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Bone morphogenetic protein-2 (BMP-2) has been commercially approved by the Food and Drug Administration for use in bone defects and diseases. BMP-2 promotes osteogenic differentiation of mesenchymal stem cells. In bone tissue engineering, BMP-2 incorporated into scaffolds can be used for stimulating bone regeneration in organoid construction, drug testing platforms, and bone transplants. However, the high dosage and uncontrollable release rate of BMP-2 challenge its clinical application, mainly due to the short circulation half-life of BMP-2, microbial contamination in bone extracellular matrix hydrogel, and the delivery method. Moreover, in clinical translation, the requirement of high doses of BMP-2 for efficacy poses challenges in cost and safety. Based on these, novel strategies should ensure that BMP-2 is delivered precisely to the desired location within the body, regulating the timing of BMP-2 release to coincide with the bone healing process, as well as release BMP-2 in a controlled manner to optimize its therapeutic effect and minimize side effects. This review highlights improvements in bone tissue engineering applying spatiotemporal and controlled BMP-2 delivery, including molecular engineering, biomaterial modification, and synergistic therapy, aiming to provide references for future research and clinical trials. Graphical Abstract

Background Osteoporosis (OP) is a disease in which weak bones increase the risk of fracture. It has been reported that the occurrence of ferroptosis accelerated the progression of OP. However, the underlying mechanism of ferroptosis in OP remains unclear. Methods Clinical samples from OP patients were collected and ovariectomized (OVX)-induced mouse models with GPX4 knockout was established. The expression of genes and proteins was determined by RT-qPCR, western blot, IHC and IF. Bone mineral density (BMD) of the lumbar vertebrae was evaluated using DXA. Pearson correlation analysis was used to analyze the relationship between GPX4 expression and BMD. The femoral morphology was detected by HE staining. Images and relevant parameters of the femur were acquired using micro-CT. Ultrastructural changes in mitochondria were observed using TEM. MDA and GSH levels in mice and cells were examined using commercial kits. Lipid peroxidation was detected using Bodipy-C11 fluorescent probe. ALP activity was measured using ALP staining and calcified nodules were examined using ARS staining. The interaction between YAP1 and GPX4 promoter was validated using ChIP and dual-luciferase reporter gene assay. Results GPX4 expression was downregulated in clinical samples of OP and positively correlated with BMD. GPX4 knockout exacerbated bone loss and promoted ferroptosis in OVX-induced mice. Besides, GPX4 overexpression inhibited ferroptosis and enhanced osteogenic potential of osteoblasts. Moreover, YAP1 positively regulated GPX4 expression in osteoblasts through activating transcriptional activity of GPX4 promoter and YAP1 overexpression suppressed ferroptosis and enhanced osteogenic potential of osteoblasts via enhancing GPX4 expression. Conclusion GPX4 was positively regulated by YAP1, which in turn inhibited ferroptosis and enhanced osteogenic potential of osteoblasts, thereby alleviating OA progression.

Osteoporosis is a highly prevalent disease characterized by bone mass loss and structural deterioration. There are evidences that altered differentiation of human bone marrow mesenchymal stromal/stem cells (hBMSCs) is a major cause for osteoporosis. Recent studies suggest that circular RNAs (circRNAs) are dysregulated in osteoporosis patients and involved in the pathogenesis of osteoporosis. In the present study, we are aimed to analyze the circRNA expression profiles in osteoporosis patients and identify potential circRNAs that involved in the differentiation of hBMSCs during osteoporosis. Transcriptome RNA-sequencing was conducted to search for differentially expressed circRNAs. Transwell assay, ARS and ALP staining, and ectopic bone formation model were performed to evaluate osteogenic differentiation of hBMSCs. RNA pull-down assay, RNA immunoprecipitation, western blot, and in vitro binding assay were conducted to evaluate the interaction of circRNAs and RNA-binding protein HuR. We found that hsa_circ_0008842 (designated as circZNF367) was upregulated in osteoporosis patients and decreased in hBMSCs during osteogenic differentiation. CircZNF367 overexpression suppressed migration, invasion and osteogenic differentiation of hBMSCs in vitro and in vivo. In comparison, knockdown of circZNF367 promoted migration, invasion and osteogenic differentiation of hBMSCs. CircZNF367 could interact with the RNA-binding protein HuR, thus reduced the mRNA stability of LRP5. Furthermore, HuR overexpression or LRP5 restoration abrogated the effects of circZNF367 overexpression on osteogenic differentiation of hBMSCs. Our results indicated that circZNF367 played a role in osteogenic differentiation of hBMSCs via reducing HuR-mediated mRNA stability of LRP5.

