Background Posterior shoulder dislocation accompanied by reverse Hill-Sachs lesions is relatively rare, whereas bilateral posterior shoulder dislocation is exceedingly rare. Case presentation We report two cases of bilateral posterior shoulder dislocations associated with reverse Hill-Sachs lesions. In Case 1, the lesions were managed using the McLaughlin procedure and the modified McLaughlin procedure. In Case 2, open reduction and internal fixation of the left shoulder was unsuccessful; consequently, reconstruction of the right humeral head was performed using bone cement. Conclusions Bilateral posterior shoulder dislocations with reverse Hill-Sachs lesions are uncommon and are therefore prone to misdiagnosis. Early recognition and appropriately selected treatment strategies, tailored to the severity of the injury, are essential to achieve satisfactory functional outcomes. For severely comminuted proximal humeral fractures, when internal fixation is not feasible and no joint replacement prostheses are unavailable, bone cement reconstruction may serve as a reasonable alternative.

Aberrant activation of HIF‑1α contributes to the maintenance of CSC phenotypes in various malignancies. Our previous work revealed that ANXA3 is up‑regulated in OS cells. Here, we further investigated how ANXA3 regulates CSC‑like properties of OS cells through the HIF‑1α/VEGF signaling pathway. Lentiviral vectors were used to modulate ANXA3 expression in OS cell lines. The expression of stemness‑associated genes was examined by qPCR and Western blotting, and sphere‑formation assays were performed to evaluate CSC self‑renewal capacity. Migration, invasion, and clonogenic survival under cisplatin treatment were assessed using Transwell and colony‑formation assays. An orthotopic intratibial implantation model in NOD-SCID mice was established to evaluate the effects of ANXA3 on tumor growth, metastasis, and CSC‑related features. Potential signaling mechanisms were analyzed by Western blotting and ELISA, and pathway‑specific inhibitors were applied to dissect the PI3K/Akt/mTOR–HIF‑1α/VEGF cascade. ANXA3 expression was markedly elevated in osteosarcoma spheres compared with parental cells. ANXA3 knockdown down‑regulated stemness‑related genes, impaired sphere formation, and increased cisplatin sensitivity, whereas ANXA3 overexpression produced opposite effects. In vivo, ANXA3 silencing significantly suppressed tumor growth and pulmonary metastasis. Mechanistically, ANXA3 activated the PI3K/Akt/mTOR pathway, thereby enhancing HIF‑1α/VEGF expression. Knockdown of PI3K or HIF‑1α abrogated ANXA3‑induced stemness and chemoresistance, confirming the signaling axis mediates ANXA3‑driven oncogenic effects. ANXA3 plays a critical role in maintaining CSC‑like traits in osteosarcoma by up‑regulating the HIF‑1α/VEGF pathway in a PI3K/Akt/mTOR‑dependent manner. Targeting ANXA3 or its downstream signaling components may represent a promising therapeutic strategy for reversing CSC phenotypes and overcoming chemoresistance in osteosarcoma.

To investigate the mechanism by which glycine inhibits chondrocyte ferroptosis and improves osteoarthritis (OA), primary rat chondrocytes were pre-treated with glycine prior to interleukin-1β (IL-1β) stimulation. Cellular viability, apoptosis, senescence, reactive oxygen species (ROS), lipid peroxide, Fe2+, and GSH level were determined. Transcriptomic analysis, chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assay were employed to confirm the MafG-Plectin regulatory axis. Loss-of-function experiments using siRNA targeting Plectin or MafG validated the functional necessity of this axis. A rat OA model was established by anterior cruciate ligament transection (ACLT), and glycine was injected intra-articularly. Glycine pretreatment significantly improved IL-1β-induced chondrocyte dysfunction, inhibited ROS accumulation, lipid peroxidation, and Fe2+ overload, and upregulated SLC7A11 and GPX4. Glycine upregulated MafG, which directly bound the Plectin promoter to promote Plectin transcription. Silencing of either MafG or Plectin reversed glycine's protective effects, confirming the MafG-Plectin axis as an essential operative module. In OA rats, glycine alleviated cartilage degradation, improved bone microstructure, and upregulated MafG, Plectin, and GPX4; these effects were abolished by si-MafG. Collectively, glycine inhibits chondrocyte ferroptosis and improves OA through a dual mechanism involving MafG-mediated GSH synthesis and MafG-dependent Plectin upregulation, providing a potential therapeutic target for OA.

