Deting Xue

Osteochondral repair using porous poly(lactide-co-glycolide)/nano-hydroxyapatite hybrid scaffolds with undifferentiated mesenchymal stem cells in a rat model.

In this study, a novel three-dimensional poly (lactide-co-glycolide) (PLGA)/nano-hydroxyapatite (NHA) scaffold was fabricated by a thermally induced phase separation technique and its potential application in cartilage tissue-engineering was investigated. The PLGA scaffold was used as a control and mesenchymal stem cells (MSCs) were seeded in both scaffolds. After 12-days culture, SEM images and confocal laser scanning microscopy illustrated that MSCs attached more moderately and more cells distributed in PLGA/NHA scaffolds. MTT test and DNA assay showed that the viability and proliferation of MSCs in PLGA/NHA scaffolds were significantly superior to PLGA scaffolds during in vitro culture. Through in vivo study, the efficacy of this scaffold combining with MSCs for repairing articular osteochondral defects was evaluated in a rat model. Osteochondral defects in rats knees were left untreated, or treated with PLGA/NHA-MSCs composites or PLGA-MSCs composites. Twelve weeks after operation, histological examination revealed that the defects in the PLGA/NHA-MSCs treated group were filled with smooth and hyaline-like cartilage with abundant glycosaminoglycan and collagen type II deposition, but deficient in collagen type I at 12 weeks after operation. To investigate the final fate of MSCs transplanted into the defect areas, the fluorescent dye CM-DiI was used to prelabel cells. At 12 weeks after transplantation, we still observed the red fluorescence in the repair area. These findings suggest that the PLGA/NHA-MSCs composite may be potentially used for cartilage repair in clinical application. (c) 2010 Wiley Periodicals, Inc. J Biomed Mater Res, 2010.

Selective COX-2 inhibitor versus nonselective COX-1 and COX-2 inhibitor in the prevention of heterotopic ossification after total hip arthroplasty: a meta-analysis of randomised trials

Whether selective cyclo-oxygenase-2 (COX-2) inhibitors are equally effective compared to nonselective NSAIDs for the prevention of heterotopic ossification (HO) after total hip arthroplasty (THA) is still unclear. We carried out a comprehensive search strategy, in which only randomised controlled trials were included. Two reviewers independently assessed methodological quality and extracted outcome data. Analyses were performed using Stata version 10.0. Four eligible randomised controlled trials totalling 808 patients were included. Meta-analysis results showed that no statistically significant difference was found in overall incidence of HO (RR 1.08; 95% CI 0.71–1.64), incidence of moderate severe HO (Brooker II and III) (RR 0.83; 95% CI 0.48–1.42) and any grade of Brooker classification between two groups. In summary, the selective COX-2 inhibitors are equally effective as nonselective NSAIDs for the prevention of HO after THA. Considering the gastrointestinal side effects of nonselective NSAIDs, we recommend selective COX-2 inhibitors for the prevention of HO after THA. However, future well-designed, randomised controlled trials are still needed to further confirm our results.

Reamed and unreamed intramedullary nailing for the treatment of open and closed tibial fractures: a subgroup analysis of randomised trials.

The choice between reamed and unreamed intramedullary nailing for the treatment of open and closed tibial fractures is an ongoing controversy. We carried out a comprehensive search strategy. Six eligible randomised controlled trials were included. Three reviewers independently assessed methodological quality and extracted outcome data. Analyses were performed using Review Manager 5.0. The results showed lower risks of tibial fracture nonunion and implant failures with reamed nails compared to unreamed nails in closed tibial fractures [relative risk (RR): 0.41, 95% confidence interval (CI): 0.21–0.89, P = 0.008 for nonunion and RR: 0.35, 95% CI: 0.22–0.56, P < 0.0001 for implant failures], but no statistical differences in risk reduction of malunion, compartment syndrome, embolism and infection. Our results suggested no statistical differences in risk reduction of all the complications evaluated between reamed and unreamed nails in open tibial fractures. In conclusion, our study recommended reamed nails for the treatment of closed tibial fractures. But the choice for open tibial fractures remains uncertain.

