Haidong Xu

Busulfan inhibits growth of human osteosarcoma through miR-200 family microRNAs in vitro and in vivo

Osteosarcoma typically arises in tissues of mesenchymal origin, and is the most malignant bone tumor characterized by high local aggressiveness, with poor therapeutic outcome. Busulfan has been widely used to treat CML. So far, there are no reports on the therapeutic effect of busulfan on osteosarcoma. Here, we showed that busulfan dose‐dependently reduced the cell viability and proliferation, and induced cell apoptosis, senescence, and reactive oxygen species levels in two osteosarcoma cell lines. Moreover, a series of loss‐of‐function and gain‐of‐function experiments further indicated that busulfan may have its anti‐osteosarcoma effect by upregulating the microRNA‐200 (miR‐200) family which subsequently downregulated its target genes ZEB1 and ZEB2. Furthermore, treatment with busulfan potentially inhibited the growth of implanted osteosarcoma in nude mice. Taken together, our data suggest that busulfan may have an anti‐osteosarcoma effect through downregulating ZEB1 and ZEB2 through activating the miR‐200 family, highlighting a possibility of using busulfan as a novel therapy for osteosarcoma.

Tumor-suppressing effects of miR-429 on human osteosarcoma.

AbstractOsteosarcoma is the most common primary bone tumor. Recent data indicated miRNAs may be involved in the pathogenesis of osteosarcoma, suggesting some novel targets for therapy. It is known that miR-429 is down-regulated and functions as a tumor suppressor by targeting c-myc and PLGG1 in gastric and breast cancer. However, the exact role of miR-429 in osteosarcoma remained unknown. In our study, we found MiR-429 was down-regulated in primary osteosarcoma lesion and osteosarcoma cell lines. Moreover, MiR-429 can inhibit the proliferation of osteosarcoma cell lines and induce more cell apoptosis. Also, we discovered MiR-429 plays a role in osteosarcoma by binding the 3′UTR of zinc finger E-box-binding homeobox 1 (ZEB1) mRNA, and that overexpression of ZEB1 could reverse the proliferation, subsequently blocking effect of miR-429. In conclusion, miR-429 serves as a tumor suppressor via interaction with ZEB1. Our finding may provide a new target for osteosarcoma therapy.

Down-Regulation of miR-3928 Promoted Osteosarcoma Growth

Background: Osteosarcoma is the most common primary bone malignancy in children and young adults. Most failures of osteosarcoma treatment were due to resistance to chemotherapy. Development of new therapy required elucidation underlying molecular mechanism. Many miRNAs have been proved to be involved in the pathogenesis of osteosarcoma. Methods: MiR-3928 expression level was assayed by qRT-PCR. MiRNA mimics or ASO were transfected for up-regulation or down-regulation of miR-3928 expression. Cell proliferation was assayed by formazan test. Apoptosis and cell cycle were assayed by FACS. MiR-3928 targeted genes were predicated by bioinformatics algorithm (TargetScanHuman). The correlation between targeted gene and miR-3928 was analyzed by Pearsons correlation coefficient analysis. Results: MiR-3928 was down-regulated in osteosarcoma tissues. Over-expression of miR-3928 inhibited tumor growth, induced cell apoptosis, increased the percent of cells in G1 phrase and decreased the percent of cells in S phrase. Down-regulation of miR-3928 promoted cell proliferation. ERBB3, IL-6R and CDK6 may be the targeted genes of miR-3928. Conclusions: Down-expression of miR-3928 in osteosarcoma promoted tumor growth by targeting ERBB3, IL-6R and CDK6. MiR-3928 may be a potential therapy target worth further investigation.

Cartilage Defect Treatments: With or without Cells? Mesenchymal Stem Cells or Chondrocytes? Traditional or Matrix-Assisted? A Systematic Review and Meta-Analyses

Articular cartilage defects have been addressed by using multiple strategies. In the last two decades, promising new strategies by using assorted scaffolds and cell sources to induce tissue regeneration have emerged, such as autologous chondrocyte implantation (ACI) and mesenchymal stem cell implantation (MSCI). However, it is still controversial in the clinical strategies when to choose these treatments. Thus, we conducted a systematic review and meta-analyses to compare the efficacy and safety of different cartilage treatments. In our study, 17 studies were selected to compare different treatments for cartilage defects. The results of meta-analyses indicated that cell-based cartilage treatments showed significant better efficacy than cell-free treatments did (OR: 4.27, 95% CI: 2.19–8.34; WMD: 10.11, 95% CI: 2.69–16.53). Another result indicated that MACT had significant better efficacy than traditional ACI did (OR: 0.49, 95% CI: 0.30–0.82). Besides, the incidence of graft hypertrophy of MACT was slightly lower than that of traditional ACI (OR: 2.43, 95% CI: 1.00–5.94). Current data showed that the cell-based treatments and MACT are better options for cartilage treatments, but more well-designed comparative studies are still needed to enhance our understanding of different treatments for cartilage defects.

