Penicopeptide A (PPA) from the deep-sea-derived fungus promotes osteoblast-mediated bone formation and alleviates ovariectomy-induced bone loss by activating the AKT/GSK-3ß/ß-catenin signaling pathway.

The potential of marine natural products as effective drugs for osteoporosis treatment is an understudied area. In this study, we investigated the ability of lead compounds from deep-sea-derived Penicillium solitum MCCC 3A00215 to promote bone formation in vitro and in vivo. We found that penicopeptide A (PPA) promoted osteoblast mineralization among bone marrow mesenchymal stem cells (BMSCs) in a concentration-dependent manner, and thus, we selected this natural peptide for further testing. Our further experiments showed that PPA significantly promoted the osteogenic differentiation of BMSCs while inhibiting their adipogenic differentiation and not affecting their chondrogenic differentiation. Mechanistic studies showed that PPA binds directly to the AKT and GSK-3ß and activates phosphorylation of AKT and GSK-3ß, resulting in the accumulation of ß-catenin. We also evaluated the therapeutic potential of PPA in a female mouse model of ovariectomy-induced systemic bone loss. In this model, PPA treatment prevented decreases in bone volume and trabecular thickness. In conclusion, our in vitro and in vivo results demonstrated that PPA could promote osteoblast-related bone formation via the AKT, GSK-3ß, and ß-catenin signaling pathways, indicating the clinical potential of PPA as a candidate compound for osteoporosis prevention.

Modified Closed Reduction and Percutaneous Kirschner Wires Internal Fixation for Treatment of Supracondylar Humerus Fractures in Children.

OBJECTIVE: Supracondylar humerus fractures are the most frequent fractures of the paediatric elbow. The present study introduced a modified surgical procedure for treatment of supracondylar humerus fractures in children. METHODS: From February 2015 to August 2019, 73 patients with Gartland's type II and III supracondylar fractures were treated with this modified method. Totally, 68 of all patients were followed up for 3-12 months (mean 8.25 months). The evaluation results included fracture nonunion, ulnar nerve injury, pin track infection, carrying angle and elbow joint Flynn score. RESULTS: The results showed that bone union was observed in all children, one case had an iatrogenic ulnar nerve injury, and the symptoms were completely relieved in 4 months after removing of the medial-side pin. All children had no cubitus varus deformity and no pin track infection, and the rate of satisfactory results according to Flynn's criteria score was 100%. CONCLUSION: The modified closed reduction and Kirschner wires internal fixation could effectively reduce the rate of open reduction, the risk of iatrogenic ulnar nerve injury, and the incidence of cubitus varus deformity in treatment of supracondylar humerus fractures in children.

PERK-mediated Autophagy in Osteosarcoma Cells Resists ER Stress-induced Cell Apoptosis.

Osteosarcoma is a bone cancer that develops commonly in children and adolescents. However, osteosarcoma treatments often fail by the development of chemoresistance to apoptosis, and the molecular mechanisms remain unclear. In this study, we propose that autophagy is responsible for osteosarcomatous resistance to apoptosis. We implicate PERK-mediated autophagy as a significant contributor to apoptosis resistance due to ER stress in osteosarcoma cells. By immunostainings and western blots, we identified that PERK activated osteosarcomatous autophagy via inhibiting mTORC1 pathway, thereby preventing cell apoptosis. While using RNAi, we knocked down PERK and found that autophagy was suppressed, result in osteosarcomatous apoptosis. Our results identify a novel role of PERK-mediated autophagy as a significant mechanism for osteosarcoma cell survival. These results will help to understand the mechanism of chemoresistance in osteosarcoma cells, and indicate a novel target for improving osteosarcoma therapy.

4-Hydroxy-2-nonenal induces apoptosis by inhibiting AKT signaling in human osteosarcoma cells.

The onset of lipid peroxidation within cellular membranes is associated with changes in their physiochemical properties and enzymatic dysfunction of the membrane environment. There are increasing bodies of evidence indicating that aldehydic molecules generated endogenously during the process of lipid peroxidation are causally involved in most of the pathophysiological effects associated with oxidative stress in cells and tissues. 4-Hydroxy-2-nonenal (4-HNE), among them, is believed to be largely responsible for cytopathological effects observed during oxidative stress in vivo and has achieved the status of one of the best recognized and most studied of the cytotoxic products of lipid peroxidation. Here, we reported that 4-HNE treatment may induce cell death in MG63 human osteosarcoma cells. The 4-HNE treatment could activate caspase-3 and alter the Bax/Bcl-2 apoptotic signaling. All these changes are due to the inhibition of AKT activity by 4-HNE treatment, and we also found that the p70S6K activity, downstream factors of AKT, was also blocked by 4-HNE. Our results revealed the molecular mechanism of how 4-HNE induces cell death in MG63 human osteosarcoma cells, which contributes to the clinical treatment of cancer therapy.

BsmI, TaqI, ApaI and FokI polymorphisms in the vitamin D receptor (VDR) gene and risk of fracture in Caucasians: a meta-analysis.

CONTEXT: Vitamin D receptor (VDR) gene polymorphisms have been strongly associated with bone mineral density in some studies. However, in a recent meta-analysis, no relationship of the VDR BsmI or TaqI polymorphism and fracture risk was found in the meta-analysis of published data. OBJECTIVE AND DESIGN: Our meta-analysis studied whether a relationship exists between BsmI, TaqI, ApaI and FokI polymorphisms in the VDR gene and risk of fracture. DATA SOURCES: Relevant studies were identified from the following electronic databases: MEDLINE, EMBASE and Current Contents before January 2010. DATA SYNTHESIS: This meta-analysis included 17 studies with a total of 21 eligible comparisons, which included 2112 fracture cases and 4521 controls. All of these studies reported on Caucasians. The combined results based on all studies showed that fracture cases had a significantly lower frequency of bb genotype of BsmI [odds ratio (OR) = 0.87, 95% confidence interval (CI)=0.76, 0.98]. When stratifying by fracture type, we found that (1) hip fracture cases had a significantly lower frequency of bb genotype of BsmI (OR=0.82, 95% CI=0.70, 0.97); (2) hip fracture cases had a significantly lower frequency of Tt genotype of TaqI (OR=0.65, 95% CI=0.43, 0.97); (3) hip fracture cases had a significantly higher frequency of tt genotype of TaqI (OR=1.74, 95% CI=1.05, 2.91); (4) vertebral fracture cases had a significantly higher frequency of Aa genotype of ApaI (OR=1.63, 95% CI=1.03, 2.59). No significant difference was found in any genotype of FokI. CONCLUSION: Our meta-analysis suggests that there is a modest but statistically significant association between the BsmI bb genotypes and fracture.