BACKGROUND AND OBJECTIVE:Accurate evaluation of the axillary lymph node (ALN) status in early-stage breast cancer is crucial for prognosis and guiding treatment decisions, while also preventing unnecessary surgeries and postoperative complications. Numerous methods have been proposed for ALN status classification using radiomic images which face the challenge of low diagnostic accuracy. This study aims to explore the potential of multi-modality that integrates clinical parameters and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to provide complementary information for image features, thereby enhancing the model's ability to predict ALN metastasis. METHODS:We proposed a Graph-based Multi-Modality network (GMM-Net) that combines DCE-MRI and clinical parameters for preoperative prediction. GMM-Net consists of Text Encoder, Local-Global Graph Neural Module (LGGNM) and Multi-Modality Feature Fusion module (MMF). Text Encoder is used to extract features from clinical parameters, and LGGNM captures MRI features by learning cross-region feature correlations within individual slices and connects tumor-related regions across adjacent slices to capture the complete spatial distribution of lesions. Finally, the MMF calculates the similarity between MRI and clinical parameter modalities for each patient. RESULTS:A paired breast tumor classification dataset containing 260 cases with 13 clinical indicators was utilized to develop and evaluate the proposed method. Experimental results demonstrate that the GMM-Net achieves an accuracy of 0.8482 and an AUC of 0.8461, outperforming other single-modality approaches. CONCLUSION:In this study, a graph-based multi-modality framework was proposed to extract clinical and DCE-MRI features for the preoperative assessment of ALN status. Numerous results demonstrated the potential of GMM-Net in non-invasively predicting the preoperative assessment of ALN status in early-stage of breast cancer.

The transcription factor SRY-related HMG-box 4 (SOX4) has been implicated in intervertebral disc diseases. This study aimed to investigate the role of SOX4 in intervertebral disc degeneration (IDD) and explore the underlying molecular mechanisms. We established an IDD rat model via surgery and analyzed SOX4 expression using qRT-PCR and Western blotting. Histological evaluation, immunohistochemistry, and Safranin O staining assessed IDD progression. In vitro, an IDD cellular model was constructed using IL-1β-stimulated nucleus pulposus (NP) cells. SOX4 knockdown and overexpression experiments in NP cells examined SOX4 effects on ECM degradation, NLRP3-mediated pyroptosis, and mitochondrial ROS-dependent NLRP3 inflammasome activation. The involvement of the EZH2/NRF2 pathway in SOX4-mediated NLRP3 activation was also examined. SOX4 expression was significantly increased in IDD rats and promoted IDD progression. Knockdown of SOX4 inhibited ECM degradation and NLRP3-mediated pyroptosis in NP cells. In vitro experiments showed that SOX4 promoted ECM degradation by upregulating MMPs and ADAMTS-5 expression, and suppressed collagen II and aggrecan synthesis. SOX4 knockdown inhibited NLRP3-mediated pyroptosis, while overexpression accelerated it in NP cells. Additionally, SOX4 was found to exacerbate mitochondrial ROS-dependent NLRP3 inflammasome activation in NP cells. Further investigation revealed that SOX4 enhanced NLRP3 inflammasome activation by upregulating EZH2 expression and modulating the EZH2/NRF2 pathway, with EZH2 inhibition attenuating SOX4-induced NLRP3 activation. Our findings suggest that SOX4 accelerates IDD progression by promoting NLRP3 inflammasome activation via modulating the EZH2/NRF2 pathway, leading to NP cell pyroptosis and ECM degradation. Targeting SOX4 may represent a potential therapeutic strategy for treating IDD.

Rhein (RH), an anthraquinone compound extracted from the Chinese herb rhubarb, exerts antitumour effects on various cancers. However, the role and underlying molecular mechanisms of RH in osteosarcoma remain unknown. In this study, we observed that RH significantly inhibited osteosarcoma cell proliferation, migration, invasion and stemness in vitro while promoting death and curtailing tumourigenesis in vivo. Mechanistically, RH downregulated the expression of FABP4 in osteosarcoma cells. The induction of death by RH was augmented by FABP4 knockdown and diminished by FABP4 overexpression. Depletion of FABP4 suppressed osteosarcoma cell proliferation in vitro and in vivo. Then, we found that TCF7L2 was directly bound to the FABP4 promoter and facilitated its transcription. Downregulation of TCF7L2 inhibited FABP4 expression and enhanced the anticancer effects of RH in osteosarcoma. Additionally, our investigations revealed that RH significantly upregulated miR-328-3p expression, resulting in the downregulation of TCF7L2 protein levels in osteosarcoma cells. Our findings indicate that miR-328-3p/TCF7L2/FABP4 axis is vital for the anticancer effects of RH and may be a potential therapeutic agent for osteosarcoma treatment.