HMGB1 promotes the secretion of multiple cytokines and potentiates the osteogenic differentiation of mesenchymal stem cells through the Ras/MAPK signaling pathway

High mobility group box 1 (HMGB1) protein has been previously been detected in the inflammatory microenvironment of bone fractures. It is well known that HMGB1 acts as a chemoattractant to mesenchymal stem cells (MSCs). In the present study, the effects of HMGB1 on cytokine secretion from MSCs were determined, and the molecular mechanisms underlying these effects of HMGB1 on osteogenic differentiation were elucidated. To detect cytokine secretion, antibody array assays were performed, which demonstrated that HGMB1 induced the differential secretion of cytokines that are predominantly associated with cell development, regulation of growth and cell migration, stress responses, and immune system functions. Moreover, the secretion of epidermal growth factor receptor (EGFR) was significantly upregulated by HMGB1. The EGFR-activated Ras/MAPK pathway regulates the osteogenic differentiation of MSCs. These results suggested that HMGB1 enhances the secretion of various cytokines by MSCs and promotes osteogenic differentiation via the Ras/MAPK signaling pathway. The present study may provide a theoretical basis for the development of novel techniques for the treatment of bone fractures in the future.

Signaling pathways involved in the effects of HMGB1 on mesenchymal stem cell migration and osteoblastic differentiation.

High mobility group box 1 (HMGB1) epxression has been found in the inflammatory microenvironment of fractures. It is well known that HMGB1 acts as a chemoattractant for mesenchymal stem cells (MSCs); however, the effects of HMGB1 on MSC migration and osteoblastic differentiation, and the signaling pathways involved in these effects, have not yet been elucidated. In this study, we aimed to investigate these effects, as well as the signaling mechanisms involved, using in vitro models. We found that HMGB1, in varying concentrations, promoted the osteoblastic differentiation of MSCs, the synthesis of receptor for advanced glycation end products (RAGE) and Toll-like receptor (TLR)2/4, and the activation of the p38 mitogen-activated protein kinase (MAPK) and nuclear factor‑κB (NF‑κB) signaling pathways. Subsequently, we cultured the MSCs in the appropriate concentration of HMGB1, and determined the signaling pathways involved in the effects of HMGB1 on MSC migration and differentiation, using receptor neutralizing antibodies and signaling pathway inhibitors. From the results of this study, we concluded that HMGB1 promotes MSC migration through the activation of the p38 MAPK signaling pathway, and also promotes MSC differentiation by binding to TLR2/4 and activating the p38 MAPK signaling pathway. These findings elucidate the mechanisms underlying the effects of HMGB1 in the fracture microenvironment, which may provide a theoretical basis for the development of improved clinical treatments for fractures.

Dihydromyricetin enhances the osteogenic differentiation of human bone marrow mesenchymal stem cells in vitro partially via the activation of Wnt /β-catenin signaling pathway.

Substantial evidence has demonstrated that the decreased osteogenic differentiation of bone mesenchymal stem cells (BMSCs) is closely related to bone metabolic diseases. Thus, it is very important to develop several potentially useful therapeutic agents to enhance BMSC osteogenesis. Flavonoids show promise in enhancing bone mass. Dihydromyricetin (DMY), a type of flavonoid, has not yet been investigated regarding its effects on BMSC osteogenesis. To investigate the effects of DMY on osteogenesis, human BMSCs were induced with or without DMY. We found that DMY (0.1–50 μm) exhibited no cytotoxic effect on proliferation, but increased alkaline phosphatase activity, osteoblast‐specific gene expression, and mineral deposition. It also enhanced active β‐catenin expression and reduced dickkopf‐1(DKK1) and sclerostin expression. The Wnt/β‐catenin signaling pathway inhibitor (DKK1 and β‐catenin‐specific siRNA) decreased the enhanced bone mineral formation caused by DMY. Taken together, these findings reveal that DMY enhances osteogenic differentiation of human BMSCs partly through Wnt/β‐catenin in vitro.