Histone Deacetylase Inhibitor Trichostatin a Promotes the Apoptosis of Osteosarcoma Cells through p53 Signaling Pathway Activation

Purpose: The purpose of this study was to investigate the profile of histone deacetylase (HDAC) activity and expression in osteosarcoma cells and tissues from osteosarcoma patients and to examine the mechanism by which a histone deacetylase (HDAC) inhibitor, Trichostatin A (TSA), promotes the apoptosis of osteosarcoma cells. Methods: HDAC activity and histone acetyltransferase (HAT) activity were determined in nuclear extracts of MG63 cells, hFOB 1.19 cells and tissues from 6 patients with primary osteosarcoma. The protein expression of Class I HDACs (1, 2, 3 and 8) and the activation of the p53 signaling pathway were examined by Western blot. Cell growth and apoptosis were determined by 3-(4, 5-dimethyl-2-thiazolyl)-2H-tetrazolium bromide (MTT) assay and flow cytometry, respectively. Results: Nuclear HDAC activity and class I HDAC expression were significantly higher in MG63 cells than in hFOB 1.19 cells, and a similar trend was observed in the human osteosarcoma tissues compared with the paired adjacent non-cancerous tissues. TSA significantly inhibited the growth of MG63 cells and promoted apoptosis in a dose-dependent manner through p53 signaling pathway activation. Conclusion: Class I HDACs play a central role in the pathogenesis of osteosarcoma, and HDAC inhibitors may thus have promise as new therapeutic agents against osteosarcoma.

miR-574-3p acts as a tumor promoter in osteosarcoma by targeting SMAD4 signaling pathway

Human osteosarcoma is the most common primary bone malignancy sarcoma that affects primarily children and people <20 years old. In the present study, it was demonstrated that miR-574-3p was downregulated in human osteosarcoma U2OS, SAOS and MG63 cells lines as well as in osteosarcoma tissue compared with the normal tissues. Downregulation of miR-574-3p by antisense miR-574-3p, inhibited cell growth and induced cell apoptosis. Overexpression of miR-574-3p by transfection with miR-574-3p mimics promoted the growth of U2OS cells. The present study then identified mothers against decapentaplegic homolog 4 (SMAD4) as a target of miR-574-3p and SMAD4 was suppressed in miR-574-3p transfected cells. Overexpression of SMAD4 could rescue the promoting effects of miR-574-3p on cancer cell growth. In conclusion, miR-574-3p exerts tumor-promoting roles by targeting the tumor-suppressing gene SMAD4 and its downstream signaling in human osteosarcoma, which provides a novel target for the treatment.

Strategies for Management of Spinal Metastases: A Comprehensive Review

Spinal metastasis is the most common tumor in the spine and can easily expand to the epidural space. A series of approaches have been developed to deal with this problem including radiation, surgery, and medicine. The further goal of the treatment is to relieve pain, stabilize spinal structure, maintain neurologic function and improve the quality of life. Different frameworks have been proposed to optimize the best therapy for different patients. This review briefly summarizes different treatments for spinal metastases and some popular decision-making frameworks.

Chronic Osteomyelitis Increases the Incidence of Type 2 Diabetes in Humans and Mice

Background: To compare the risk of type 2 diabetes (T2DM) between patients with and without chronic osteomyelitis (COM), both in humans and in mice, and to explore risk factors in COM patients who developed T2DM. Methods: One hundred seven patients with COM and 114 patients without COM were consecutively enrolled and retrospectively analysed. Clinical data concerning the time to develop diabetes, glucose metabolism, lipid metabolism, inflammatory factors, mental health and frequency of specialist visits were collected. A mouse model of osteomyelitis was used to verify the presence of impaired glucose metabolism and depression. All data were processed by SPSS. Results: The incidence of T2DM was 2.37-fold higher in patients with COM than in those without. In COM patients, subjects with T2DM (DDM) had higher BMI, less exercise and more frequent visits to specialists than those without (Con). Glucose and lipid metabolism were worse in patients with DDM. Patients with DDM had higher levels of white blood cells (12.9±2.1×109/L vs. 11.7±2.2×109/L, p=0.027), CRP (28.4±4.5 mg/L vs. 22.0±4.8 mg/L, p<0.001), TNF-α (13.5±5.0 pg/mL vs. 9.4±2.6 pg/mL, p= 0.003) and IL-6 (12.9±3.2 pg/mL vs. 9.2±2.7 pg/mL, p<0.001). Significantly increased fasting blood glucose concentrations and impairment of oral glucose tolerance tests were also observed in mice modelling osteomyelitis, which were accompanied by elevated TNF-α and IL-6 levels. Furthermore, the proportion of depression (63.2% vs. 35.2%, p=0.003) and severe anxiety (31.6% vs. 9.1%, p=0.002) were significantly higher in the DDM group. Osteomyelitis mice showed obvious depressive-like behaviours. The levels of TNF-α, IL-6, CRP, BMI, and LDL; lack of exercise; SAS; HAQ; and SF36 assessment were risk factors for the development of T2DM in COM patients. Conclusions: Chronic osteomyelitis increased the incidence of T2DM in both humans and mice. Inflammation, mental illness and lack of exercise were risk factors for the occurrence of T2DM in osteomyelitis. Comprehensive consideration of patient history, including metabolism and mental health, is needed in planning future treatment.