gene expression patterns of under formononetin treatment. We found that formononetin can significantly inhibit tumor growth in the osteosarcoma PDX model, on which the single-cell sequencing identified MYO1B as a key target mediating the anti-osteosarcoma effects of formononetin. In vitro experiments demonstrated that MYO1B overexpression enhanced the proliferation, invasion, and migration of osteosarcoma cells, while MYO1B silencing exhibited the opposite effects. Further investigation revealed that formononetin treatment markedly downregulated MYO1B expression, effectively suppressing the proliferative, invasive, and migratory phenotypes of osteosarcoma cells. Moreover, single-cell transcriptomic analysis of murine-derived cells showed that formononetin enhanced the cytotoxic activity of NK cells, promoted M1 macrophage polarization and inhibited M2 polarization, and reduced the proportion of senescent neutrophils, thereby alleviating the immunosuppressive state of the tumor microenvironment. Overall, our findings provide a comprehensive single-cell-level elucidation of the molecular mechanisms underlying the anti-osteosarcoma effects of formononetin, primarily involving downregulating the expression of MYO1B and remodeling the tumor immune microenvironment.

OBJECTIVES:To investigate the inhibitory effect of polyphyllin VII (PP7) on osteosarcoma xenograft growth in mice and explore the underlying molecular mechanism. METHODS:Ultra‑performance liquid chromatography‑tandem mass spectrometry was used to analyze the main active components of Paris polyphylla. Six nude mice bearing patient‑derived xenograft (PDX) were randomized into two groups for treatment with 2 mg/kg PP7 gavage or saline every other day for 28 days, and the changes in tumor volume and mass were measured. In cultured 143B and HOS cells, the effect of PP7 treatment (0, 1.25, 2.5, 5, and 10 μmol/L) on cell proliferation was assessed with CCK‑8 assay, and Transwell assays were employed to examine the changes in cell migration and invasion. The target of PP7 was predicted by integrated analyses with single‑cell RNA sequencing (scRNA‑seq), bulk RNA sequencing (bulk RNA‑seq) and molecular docking and verified using Western blotting. In osteosarcoma cells transfected with SOHLH1 siRNAs or a negative control sequence, the effects of PP7 treatment (5 μmol/L) on cell migration, invasion, ferroptosis, reactive oxygen species (ROS) production and lipid peroxidation (LPO) were analyzed. RESULTS:PP7 was identified as one of the major active constituents of Paris polyphylla. In the tumor-bearing mice, PP7 treatment significantly lower the tumor volume and mass. In 143B and HOS cells, PP7 concentration‑dependently inhibited cell proliferation, and at 5 μmol/L, PP7 significantly inhibited cell proliferation, migration and invasion. Multi‑omics analysis identified SOHLH1 as a potential target of PP7, and Western blotting confirmed that PP7 upregulated SOHLH1 expressions at both the mRNA and protein levels. SOHLH1 silencing obviously attenuated the inhibitory effects of PP7 on cell migration and invasion and reduced PP7‑induced ferroptosis. CONCLUSIONS:PP7 suppresses osteosarcoma xenograft growth in mice by inducing ferroptosis via upregulating SOHLH1 expression.

As the most common primary malignant bone tumor, osteosarcoma (OS) is characterized by drug resistance and poor prognosis, highlighting the urgent need for promising therapeutic agents. Formononetin (FMN), a natural product derived from Spatholobi Caulis, has been reported to possess anti-tumor properties. However, its role in OS has not yet been elucidated. In the present study, we established an OS patient-derived xenograft model to investigate the effects of FMN and the underlying mechanisms of its effects on OS. When FMN treatment was completed, bulk transcriptome sequencing was conducted, and the analyses were combined with OS single-cell RNA sequencing (scRNA-seq) data. Results indicated that GTSF1 was up-regulated in OS but down-regulated after FMN intervention, which may regulate the apoptosis of OS cells. Furthermore, the qRT-PCR and IHC results demonstrated that GTSF1 expression was significantly up-regulated in OS cells, whereas FMN expression was down-regulated both in vitro and in vivo. Moreover, in vitro experiments revealed that FMN effectively promoted apoptosis and suppressed the proliferation, migration, and invasion of OS cells. Therefore, this study demonstrated that FMN exerts anti-OS effects by down-regulating GTSF1 expression, thus effectively promoting the apoptosis and inhibiting the proliferation of OS cells, making FMN a promising anti-OS drug.