The oncogenic properties of Nucleobindin2 (NUCB2) have been observed in various cancer types. Nevertheless, the precise understanding of the biological functions and regulatory mechanisms of NUCB2 in osteosarcoma remains limited. This investigation reported that NUCB2 was significantly increased upon glucose deprivation-induced metabolic stress. Elevated NUCB2 suppressed glucose deprivation-induced cell death and reactive oxygen species (ROS) increase. Depletion of NUCB2 resulted in a reduction in osteosarcoma cell proliferation as well as metastatic potential in vitro and in vivo. Mechanically, NUCB2 ablation suppressed C-X-C Motif Chemokine Ligand 8 (CXCL8) expression which then reduced programmed cell death 1 ligand 1 (PD-L1) expression and stimulated anti-tumor immunity mediated through cytotoxic T cells . Importantly, a combination of NUCB2 depletion with anti-PD-L1 treatment improved anti-tumor T-cell immunity in vivo. Moreover, we further demonstrated that NUCB2 interacted with NUCKS1 to inhibit its degradation, which is responsible for the transcriptional regulation of CXCL8 expression. Altogether, the outcome emphasizes the function of NUCB2 in osteosarcoma and indicates that NUCB2 elevates osteosarcoma progression and immunosuppressive microenvironment through the NUCKS1/CXCL8 pathway.

Background Osteosarcoma, a tumor that originates from bone cells, has a poor prognosis and a high degree of malignancy. Anlotinib, a small-molecule multi-target tyrosine kinase inhibitor (TKI), is the first-line drug in treating osteosarcoma, especially in late-stage osteosarcoma. However, patients often develop resistance after using anlotinib for a certain period, which poses a challenge to its further clinical application. Recently, several TKIs, for instance regorafenib and cabozantinib, have showed clinical interest in treating osteosarcoma and target both vascular endothelial growth factor receptor (VEGFR) and mesenchymal epithelial transition factor (c-MET). Therefore, the identification of new TKI warrants further investigation. Methods We performed CCK8 aasays to confirm that BMS-794833 sensitization osteosarcoma cells to anlotinib. Bioinformatics analysis and rescue experiments showed that the reduce of resistance were dependent on the VEGFR/Ras/CDK2 pathway. Cell line based xenograft model were used to demonstrate that BMS-794833 and anlotinib could synergistically treat OS. Results Here, we found that BMS-794833 reduced anlotinib resistance in osteosarcoma by targeting the VEGFR/Ras/CDK2 pathway. CCK8 assay showed that BMS-794833 significantly improved the resistance of osteosarcoma cells to anlotinib. The results of rescue experiments showed that the regulatory effects of BMS-794833 on the proliferation and drug resistance of osteosarcoma cells were dependent on the VEGFR/Ras/CDK2 pathway. In addition, BMS-794833 affected the resistance of osteosarcoma cells to anlotinib through epithelial–mesenchymal transition (EMT) and apoptosis pathways. More importantly, BMS-794833 and anlotinib exerted synergistic therapeutic effects against osteosarcoma in vivo. Conclusion Altogether, this study reveals a new (VEGFR)-targeting drug that can be combined with anlotinib for the treatment of osteosarcoma, which provides an important theoretical basis for overcoming anlotinib resistance.

Background: Osteosarcoma, a tumor that originates from bone cells, has a poor prognosis and a high degree of malignancy. Anlotinib, a small -molecule multi -target tyrosine kinase inhibitor (TKI), is the first -line drug in treating osteosarcoma, especially in late -stage osteosarcoma. However, patients often develop resistance after using anlotinib for a certain period, which poses a challenge to its further clinical application. Recently, several TKIs, for instance regorafenib and cabozantinib, have showed clinical interest in treating osteosarcoma and target both vascular endothelial growth factor receptor (VEGFR) and mesenchymal epithelial transition factor (cMET). Therefore, the identification of new TKI warrants further investigation. Methods: We performed CCK8 aasays to confirm that BMS-794833 sensitization osteosarcoma cells to anlotinib. Bioinformatics analysis and rescue experiments showed that the reduce of resistance were dependent on the VEGFR/Ras/CDK2 pathway. Cell line based xenograft model were used to demonstrate that BMS-794833 and anlotinib could synergistically treat OS. Results: Here, we found that BMS-794833 reduced anlotinib resistance in osteosarcoma by targeting the VEGFR/ Ras/CDK2 pathway. CCK8 assay showed that BMS-794833 significantly improved the resistance of osteosarcoma cells to anlotinib. The results of rescue experiments showed that the regulatory effects of BMS-794833 on the proliferation and drug resistance of osteosarcoma cells were dependent on the VEGFR/Ras/CDK2 pathway. In addition, BMS-794833 affected the resistance of osteosarcoma cells to anlotinib through epithelial -mesenchymal transition (EMT) and apoptosis pathways. More importantly, BMS-794833 and anlotinib exerted synergistic therapeutic effects against osteosarcoma in vivo . Conclusion: Altogether, this study reveals a new (VEGFR)-targeting drug that can be combined with anlotinib for the treatment of osteosarcoma, which provides an important theoretical basis for overcoming anlotinib resistance.

