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Brain metastasis in osteosarcoma (BMO) is rare and its clinical characteristics are often buried among studies on brain metastasis of bone and soft tissue sarcomas. The aim of the present study was to summarize the incidence, clinical characteristics, treatment and outcomes of patients with BMO. This retrospective study included 7 patients with BMO who received treatment in our center between 2005 and 2019. The clinical medical records of the 7 patients, together with data of 70 BMO patients published in 33 articles and retrieved by means of PubMed and Medline, were analyzed, retrospectively. Data analysis of the 97 BMO patients showed a high correlation between the interval from the primary diagnosis to BMO occurrence and the interval from the primary diagnosis to prior metastases. Multivariate analysis showed that chemotherapy, radiotherapy and surgery were three main factors affecting the overall survival of BMO patients (HR = 0.427; HR = 0.372; HR = 0.296). Surgery combined with chemotherapy or radiotherapy offered a better overall survival than surgery alone. Patients with BMO may obtain survival benefits from regular neuroimaging and early aggressive multi-disciplinary interventions including surgical resection, postoperative radiotherapy and chemotherapy. This is a retrospective study describing the characteristics of metastasic intervals, locations, clinical features and prognosis in 97 patients with brain metastasis of osteosarcoma (BMO). Multivariate analysis showed that chemotherapy was effective as surgery and radiotherapy for the treatment of BMO. Our findings emphasize the importance of regular neuroimaging and early aggressive multi-disciplinary interventions including surgical resection, postoperative radiotherapy and chemotherapy. [ABSTRACT FROM AUTHOR]

Rotator cuff tear (RCT) is a common shoulder disorder related to pain and dysfunction. However, the pathological mechanism of RCT remains unclear. Thus, this study aims to investigate the molecular events in RCT synovium and identify possible target genes and pathways as determined by RNA sequencing (RNA-Seq). The synovial tissue was biopsied from 3 patients with RCT (RCT group) and 3 patients with shoulder instability (Control group) during arthroscopic surgery. Then, differentially expressed (DE) mRNAs, long non-coding RNAs (lncRNAs) and micro RNAs (miRNAs) were comprehensively profiled by RNA-Seq. Gene ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and competing endogenous RNA (ceRNA) network analysis were performed to identify the potential functions of these DE genes. 447 mRNAs, 103 lncRNAs and 15 miRNAs were identified differentially expressed. The DE mRNAs were highlighted in inflammatory pathway including up-regulated T cell costimulation, positive regulation of T cell activation, and T cell receptor signaling. Down-regulated fatty acid degradation pathway and 5′-AMP-activated protein kinase (AMPK) signaling in RCT group are also enriched. Validation assay showed that the expression of pro-inflammatory molecules including IL21R, CCR5, TNFSF11, and MMP11 was significantly increased in RCT group compared with Control group. CeRNA analysis further revealed lncRNA-miRNA-mRNA regulatory networks involving IL21R and TNFSF11 in RCT. Activated synovial inflammation is the remarkable event of RCT. Importantly, increased T cell activation and disordered fatty acid metabolism signaling might play a significant role. ceRNA networks involving IL21R and TNFSF11 identified could potentially control the progression of RCT. In conclusion, our findings could provide new evidence for the molecular mechanisms of RCT and might identify new therapeutic targets. [ABSTRACT FROM AUTHOR]

Microbial communities regulating multiple ecosystem functions in agricultural ecosystems remain unclear, limiting our ability to predict how agricultural systems will respond to nutrient management. Here, we assessed the effects of 5‐year different fertilization treatments (CK, no‐fertilization; M, organic fertilization; MNPK, combined inorganic and organic fertilization; NPK, inorganic fertilization) on the bacterial and fungal composition, co‐occurrence networks complexity and the relationship of keystone taxa with soil multifunctionality. Our results showed that fertilization shifted the bacterial and fungal community composition. The increased nodes of degree and decreased average path length with the application of organic fertilizer suggested a more stable network. The improved soil multifunctionality was also observed in combined organic and inorganic fertilization treatment, which positively correlated with the fungal community composition rather than bacterial, indicating that fungi are important in driving soil functions. Notably, the keystone taxa fOTU3995 and fOTU2868 belong to Sordariomycetes and were correlated with soil organic carbon, total nitrogen, total phosphorus, and alkaline phosphatase. These indicated that the keystone taxa play an important role in increasing in soil nutrient, C cycling, and P cycling. Together, our findings highlight that combined organic and inorganic fertilization increases the network complexity and soil multifunctionality, further confirming the role of keystone taxa Sordariomycetes in driving soil multifunctionality. This suggested that combined organic and inorganic have the potential to preserve agroecosystem sustainability and strengthen the role of microorganisms in ecosystem functions. [ABSTRACT FROM AUTHOR]