Abstract Background Osteosarcoma (OS) is the most common primary malignant bone tumor and is highly prone to metastasis. OS can metastasize to the lymph node (LN) through the lymphatics, and the metastasis of tumor cells reestablishes the immune landscape of the LN, which is conducive to the growth of tumor cells. However, the mechanism of LN metastasis of osteosarcoma and remodeling of the metastatic lymph node (MLN) microenvironment is not clear. Methods Single-cell RNA sequencing of 18 samples from paracancerous, primary tumor, and lymph nodes was performed. Then, new signaling axes closely related to metastasis were identified using bioinformatics, in vitro experiments, and immunohistochemistry. The mechanism of remodeling of the LN microenvironment in tumor cells was investigated by integrating single-cell and spatial transcriptomics. Results From 18 single-cell sequencing samples, we obtained 117,964 cells. The pseudotime analysis revealed that osteoblast(OB) cells may follow a differentiation path from paracancerous tissue (PC) → primary tumor (PT) → MLN or from PC → PT, during the process of LN metastasis. Next, in combination of bioinformatics, in vitro and in vivo experiments, and immunohistochemistry, we determined that ETS2/IBSP, a new signal axis, might promote LN metastasis. Finally, single-cell and spatial dissection uncovered that OS cells could reshape the microenvironment of LN by interacting with various cell components, such as myeloid, cancer-associated fibroblasts (CAFs), and NK/T cells. Conclusions Collectively, our research revealed a new molecular mechanism of LN metastasis and clarified how OS cells influenced the LN microenvironment, which might provide new insight for blocking LN metastasis.

Osteosarcoma (OS) is a common primary malignant tumor of the bone in children and adolescents. The five-year survival rate is estimated to be ~70% based on the currently available treatment modalities. It is well known that tumor-infiltrating immune cells (TIICs) that are the most important components in the tumor microenvironment can exert a killing effect on tumor cells. Therefore, in the present study, 85 RNA-sequencing OS samples were categorized into high- and low-immune score groups with ESTIAMATE. Based on the immune score groups, 474 differentially expressed genes (DEGs) were acquired using the LIMMA package of R language. Subsequently, 86 DEGs were taken through univariate COX regression analysis, of which 14 were screened out by least absolute shrinkage and selection operator regression analysis. Furthermore, multivariate COX regression analysis was performed to obtain 4 DEGs. Finally, ecotropic virus integration site 2B (EVI2B) or CD361 gene was screened out via Kaplan-Meier analysis. In addition, CIBERSORT algorithm was used to evaluate the proportion of 22 kinds of TIICs in OS. Correlation analysis revealed that the high expression level of EVI2B can elevate the infiltrated proportion of CD8+ T cells. Moreover, analysis of single cell RNA-sequencing transcriptome datasets and immunohistochemical staining uncovered that EVI2B was mainly expressed on CD8+ T cells and that EVI2B could promote the expression of granzyme A and K of CD8+ T cells to exhibit a potent killing effect on tumor cells. Therefore, EVI2B was identified as a protective immune-related gene and contributed to good prognosis in OS patients.

Osteosarcoma (OS) is a primary bone tumor with high malignancy and the mechanism of hematogenous metastasis in OS is still not clear. The plasma exosomes derived from osteosarcoma play a key role in the process of tumor metastasis. Here, we established RNA-seq dataset for lncRNAs, circRNAs and mRNAs in plasma exosomes from 10 OS patients and 5 healthy donors. A total of 329.52 Gb of clean data was obtained. Besides, 1754 lincRNAs, 7096 known and 1935 new circRNA was identified. Finally, gene expression profiles and differentially expressed genes (DEGs) were analyzed among these 15 samples. There were 331 DEGs of mRNA, 132 of lincRNA and 489 of circRNA was obtained, respectively. This data set provides a significant resource for relevant researchers to excavate potential dysregulated lncRNAs, circRNAs and mRNAs of plasma exosomes in OS versus normal conditions.