Homeobox B9 (HOXB9) has been shown to play a critical role in several tumors. However, the precise biological mechanisms and functions of HOXB9 in osteosarcoma remain largely unknown. In this study, we found that HOXB9 was increased upon glucose starvation. Elevated HOXB9 suppressed osteosarcoma cell death and supported cell growth and migration under glucose starvation. Further mechanistic studies demonstrated that HOXB9 directly bound to the promoter of secreted phosphoprotein 1 (SPP1) and transcriptionally upregulated SPP1 expression which then led cell death decrease and cell growth increase under glucose deprivation environment. Clinically, HOXB9 was significantly upregulated in osteosarcoma compared with normal tissues and increase of HOXB9 expression was positively associated with the elevation of SPP1 in osteosarcoma. Overall, our study illustrates that HOXB9 contributes to malignancy in osteosarcoma and inhibits cell death through transcriptional upregulating SPP1 under glucose starvation.

Additional file 7: Supplementary Table 1. The shRNAs used in the article.

Background Chemotherapeutic insensitivity remains a big challenge in prostate cancer treatment. Recently, increasing evidence has indicated that KLF4 plays a key role in prostate cancer. However, the potential biological role of KLF4 in Chemotherapeutic insensitivity of prostate cancer is still unknown. Methods The role of KLF4 in cisplatin-induced apoptosis was detected by western blotting and a cell counting kit (CCK8). The potential molecular mechanism of KLF4 in regulating prostate cancer chemosensitivity was investigated by RNA sequencing analysis, q-RT-PCR, western blotting and chromatin immunoprecipitation (ChIP). The expression level of KLF4 mediated by miR-32-5p was confirmed by bioinformatic analysis and luciferase assays. Results Here, we found that KLF4 was induced by cisplatin in prostate cancer cells and that the increase in KLF4 promoted cell apoptosis. Further mechanistic studies revealed that KLF4 directly bound to the promoter of BIK, facilitating its transcription. Additionally, we also found that the gene encoding KLF4 was a direct target of miR-32-5p. The downregulation of miR-32-5p in response to cisplatin treatment promoted KLF4 expression, which resulted in a increase in the chemosensitivity of prostate cancer. Conclusion Thus, our data revealed that KLF4 is an essential regulator in cisplatin-induced apoptosis, and the miR-32-5p-KLF4-BIK signalling axis plays an important role in prostate cancer chemosensitivity.