Background Osteoporosis, characterized by reduced bone mass and deterioration of bone quality, is a significant health concern for postmenopausal women. Considering that the specific role of circRNAs in osteoporosis and osteoclast differentiation remains poorly understood, this study aims to shed light on their involvement in these processes to enhance our understanding and potentially contribute to improved treatment strategies for osteoporosis. Methods An osteoporotic model was constructed in vivo in ovariectomized mouse. In vitro, we induced osteoclast formation in bone marrow-derived macrophages (BMDMs) using M-CSF + RANKL. To assess osteoporosis in mice, we conducted HE staining. We used MTT and TRAP staining to measure cell viability and osteoclast formation, respectively, and also evaluated their mRNA and protein expression levels. In addition, RNA pull-down, RIP and luciferase reporter assays were performed to investigate interactions, and ChIP assay was used to examine the impact of circZNF367 knockdown on the binding between FUS and CRY2. Results We observed increased expression of CircZNF367, FUS and CRY2 in osteoporotic mice and M-CSF + RANKL-induced BMDMs. Functionally, knocking down circZNF367 inhibited osteoporosis in vivo . Furthermore, interference with circZNF367 suppressed osteoclast proliferation and the expression of TRAP, NFATc1, and c-FOS. Mechanistically, circZNF367 interacted with FUS to maintain CRY2 mRNA stability. Additionally, knocking down CRY2 rescued M-CSF + RANKL-induced osteoclast differentiation in BMDMs promoted by circZNF367 and FUS. Conclusion This study reveals that the circZNF367/FUS axis may accelerate osteoclasts differentiation by upregulating CRY2 in osteoporosis and suggests that targeting circZNF367 may have potential therapeutic effects on osteoporosis.

A chitosan-based microsphere delivery system has been fabricated for controlled release of alendronate (AL). The present study aimed to incorporate the chitosan/hydroxyapatite microspheres-loaded with AL (CH/nHA-AL) into poly(L-lactic acid)/nanohydroxyapatite (PLLA/nHA) matrix to prepare a novel microspheres-scaffold hybrid system (CM-ALs) for drug delivery and bone tissue engineering application. The characteristics of CM-ALs scaffolds containing 10% and 20% CH/nHA-AL were evaluated in vitro , including surface morphology and porosity, mechanical properties, drug release, degradation, and osteogenic differentiation. The in vivo bone repair for large segmental radius defects (1.5 cm) in a rabbit model was evaluated by radiography and histology. In vitro study showed more sustained drug release of CM-AL-containing scaffolds than these of CM/nHA-AL and PLLA/nHA/AL scaffolds, and the mechanical and degradation properties of CM-ALs (10%) scaffolds were comparable to that of PLLA/nHA control. The osteogenic differentiation of adipose-derived stem cells (ASCs) was significantly enhanced as indicated by increased alkaline phosphates (ALP) activity and calcium deposition. In vivo study further showed better performance of CM-ALs (10%) scaffolds with complete repair of large-sized bone defects within 8 weeks. A microspheres-scaffold-based release system containing AL-encapsulated chitosan microspheres was successfully fabricated in this study. Our results suggested the promising application of CM-ALs (10%) scaffolds for drug delivery and bone tissue engineering.

Sustained delivery of growth factors has emerged as an essential requirement for bone tissue engineering applications for the treatment of various kinds of bone defects. Chitosan (CH) has attracted particular attention for drug delivery and bone tissue engineering because of its favorable biocompatibility and biodegradability. In this study, a composite microsphere system containing CH and nanohydroxyapatite (nHA)-alendronate (AL) particles was fabricated by employing both emulsification and cross-linking strategies. The microspheres were characterized for their surface morphology, composition, size distribution, drug loading efficiency and release properties. The results showed that loading efficiency and sustained release of hydrophilic AL were significantly improved, which is ideal for locally sustained release in the bone microenvironment. In vitro osteogenic studies showed that the microspheres could enhance the osteogenic activity of rabbit adipose-derived stem cells. In conclusion, the CH/nHA-AL composite microspheres exhibit promising properties as a candidate for local treatment for bone defects.

