Aseptic loosening of the prosthesis caused by wear-particle-induced osteolysis is a long-term complication and one of the most common reasons for the failure of joint implants. The primary cause of aseptic loosening of the prosthesis is overactive bone resorption caused by wear-particle-activated osteoclasts in both direct and indirect ways. Therefore, drugs that can inhibit differentiation and bone resorption of osteoclasts need investigation as a potential therapeutic strategy to prevent and treat peri-prosthetic osteolysis and thereby prolong the service life of the prosthesis. This study has verified the potential inhibitory effect of LY450139 on inflammatory osteolysis induced by titanium particles in a mice skull model. In addition, we found that LY450139 inhibited receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis, bone resorption, and podosomal actin belt formation in a dose-dependent manner without evidence of cytotoxicity in vitro. In addition, LY450139 significantly decreased the expression of osteoclast-specific markers, including TRAP, CTSK, V-ATPase d2, CTR, DC-STAMP, NFATc1, and the downstream target gene Hes1 in Notch signaling pathway. Further investigation of the molecular mechanism demonstrated that LY450139 inhibited the formation of osteoclasts via inhibition of the NF-κB and Notch signaling pathways. In summary, LY450139 inhibited the formation of RANKL-mediated osteoclasts via NF-κB and Notch signaling and inhibited Ti particle-induced inflammatory osteolysis in vivo. LY450139 is a potential targeted drug for the treatment of peri-prosthetic osteolysis and other osteolytic disease associated with overactive osteoclasts.
Background We aimed to establish an osteosarcoma prognosis prediction model based on a signature of endoplasmic reticulum stress-related genes. Methods Differentially expressed genes (DEGs) between osteosarcoma with and without metastasis from The Cancer Genome Atlas (TCGA) database were mapped to ERS genes retrieved from Gene Set Enrichment Analysis to select endoplasmic reticulum stress-related DEGs. Subsequently, we constructed a risk score model based on survival-related endoplasmic reticulum stress DEGs and a nomogram of independent survival prognostic factors. Based on the median risk score, we stratified the samples into high- and low-risk groups. The ability of the model was assessed by Kaplan–Meier, receiver operating characteristic curve, and functional analyses. Additionally, the expression of the identified prognostic endoplasmic reticulum stress-related DEGs was verified using real-time quantitative PCR (RT-qPCR). Results In total, 41 endoplasmic reticulum stress-related DEGs were identified in patients with osteosarcoma with metastasis. A risk score model consisting of six prognostic endoplasmic reticulum stress-related DEGs (ATP2A3, ERMP1, FBXO6, ITPR1, NFE2L2, and USP13) was established, and the Kaplan–Meier and receiver operating characteristic curves validated their performance in the training and validation datasets. Age, tumor metastasis, and the risk score model were demonstrated to be independent prognostic clinical factors for osteosarcoma and were used to establish a nomogram survival model. The nomogram model showed similar performance of one, three, and five year-survival rate to the actual survival rates. Nine immune cell types in the high-risk group were found to be significantly different from those in the low-risk group. These survival-related genes were significantly enriched in nine Kyoto Encyclopedia of Genes and Genomes pathways, including cell adhesion molecule cascades, and chemokine signaling pathways. Further, RT-qPCR results demonstrated that the consistency rate of bioinformatics analysis was approximately 83.33%, suggesting the relatively high reliability of the bioinformatics analysis. Conclusion We established an osteosarcoma prediction model based on six prognostic endoplasmic reticulum stress-related DEGs that could be helpful in directing personalized treatment.
In recent years, deep venous thrombosis (DVT) after spine surgery has received extensive attention, but perioperative prevalence of DVT in patients undergoing percutaneous kyphoplasty (PKP) is lacking. To assess the perioperative prevalence of deep vein thrombosis (DVT) in patients undergoing PKP with routinely applied ultrasonography. We reviewed 1113 consecutive patients undergoing PKP from January 2014 to August 2017. The surgical procedure was bilateral PKP. All patients were routinely examined with ultrasonography when admitted to the hospital and on the first post-operative day. Clinical signs of DVT were checked and recorded before examination. Forty (3.6%) out of 1113 patients were diagnosed with DVT by ultrasonography. Of the 40 detected cases of DVT, only six (0.54%) patients presented with clinical signs of DVT, demonstrating that there were 34 (3.05%) asymptomatic cases. No patient presenting with clinically suspected pulmonary embolism (PE) was observed. Gender, body mass index (BMI), operative time, hypertension, diabetes, heart disease, and lower limb fracture were not significant risk factors for DVT ( P > .05). In contrast, patient age, oncologic conditions, DVT history, and paraplegia appeared to be significant risk factors for DVT ( P < .01). There was no significant difference in the incidence of DVT found between the three PKP surgical levels ( P > .05). The total incidence of perioperative DVT diagnosed with ultrasonography in patients undergoing PKP was 3.6%, of which only 0.54% was symptomatic cases. It is necessary to assess DVT using ultrasonography during the perioperative procedure of PKP, especially for high-risk patients. Level of evidence: Level IV.
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