Local delivery of HMGB1 in gelatin sponge scaffolds combined with mesenchymal stem cell sheets to accelerate fracture healing

Fracture nonunion and delayed union continue to pose challenges for orthopedic surgeons. In the present study, we combined HMGB1 gelatin sponges with MSC sheets to promote bone healing after surgical treatment of rat tibial fractures. The HMGB1 gelatin sponge scaffolds supported the expansion of mesenchymal stem cells (MSCs) and promoted the osteogenic differentiation of MSCs and MSC sheets. Lentiviral vectors were then used to overexpress HMGB1 in MSCs. The results indicated that HMGB1 promotes the osteogenic differentiation of MSCs through the STAT3 pathway. Both siRNA and a STAT3 inhibitor downregulated STAT3, further confirming that HMGB1 induces the osteogenic differentiation of MSCs partly via the STAT3 signal pathway. In a rat tibial osteotomy model, we demonstrated the ability of HMGB1 gelatin sponge scaffolds to increase bone formation. The addition of MSC sheets further enhanced fracture healing. These findings support the use of HMGB1-loaded gelatin sponge scaffolds combined with MSC sheets to enhance fracture healing after surgical intervention.

IGFBP7 regulates the osteogenic differentiation of bone marrow–derived mesenchymal stem cells via Wnt/β-catenin signaling pathway

Insulin‐like growth factor‐binding protein 7 (IGFBP7), a low‐affinity IGF binder, may play an important role in bone metabolism. However, its function in osteogenic differentiation of human bone marrow‐derived mesenchymal stem cells (BMSCs) remains unclear. Therefore, we investigated its effects on osteogenic differentiation. Overexpression of IGFBP7 enhanced the expression of osteo‐specific genes and proteins, and IGFBP7 knockdown decreased osteogenesis‐specific markers. More mineral deposits and higher alkaline phosphatase activity were observed after the up‐regulation of IGFBP7. Moreover, β‐catenin levels were up‐regulated by the overexpression of IGFBP7 or the addition of extracellular IGFBP7 protein and were reduced by the depletion of IGFBP7. The increase in osteogenic differentiation due to the overexpression of IGFBP7 was partially decreased by specific Wnt/β‐catenin signaling inhibitors. Using a rat tibial osteotomy model, a sheet of IGFBP7–overexpressing BMSCs improved bone healing, as demonstrated by imaging, biomechanical, and histologic analyses. Taken together, these findings indicate that IGFBP7 regulates the osteogenic differentiation of BMSCs partly via the Wnt/ β‐catenin signaling pathway.— Zhang, W., Chen, E., Chen, M., Ye, C., Qi, Y., Ding, Q., Li, H., Xue, D., Gao, X., Pan, Z. IGFBP7 regulates the osteogenic differentiation of bone marrow‐derived mesenchymal stem cells via Wnt/β‐catenin signaling pathway. FASEB J. 32, 2280–2291 (2018). www.fasebj.org

The role of hesperetin on osteogenesis of human mesenchymal stem cells and its function in bone regeneration

Hesperetin has been suggested to be involved in bone strength. We aimed to investigate the effects of hesperetin on the osteogenic differentiation of human mesenchymal stem cells and its related mechanisms. We showed that hesperetin promoted osteogenic differentiation of human mesenchymal stem cells in vitro. It potentially exerts its effects via the ERK and Smad signaling pathways. Using a rat osteotomy model, we showed that human mesenchymal stem cells combined with a hesperetin/gelatin sponge scaffold resulted in accelerated fracture healing in vivo. Due to the low cost of hesperetin, it could be used as a growth factor for bone tissue engineering or surgical fracture treatment.

Local lipopolysaccharide injection: A potential novel treatment for heterotopic ossification

Heterotopic ossification (HO) is a frequent complication after musculoskeletal trauma and surgical procedures. It usually decreases joint mobility and eventually causes loss of joint function. However, there is no satisfied treatment available for HO. Lipopolysaccharide (LPS) is traditionally recognized as an endotoxin. Recently, studies found LPS was associated with loss of bone during bacterial infection and periprosthetic osteolysis after total joint replacement. Cell and molecular biology studies further found that LPS initiated the osteoclast formation, stimulated osteoclast activity and inhibited osteoblast differentiation. Given HO is an abnormality in bone modeling which increases bone mass within extraskeletal soft tissues, we herein hypothesize that local LPS injection might be a potential novel treatment for HO.