Denosumab is a human monoclonal antibody that targets nuclear factor-kappa B ligand and is highly effective in blocking bone resorption. Bibliometrics can intuitively show the research development process, research status, research hotspots and development trend of a certain topic for researchers. This study assessed the course of research and development for denosumab in terms of publications over the past 2 decades. Web of Science databases were searched to identify publications related to research on denosumab from January 1, 2005 to December 31, 2022. The VOS Viewer software (version 1.6.17) and Bibliometrix package in R (version 4.1.3) were used in this study. There were 5119 denosumab-related publications during this period. The total number of citations of denosumab-related publications reached 94917. The most articles were published in the field of Endocrinology Metabolism. As an international language, English remains the most popular language for writing papers. Five of the top ten institutions originated in the USA. Through the VOS Viewer analysis, we found that the relationships between Amgen Inc. with its collaborations were grouped into 4 clusters, the USA was the mainland for research and development on denosumab, closely collaborating with many other countries, such as Canada, Japan, England, and China. Wagman RB from USA was the most prolific author with 119 publications. The journal with the most publications was Osteoporosis International (481 publications). The most cited article was “Denosumab for Prevention of Fractures in Postmenopausal Women with Osteoporosis” with 2053 citations. The clinical trial comprised 6 of the 10 most frequently cited publications, and the rest consisted of reviews. The most frequent keywords for publications since January 1, 2014 were “prevention” and “management,” indicating that a number of prevention and management measures have been developed to regulate the use of denosumab in treating osteoporosis. Our research provided a comprehensive review of denosumab-related publications, suggesting that the development of denosumab is a long process and numerous clinical trials have been conducted before applications in clinical settings.

Osteosarcoma (OS) stood as the most prevalent primary malignant bone tumor among children and adolescents, characterized by its aggressive nature and high propensity for metastasis, thus earning its classification as a highly malignant disease. The primary routes of metastasis in osteosarcoma encompassed hematogenous dissemination (the most common metastasis was lung metastasis) and lymph node involvement, with lymph node metastasis carrying a notably poorer prognosis when contrasted with lung metastasis. However, it was noteworthy that, at that time, clinical practice often overlooked the crucial aspect of conducting regional lymph node screening for newly diagnosed osteosarcoma patients, and there remained a dearth of standardized treatment protocols for osteosarcoma lymph node metastasis. The intricate mechanisms at the heart of osteosarcoma lymph node metastasis primarily revolved around the infiltration of lymphatic vessels by osteosarcoma cells possessing metastatic capabilities and the induction of lymphatic vessel formation by these cells. Nevertheless, it was imperative to underscore that our understanding of the comprehensive mechanisms underpinning the initiation and progression of these processes still remained incomplete. Moreover, following the adaptive proliferation of osteosarcoma cells within regional lymph nodes, there existed a complex biological process that involved a myriad of cytokines and signaling pathways. This process facilitated the metastasis of osteosarcoma cells to distant target organs, most notably the lungs, by virtue of the intimate anatomical relationships between the lymphatic and circulatory systems. Consequently, that comprehensive review sought to provide an all-encompassing exposition on various facets of osteosarcoma lymph node metastasis. These facets included the direct invasion of surrounding lymphatic vessels by osteosarcoma cells, the osteosarcoma cell-induced development of lymphatic vessels through the VEGFC/VEGFR-3 signaling axis, the remodeling of the lymph node microenvironment by osteosarcoma cells via Hsp5B and the Wnt/β-Catenin signaling pathway to ensure their adaptation and survival, the epithelial-mesenchymal transition of osteosarcoma cells promoting metastasis from lymph nodes to the lung, and the utilization of small-molecule compounds in the battle against osteosarcoma lymph node metastasis. The aim was to provide a comprehensive and systematic elucidation of the intricate mechanisms governing osteosarcoma lymph node metastasis and to furnish invaluable insights for the development of therapeutic strategies.