The present study aimed to evaluate anti‐rheumatoid arthritis (RA) effect of Lonicerin (LON), a safe compound with anti‐inflammatory and immunomodulatory properties. Nevertheless, the exact role of LON in RA remains elusive. In this test, the anti‐RA effect of LON was evaluated in collagen‐induced arthritis (CIA) mouse model. Relevant parameters were measured during the experiment; ankle tissue and serum were collected at the end of the experiment for radiology, histopathology, and inflammation analysis. ELISA, qRT‐PCR, immunofluorescence, and western blot were used to explore the effect of LON on the polarization of macrophages and related signal pathways. It was discovered that LON treatment attenuated the disease progression of CIA mice with lower paw swelling, clinical score, mobility, and inflammatory response. LON treatment significantly decreased M1 marker levels in CIA mice and LPS/IFN‐γ‐induced RAW264.7 cells, while slightly increasing M2 marker levels in CIA mice and IL‐4‐induced RAW264.7 cells. Mechanistically, LON attenuated the activation of the NF‐κB signaling pathway, which contributes to M1 macrophage polarization and inflammasome activation. In addition, LON inhibited NLRP3 inflammasome activation in M1 macrophages, thereby reducing inflammation by inhibiting IL‐1β and IL‐18 release. These results indicated that LON might exert anti‐RA effects by regulating the polarization of M1/M2 macrophage, especially by inhibiting macrophage polarization toward M1. [ABSTRACT FROM AUTHOR]

The aim of this study was to explore a novel method to determine the orientation of acetabular prosthesis in total hip arthroplasty (THA) by refering to the anatomical landmarker of acetabular notches. Forty-one normal developmental hips were included in the present study. The acetabulums were reamed according to standard surgical procedures of THA on life-size 3D printing pelvis models. The inferior edge of acetabular cup were placed (1–5) mm proximal and distal to the proximal line of the anterior and posterior acetabular notches (PLAPAN) respectively to determine cup inclination. The inferior edge of acetabular cup were placed (1–5) mm pronating and supinating around the proximal point of acetabular posterior notch (PPAPN) respectively to determine cup anteversion. The pelvis plain radiographs were took and the inclination and anteversion of the acetabular cup at 22 positions were calculated. In the normal developmental hip, the mean inclination of acetabular prothesis were (35.10 ± 3.22)° and (45.90 ± 2.68)° when the inferior edge of the acetabular cup was 3 mm proximal and 1 mm distal to the PLAPAN. The optimal cup inclination could be obtained when the inferior edge of the acetabular cup was 1 mm proximal to the PLAPAN (the mean inclination was (40.71 ± 2.80)°). The mean anteversion of acetabular prothesis were (10.67 ± 4.55)° and (20.86 ± 4.44)° when the inferior edge of the acetabular cup was 1 mm pronating and 1 mm supinating around the PPAPN. The optimal cup anteversion could be obtained when the inferior edge of the acetabular cup was parallel to the PLAPAN (the mean anteversion was (18.00 ± 1.64)°). The inclination and anteversion of acetabular prosthesis could be determined by refering the anatomical landmarks of acetabular notches, which could help orthopedists to install the acetabular prosthesis quickly and safely in THA. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the biomechanical effects of different miniplates on restorative laminoplasty. Methods: Assembled restorative laminoplasty models were developed based on 3D printed L4 lamina. Based on different internal fixations, the research was divided into H-shaped miniplates (HSMs) group, two-hole miniplates (THMs) group, and L-shaped miniplates (LSMs) group. The static and dynamic compression tests were analyzed to investigate the biomechanical effects of different internal fixations in restorative laminoplasty, until the failure and fracture of miniplates, or the collapse of miniplates. The static compression tests adopted the speed control mode, and the dynamic fatigue compression tests adopted the load control mode. Results: The "door close" and the collapse of lamina occurred in THMs group and LSMs group, and plate break occurred in LSMs group. However, these phenomenon was absent in HSMs group, and only plate crack around a screw and looseness of a screw tail cap were found in HSMs group. The sustainable yield load of HSMs group was greater than that of THMs group and LSMs group (P < 0.05). No significant difference in yielding-displacement was found between HSMs group and LSMs group (P > 0.05), while both were much less than that of THMs (P < 0.05). Moreover, the compressive stiffness and the axial displacement under the same mechanical load were arranged as follows: HSMs group > LSMs group > THMs group (P < 0.05). The results of dynamic compression test revealed that the peak load of HSMs group could reached 873 N and was 95% of the average yield load of the static compression, and was better than that in THMs group and LSMs group (P < 0.05). Besides, according to the fatigue life-peak load diagram, the ultimate load of HSMs group was more than twice that of THMs group or LSMs group. Conclusions: The mechanical strength of H-shaped miniplates was superior to two-hole miniplates and L-shaped miniplates in maintaining spinal canal enlargement and spinal stability, and was more excellent in fatigue stability and ultimate load. [ABSTRACT FROM AUTHOR]