Objective:To compare the effectiveness between the posterolateral approach and the posterolateral combined posteromedial approaches in the treatment of Mason type 2B posterior malleolar fracture. Methods:A retrospective analysis was performed on the clinical data of 79 patients with posterior ankle fracture who met the selection criteria between January 2015 and January 2022. There were 62 cases of Mason 2B Pilon subtype and 17 cases of avulsion subtype. Among Mason 2B Pilon subtype patients, 35 were treated with posterolateral approach (group A), 27 patients were treated with combined approach (group B). There was no significant difference in gender, age, injured side, cause of injury, time from injury to operation, preoperative hospital stay, preoperative visualanalogue scale (VAS) score, and intraoperative internal fixation between the two groups ( P>0.05). All patients with Mason 2B avulsion subtype were treated by posterolateral approach, including 7 males and 10 females, aged from 25 to 68 years, with an average of 46.1 years. The operation time, intraoperative blood loss, postoperative hospital stay, and complications were recorded. The reduction quality was evaluated by Ovadia deals radiographic score, and the ankle function and pain were evaluated by VAS score, American Orthopaedic Foot and Ankle Society (AOFAS) score, and ankle range of motion. Results:Mason 2B Pilon subtype: There was no significant difference in operation time, intraoperative blood loss, postoperative hospital stay, and follow-up time between the two groups ( P>0.05). The radiological evaluation of Ovadia deals in group A was significantly worse than that in group B ( P<0.05). The VAS score in the two groups significantly improved at each time point after operation, and the VAS score and AOFAS score further improved with the extension of time after operation, and the differences were significant ( P<0.05). Except that the AOFAS score of group A was significantly lower than that of group B at last follow-up ( P<0.05), there was no significant difference in VAS score and AOFAS score between the two groups at other time points ( P>0.05). At last follow-up, the ankle range of motion in group A was significantly less than that in group B ( P<0.05). There was no significant difference in the incidence of sural nerve injury, deep tissue infection, limitation of toe movement, and traumatic ankle arthritis between the two groups ( P>0.05). Mason 2B avulsion subtype: The operation time was (119.47±20.61) minutes and the intraoperative blood loss was 50 (35, 55) mL. Seventeen patients were followed up 13-25 months, with an average of 18 months. The Ovadia deals score was excellent in 10 cases, good in 6 cases, and poor in 1 case at 1 week after operation, and the excellent and good rate was 94.1%. All fractures healed in 8-18 weeks with an average of 12.35 weeks. There were 1 case of sural nerve injury and 3 cases of traumatic ankle arthritis after operation. No deep tissue infection or limitation of toe movement occurred. The VAS score decreased significantly and AOFAS score increased significantly with time, and the differences were significant between different time points before and after operation ( P<0.05). The ankle range of motion at last follow-up was (56.71±2.47)°. Conclusion:Compared with the posterolateral approach, the combined approach is a better choice for the treatment of Mason 2B Pilon subtype. If the posteromedial bone block does not affect the reduction of the medial malleolus, the posterolateral approach can achieve good effectiveness for Mason 2B avulsion subtype.

Nuclear ubiquitous casein and cyclin-dependent kinase substrate 1 (NUCKS1) has been reported to play an oncogenic role in several cancers. However, the biological functions and regulatory mechanism of NUCKS1 in osteosarcoma have not been fully understood. In this study, we reported that NUCKS1 was significantly increased in osteosarcoma. Depletion of NUCKS1 decreased osteosarcoma cell proliferation and metastasis in vivo and in vitro. Overexpression of NUCKS1 accelerated osteosarcoma cell aggressiveness. Mechanistically, NUCKS1 facilitated asparagine (Asn) synthesis by transcriptionally upregulating asparagine synthetase (ASNS) expression and elevating the levels of Asn in osteosarcoma cells, leading to increased cell growth and metastasis. Inhibition of ASNS or reduction of Asn decreased osteosarcoma cell aggressiveness and impaired the promoting effects of NUCKS1 on tumorigenesis and metastasis. Furthermore, we also found that by acting as a sponge for miR-4768-3p, LINC00629 promoted NUCKS1 expression. Collectively, our findings highlight the role of NUCKS1 in regulating asparagine metabolism and reveal that LINC00629 is an important regulator of NUCKS1 that contributes to NUCKS1 upregulation in osteosarcoma.

Objective: Ultrasound imaging can be used to monitor bone healing after fracture. It has the advantages of simplicity, rapidity, non-radiation, and real-time dynamic observation of fracture healing. It is increasingly valued and developed in clinical applications. Deep learning is an essential branch of artificial intelligence widely used in the medical field.Methods: After fracture surgery, 134 patients were selected for ultrasonic imaging at 2 weeks, 4 weeks, 8 weeks, and 12 weeks after surgery. Among them, 104 patients were selected for ultrasonic imaging to establish a prediction model for ultrasonic deep learning, and then 30 patients were used for imaging to verify and improve the model. Finally, 30 patients were selected for ultrasonic imaging and X-ray imaging at 2 weeks, 4 weeks, 8 weeks, and 12 weeks after fracture surgery for the same patient; test the ultrasonic imaging prediction model, compare the ultrasonic imaging and X-ray imaging manual reading, and evaluate the ultrasonic imaging prediction model by accuracy, loss curve, F1 score value, roc curve, AUC value, etc.Results: The accuracy of the ultrasonic imaging deep learning prediction model in the test set was 0.73. In the test set, the predicted AUC values for 2 weeks, 4 weeks, 8 weeks, and 12 weeks after fracture surgery were 0.82, 0.90, 0.86, and 0.67, respectively. The accuracy of ultrasonic imaging manual film reading was 0.7, and the AUC values for the four periods were 0.76, 0.81,0.81, and 0.86, respectively. X-ray imaging manual film reading accuracy was 0.7, and the AUC values for the four periods were 0.86, 0.76, 0.81, and 0.84, respectively.Conclusion: Based on the artificial intelligence framework, a deep learning prediction model is constructed by preprocessing the ultrasonic imaging after fracture surgery to predict fracture healing, and its application value is discussed. The prediction model of ultrasonic imaging based on deep learning can be used as an effective monitoring method for bone healing after fracture surgery.