Background Guanine nucleotide binding (G) protein subunit γ 4 (GNG4) is closely related to the malignant progression and poor prognosis of various tumours. However, its role and mechanism in osteosarcoma remain unclear. This study aimed to elucidate the biological role and prognostic value of GNG4 in osteosarcoma. Methods Osteosarcoma samples in the GSE12865, GSE14359, GSE162454 and TARGET datasets were selected as the test cohorts. The expression level of GNG4 between normal and osteosarcoma was identified in GSE12865 and GSE14359. Based on the osteosarcoma single-cell RNA sequencing (scRNA-seq) dataset GSE162454, differential expression of GNG4 among cell subsets was identified at the single-cell level. As the external validation cohort, 58 osteosarcoma specimens from the First Affiliated Hospital of Guangxi Medical University were collected. Patients with osteosarcoma were divided into high- and low-GNG4 groups. The biological function of GNG4 was annotated using Gene Ontology, gene set enrichment analysis, gene expression correlation analysis and immune infiltration analysis. Kaplan–Meier survival analysis was conducted and receiver operating characteristic (ROC) curves were calculated to determine the reliability of GNG4 in predicting prognostic significance and diagnostic value. Functional in vitro experiments were performed to explore the function of GNG4 in osteosarcoma cells. Results GNG4 was generally highly expressed in osteosarcoma. As an independent risk factor, high GNG4 was negatively correlated with both overall survival and event-free survival. Furthermore, GNG4 was a good diagnostic marker for osteosarcoma, with an area under the receiver operating characteristic curve (AUC) of more than 0.9. Functional analysis suggested that GNG4 may promote the occurrence of osteosarcoma by regulating ossification, B-cell activation, the cell cycle and the proportion of memory B cells. In in vitro experiments, silencing of GNG4 inhibited the viability, proliferation and invasion of osteosarcoma cells. Conclusion Through bioinformatics analysis and experimental verification, high expression of GNG4 in osteosarcoma was identified as an oncogene and reliable biomarker for poor prognosis. This study helps to elucidate the significant potential of GNG4 in carcinogenesis and molecular targeted therapy for osteosarcoma.

The lung is the primary organ for the metastasis of osteosarcoma. Although the application of neoadjuvant chemotherapy and surgery has remarkably improved the survival rate of patients with osteosarcoma, prognosis is still poor for those patients with metastasis. In this study, we performed further bioinformatics analysis on single-cell RNA sequencing (scRNA-seq) data published before, containing 75,317 cells from two osteosarcoma lung metastasis and five normal lung tissues. First, we classified 17 clusters, including macrophages, T cells, endothelial cells, and so on, indicating highly intratumoral heterogeneity in osteosarcoma lung metastasis. Next, we found macrophages in osteosarcoma lung metastasis did not have significant M1 or M2 polarizations. Then, we identified that T cells occupied the most abundant among all cell clusters, and found CD8(+) T cells exhibited a low expression level of immune checkpoints in osteosarcoma lung metastasis. What is more, we identified C2_Malignant cells, and found CD63 might play vital roles in determining the infiltration of T cells and malignant cells in conventional-type osteosarcoma lung metastasis. Finally, we unveiled C1_Therapeutic cluster, a subcluster of malignant cells, was sensitive to oxfendazole and mevastatin, and the potential hydrogen-bond position and binding energy of oxfendazole-KIAA0907 and mevastatin-KIAA0907 were unveiled, respectively. Our results highlighted the power of scRNA-seq technique in identifying the complex tumor microenvironment of osteosarcoma lung metastasis, making it possible to devise precision therapeutic approaches.

Circular RNA (circRNA) is involved in the occurrence and development of various cancers. To this day, the expression and mechanism of circRNA in osteosarcoma (OS) remain unclear. We previously found that circ_0001060 was highly expressed in OS tumor tissues. In this work, we identified that high level expression of circ_0001060 was significantly associated with late clinical stage, larger tumor volume, higher frequency of metastasis, and poor prognosis in OS patients. Furthermore, we confirmed that silencing circ_0001060 inhibited the proliferation and migration of OS cell. Using bioinformatics analysis, we built three circRNA-miRNA-mRNA regulatory modules (circ_0001060-miR-203a-5p-TRIM21, circ_0001060-miR-208b-5p-MAP3K5, and circ_0001060-miR-203a-5p-PRKX), suggesting that these signaling axes may be involved in the inhibitory effect of circ_0001060 on OS. To sum up, circ_0001060 is a novel tumor biomarker for OS as well as a potential therapeutic target.

Background Osteosarcoma is a common solid malignancy of the bone in children and adolescents, and its metastasis and recurrence are the principal causes of poor treatment outcomes. Methods Autophagy-related genes were used to cluster osteosarcoma patients by consensus clustering analysis using the GSE21257 database. Differentially expressed genes (DEGs) were identified by limma package. Multiple-gene risk signature was constructed using least absolute shrinkage and selection operator (LASSO) analysis and Cox regression analyses. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to determine gene expression levels. Then, single-cell RNA-sequencing dataset GSE152048 were used to identify the correlation between the DEGs and effector molecules expressed in specific tumor-infiltrating immune cells. Results Two clusters were identified in the consensus clustering analysis, which were confirmed by principal component analysis. Limma analysis revealed that 15 genes were related, and 9 genes were screened using protein-protein interaction network and LASSO regression analysis. Cox regression analyses identified 5 genes. Combined with survival analysis, only the autophagy related 16 like 1 gene (ATG16L1) was significant. The results of qRT-PCR showed low expression levels of ATG16L1 in tumor cells group. Immune infiltration analysis revealed significantly lower expression of CD8+ T cells in the high ATG16L1 gene expression group. ScRNA-seq revealed that in the ATG16L1+CD8+ T cell group, the expression of GZMB was lower, whereas the expression of ITGA1 was higher. These results showed that ATG16L1 is an immune-related gene, which is associated with poor prognosis in patients with osteosarcoma. Conclusion ATG16L1 is a potential prognostic biomarker and immune signature and may be a therapeutic target for osteosarcoma.