Malignant peripheral nerve sheath tumor (MPNST) is a rare and aggressive soft tissue sarcoma for which effective treatments have not yet been established due to poor understanding of its pathogenesis. Our previous study indicated that miR-210-mediated Ephrin-A3 (EFNA3) promotion of proliferation and invasion of MPNST cells plays an important role in MPNST tumorigenesis and progression. The purpose of the present study was to further investigate the roles of EFNA3 in MPNST. Constructed transcription activator-like effector nucleases (TALENs) and lentiviral vectors were transfected into MPNST ST88-14 (NF1 wild-type) and sNF96.2 (NF1 mutant type) cell lines to obtain gain- and loss-of-function cell lines for the EFNA3 function study. The results showed that the knockout of ENFA3 increased cellular viability and invasiveness of the MPNST cells. However, the adhesion ability of MPNST cells was enhanced or inhibited when EFNA3 was overexpressed or knocked out, respectively. It was also observed that knockout of EFNA3 significantly decreased the expression of phosphorylated FAK (p-FAK) and the tumor necrosis factor α (TNF-α) compared to that in the control cells, yet the expression of phosphatidylinositol 3-kinase (PI3K), GTPase, integrins, vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1α (HIF-α) increased significantly. Inversely, overexpression of EFNA3 significantly increased the expression of p-FAK and TNF-α compared to that in the control cells, yet the expression of PI3K, GTPase, integrins, VEGF and HIF-α decreased significantly. The results indicated that EFNA3 serves as a tumor suppressor in MPNST cells and it may play a critical role in the focal adhesion kinase (FAK) signaling and VEGF-associated tumor angiogenesis pathway. These findings may not only facilitate the better understanding of MPNST pathogenesis, but also suggest EFNA3 as a promising target for MPNST treatment.

We propose a general formalism beyond Weisskopf–Wigner approximation to efficiently calculate the coupling matrix element, evolution spectrum and population evolution of two quantum emitters in arbitrary metallic nanostructures. We demonstrate this formalism to investigate the radiative coupling and decay dynamics of two quantum emitters embedded in the two hot spots of three silver nano-spheroids. The vacuum Rabi oscillation in population evolution and the anti-crossing behavior in evolution spectrum show strong radiative coupling is realized in this metallic nanostructure despite its strong plasmon damping. Our formalism can serve as a flexible and efficient calculation tool to investigate the distant coherent interaction in a large variety of metallic nanostructures, and may be further developed to handle the cases for multiple quantum emitters and arbitrary dielectric–metallic hybrid nanostructures.

BackgroundTo develop and evaluate the feasibility of a data-driven deep learning approach (deepAC) for positron-emission tomography (PET) image attenuation correction without anatomical imaging. A PET attenuation correction pipeline was developed utilizing deep learning to generate continuously valued pseudo-computed tomography (CT) images from uncorrected 18F-fluorodeoxyglucose (18F-FDG) PET images. A deep convolutional encoder-decoder network was trained to identify tissue contrast in volumetric uncorrected PET images co-registered to CT data. A set of 100 retrospective 3D FDG PET head images was used to train the model. The model was evaluated in another 28 patients by comparing the generated pseudo-CT to the acquired CT using Dice coefficient and mean absolute error (MAE) and finally by comparing reconstructed PET images using the pseudo-CT and acquired CT for attenuation correction. Paired-sample t tests were used for statistical analysis to compare PET reconstruction error using deepAC with CT-based attenuation correction.ResultsdeepAC produced pseudo-CTs with Dice coefficients of 0.80 ± 0.02 for air, 0.94 ± 0.01 for soft tissue, and 0.75 ± 0.03 for bone and MAE of 111 ± 16 HU relative to the PET/CT dataset. deepAC provides quantitatively accurate 18F-FDG PET results with average errors of less than 1% in most brain regions.ConclusionsWe have developed an automated approach (deepAC) that allows generation of a continuously valued pseudo-CT from a single 18F-FDG non-attenuation-corrected (NAC) PET image and evaluated it in PET/CT brain imaging.

Frequent burst events in water distribution systems cause severe water loss and other environmental issues such as contamination and carbon emissions. The availability of massive monitored data has facilitated the development of data-driven burst detection methods. This paper proposes the flow subsequences clustering–reconstruction analysis method for burst detection in district metering areas (DMAs). The sliding window is used to create flow subsequence libraries for all time points of a day using a historical data set and thereafter the clustering–reconstruction analysis is conducted to obtain flow pattern libraries and reconstruction error subsequences. The threshold vector is determined by the detection matrix extracted from the reconstruction error subsequences at each time point. At the detection stage, the new flow subsequence is created and its reconstruction version is obtained based on the flow pattern library at the same time point. The new detection vector is extracted and compared with the threshold vector to identify bursts. The proposed method is applied to two real-world DMAs and its detection performance is demonstrated and compared with two previous methods. The proposed method is proven to be effective in detecting burst events with fewer false alarms.