Osteosarcoma is a bone tumor that often affects children, adolescents and young people. Non-coding RNA activated by DNA damage (NORAD) can promote the proliferation of cancer cells in multiple tumors. Thus, the current study set out to explore the role of NORAD derived from extracellular vesicles (EVs) of bone mesenchymal stem cells (BMSCs) in osteosarcoma. First, NORAD was highly expressed in osteosarcoma cells and tissues, which might be associated with the progression and metastasis of osteosarcoma. We isolated EVs from the characterized BMSCs, and found that NORAD was transferred from BMSCs to osteosarcoma cells via EVs in the co-culture system. Consequently, NORAD delivered by BMSC-derived EVs promoted the proliferation and invasion of osteosarcoma cells. Subsequently, bioinformatics analyses suggested potential binding relationship between NORAD and microRNA-30c-5p (miR-30c-5p) as well as between miR-30c-5p and Krueppel-like factor 10 (KLF10), and the results of which were further verified by dual luciferase reporter gene assay, RNA immunoprecipitation, and RNA pull-down assay. Mechanistically, NORAD acted as a sponge of miR-30c-5p and up-regulated the expression of KLF10 where miR-30-c-5p mimic declined the effect induced by NORAD on cancer cells. The osteosarcoma cells were injected into mice to develop tumor growth and metastasis models. In these two models, injection of BMSC-EVs elevated NORAD expression and KLF10 but reduced miR-30c-5p expression, whereby suppressing tumor growth and lung metastasis. To conclude, BMSC-EVs deliver NORAD to osteosarcoma cells to regulate the miR-30c-5p/KLF10 axis, thereby accelerating the progression and metastasis of osteosarcoma.

Osteoporosis is characterized by low bone mass resulting from an imbalance between bone resorption by osteoclasts and bone formation by osteoblasts. Therefore, decreased bone formation by osteoblasts may lead to the development of osteoporosis, and rate of apoptosis is responsible for the regulation of bone formation. Arsenic (As) exists ubiquitously in our environment and increases the risk of neurotoxicity, liver injury, peripheral vascular disease and cancer. However, the effect of As on apoptosis of osteoblasts is mostly unknown. Here, we found that As induced cell apoptosis in osteoblastic cell lines (including hFOB, MC3T3-E1 and MG-63) and mouse bone marrow stromal cells (M2-10B4). As also induced upregulation of Bax and Bak, downregulation of Bcl-2 and dysfunction of mitochondria in osteoblasts. As also triggered endoplasmic reticulum (ER) stress, as indicated by changes in cytosolic-calcium levels. We found that As increased the expression and activities of glucose-regulated protein 78 (GRP78) and calpain. Transfection of cells with GRP78 or calpain siRNA reduced As-mediated cell apoptosis in osteoblasts. Therefore, our results suggest that As increased cell apoptosis in cultured osteoblasts and increased the risk of osteoporosis.

Pleckstrin homology-like domain family A, member 3 (PHLDA3), is emerging as a critical regulator for multiple cancers. Nevertheless, the expression and role of PHLDA3 in osteosarcoma remain unknown. Herein, we purposed to elucidate the role of PHLDA3 in the progression and chemoresistance of osteosarcoma. According to the bioinformatics analysis, PHLDA3 expression was low in osteosarcoma patients, and low content was linked to poor prognosis. Additionally, activation of PHLDA3 suppressed osteosarcoma cell proliferation, migration, and chemoresistance, whereas PHLDA3 inhibition caused the opposite effects. Mechanistically, our data revealed that PHLDA3 negatively regulates the Akt/GSK3β signaling cascade in osteosarcoma. Furthermore, we found that miR-19a-3p might exert its oncogenic function by inhibiting PHLDA3 expression in osteosarcoma. These results demonstrated miR-19a-3p/ PHLDA3/ Akt/GSK3β axis has a pivotal role in osteosarcoma, and PHLDA3 is a prospective therapeutic target for treating osteosarcoma.