Primary hyperparathyroidism (PHPT) with pathological fracture is rare, and the early symptoms of PHPT lack specificity, leading to misdiagnosis. Therefore, this study aimed to summarize the clinical characteristics and treatment of PHPT patients with pathological fractures and to improve the attention of orthopedic clinicians to PHPT. It is a retrospective study, 2226 patients with hyperparathyroidism in our hospital from 2009 to 2019 were screened, excluding secondary hyperparathyroidism and patients without limb fracture, and the remaining 20 patients with PHPT accompanied by pathological fractures were finally analyzed. Parathyroid hormone (PTH) and calcium levels were compared on the first postoperative day, and the prognosis of the patients was assessed by bone mineral density and Visual Analogue Scale scores at 3 and 12 months postoperatively. The early symptoms of PHPT patients in this study included urinary calculi (80%), bone pain (30%), and digestive tract symptoms (25%). Fourteen (70%) cases were misdiagnosed at the initial diagnosis. After parathyroidectomy, the blood calcium and PTH levels decreased significantly in all patients (P < .05). For the treatment of fracture, 9 of the patients underwent surgical treatment of the fracture, while the remaining patients received splint external fixation. The follow-up time was 4.60 +/- 0.62 years (1-10 years). All patients recovered well from the fracture, the symptoms of systemic bone pain were markedly improved, and bone mineral density was significantly improved after surgery. Orthopedic surgeons need to avoid misdiagnosis and pay attention to the early symptoms in PHPT patients with pathological fracture, and better therapeutic effects can be obtained by combining parathyroidectomy with fractures fixation.

Osteoporosis is a systemic and metabolic bone disease that usually occurs in postmenopausal women, which mainly manifests as bone loss and increased bone fragility that both facilitate fracture. However, few drugs for osteoporosis have shown good efficacy and limited side effects. Vaccarin has demonstrated its antiosteoporosis effects by inhibiting the formation and osteolytic activities of osteoclasts in our previous investigation. In this study, multivariate statistical analysis and ultrahigh-performance liquid chromatography and quadrupole time-of-flight tandem mass spectrometry were used to analyze the serum metabolites of ovariectomized mice treated with or without vaccarin. As a result, 9 serum metabolites were identified as biomarkers. The metabolic levels of 3 crucial biomarkers, namely, lysophosphatidylcholine [22 : 6, (4Z, 7Z, 10Z, 13Z, 16Z, 19Z)], 1-linoleoylglycerophosphocholine and 1-palmitoyl-Sn-glycero-3-phosphocholine, that were correlated with glycerophospholipid metabolism increased and then decreased significantly after vaccarin treatment. Molecular docking analysis and osteoclasts differentiation experiment further revealed that vaccarin may bind with phospholipase A2 and downregulated its activity to reduce the osteoclastogenesis. Therefore, the occurrence of osteoporosis is closely related with glycerophospholipid metabolism disorders, and vaccarin exerts antiosteoporosis effects by reducing the levels of glycerophospholipid metabolites.

Osteoporosis is among the major contributors of pathologic fracture in postmenopausal women, which is caused by the bone metabolic disorder owing to the over-activation of osteoclasts. Inhibition of osteoclast differentiation and maturation has become a mainstream research interest in the prevention of osteoporosis. Isoliensinine (Iso) is a dibenzyl isoquinoline alkaloid with antioxidant, anti-inflammatory, and anti-cancer activities. However, whether it can be used as a potential treatment for osteoporosis remains undiscovered. Here, we investigated whether Iso might suppress the differentiation of osteoclasts in vitro and in vivo to play an anti-osteoporosis role. Our results showed that Iso inhibits the formation of mature multinuclear osteoclasts induced by RANKL, the bone resorption, and the osteoclast-specific genes expression by blocking the nuclear translocation of NF-κB p65, and the effect was in a dosage-dependent way. Furthermore, we investigated the therapeutic effect of Iso on osteoporosis in ovariectomized (OVX) mice. We found that Iso attenuated bone loss in the OVX mice and significantly promoted BS, Conn. DN, Tb.Th, TB.N, and BV/TV Index. All in all, Iso showed a prominent effect of osteoclast inhibition, with great promise for treating osteoporosis.

The purpose of this study was to investigate the significance of preoperative C-reactive protein-to-albumin ratio (CAR), neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in predicting overall survival (OS) of osteosarcoma, to establish a nomogram of an individualized prognostic prediction model for osteosarcoma.Two hundred thirty-five patients with osteosarcoma from multiple centers were included in this study. Receiver operating characteristic (ROC) and Youden index were used to determine the optimal cutoff values ​​for CAR, NLR, and PLR. Univariate analysis using COX proportional hazards model to identify factors associated with OS in osteosarcoma, and multivariate analysis of these factors to identify independent prognostic factors. R software (4.1.3-win) rms package was used to build a nomogram, and the concordance index (C-index) and calibration curve were used to assess model accuracy and discriminability.Univariate analysis revealed that the OS of osteosarcoma is significantly correlated (P < 0.05) with CAR, NLR, PLR, Enneking stage, tumor size, age, neoadjuvant chemotherapy (NACT), and high alkaline phosphatase. Multivariate analysis confirmed that CAR, NLR, Enneking stage, NACT and tumor size are independent prognostic factors for OS of osteosarcoma. The calibration curve shows that the nomogram constructed from these factors has acceptable consistency and calibration capability.Preoperative CAR and NLR were independent predictors of osteosarcoma prognosis, and the combination of nomogram model can realize individualized prognosis prediction and guide medical practice.

Osteosarcomas are the most common primary malignant bone tumors in children and adolescents. Osteolysis is a common feature of all osteosarcomas (traditional, intramedullary, and periosteum). However, the specific mechanism of osteolysis is unknown and many researchers have studied it from different perspectives. Osteolysis is a process in which physiological bone remodeling is disrupted and excessive bone resorption occurs. Osteoclasts, the only cells with bone resorption function in the human body, play a key role in the pathological process of osteolysis in osteosarcomas. Osteoclasts play a leading role in osteolysis by secreting a high concentration of acid and collagenase, and they also mediate the occurrence and development of osteolysis in osteosarcoma through synergistic interaction with osteosarcoma cells. At the same time, osteolysis is an essential part of the pathological process of osteosarcoma, which can promote the occurrence and development of osteosarcoma and form a vicious cycle. Inhibiting osteolysis is of great significance to break this cycle and prevent the occurrence and development of osteosarcoma. However, the specific regulatory mechanism between osteosarcoma cells and osteoclasts and whether other cells in osteosarcoma are also involved in this pathological process remain unclear. Currently, bisphosphonates, small molecule inhibitors and natural compounds are the main drugs used to treat osteolysis of osteosarcoma. However, their efficacy and mechanism are still in the early stage of research. Previous studies on neoplastic osteolysis have mostly focused on metastatic bone tumors. Recently, studies on osteolysis of osteosarcoma have attracted more and more attention. The mechanism of osteoclasts and osteosarcoma cells in tumor-mediated osteolysis and the status of drug therapy of these two cell types as therapeutic targets are reviewed and analyzed. A deeper understanding of the role of osteolysis in the initiation and development of osteosarcoma will provide a theoretical basis and direction for the treatment of osteolysis in the context of osteosarcoma.

目前,骨质疏松症作为全球性的公共卫生健康问题已严重影响人类健康,虽然近年来对骨质疏松症的研究不断深入,但仍不能完整及正确地诠释其相关的发病机制.由于炎症因子在炎症性骨病中发挥重要作用,不但可以作为监测疾病进展的生物标志物,也可作为临床诊疗的诊断指标.大量研究表明,炎症因子可通过激活或抑制相关的信号通路及影响相关酶蛋白的表达量等来影响成骨细胞与破骨细胞的活性和功能,进而在影响骨质疏松症的发生发展中起着至关重要的作用.本文根据炎症因子对骨质疏松症的不同作用分为促进、抑制、双作用炎症因子三大类型,并就它们影响骨质疏松症发病机制中的作用作一简要综述,从而为骨质疏松症的相关研究提供理论依据.