In this study, we conducted a field experiment to investigate the effect of reduced chemical fertilizer and combined application of organic materials on nematode community in a wheat-maize cropping system over two crop seasons (wheat and maize). The results showed that the soil moisture emerged as the major determinant of nematode community structure in wheat season, while the soil pH was the main factor influencing the nematode variation in maize season. The effect of soil properties accounted for 2.4% of the total variation in nematode community. The Shannon index in the straw addition treatment significantly increased by 38.5% in comparison with the NPK treatment in wheat season. The ecological network showed that organic fertilizer simplified the complexity of the ecological network of straw treatment and the separate return of straw suppressed the efficiency of material circulation, energy flow, and information transmission among nematode network species. These results indicate that reduced chemical fertilizer and combined application of organic materials made the nematode community structure more stable and improved the sustainability of agroecosystems. [ABSTRACT FROM AUTHOR]

Whether long non-coding RNA Mir-99a-Let-7c Cluster Host Gene (LncRNA MIR99AHG) is involved in osteoporosis (OP) remains vague, so we hereby center on its implication. Old C57BL/6J mice were injected with the silencing lentivirus of MIR99AHG and subjected to microCT analysis and immunohistochemistry on osteogenic cells. The osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) with or without transfection was determined by alkaline phosphatase (ALP) and Alizarin Red S staining. Total N(6)-methyladenosine (m6A) on the bone marrow mesenchymal stem cells (BMSCs) was quantified. The potential methylation site and the complementary binding sites with candidate microRNA (miR) were predicted via bioinformatic analyses, with the latter being confirmed via dual-luciferase reporter, RNA immunoprecipitation and RNA pull-down assays. Quantitative real-time PCR and Western blot were used for quantification assays. MIR99AHG was decreased during the osteogenic differentiation of BMSCs, where increased Osterix (OSX), Collagen, Type I, Alpha 1 (Col1A1), Osteocalcin (OCN) and RUNX Family Transcription Factor 2 (RUNX2) as well as more color-stained areas were found. Also, silencing MIR99AHG relieved the OP in mice and reduced the loss of osteogenic cells. M6A methylation in undifferentiated BMSCs was low and MIR99AHG overexpression abolished the effects of overexpressed METTL3 on promoting osteogenic differentiation. MiR-4660, which was downregulated in BMSCs without differentiation but increased during osteogenic differentiation, could bind with MIR99AHG. Furthermore, miR-4660 promoted osteogenic differentiation and reversed the effects of overexpressed MIR99AHG. The present study demonstrated that METTL3-mediated LncRNA MIR99AHG methylation enhanced the osteogenic differentiation of BMSCs via targeting miR-4660. [ABSTRACT FROM AUTHOR]

Background. Osteosarcoma (OS) is the most common primary aggressive sarcoma of bone, with massive aberrant expression of oncogenes related to the development of OS. RALA, a kind of small Ras-like guanosine triphosphatases, has been identified as a potential therapeutic target in several types of tumor, but its role in OS remains largely unknown. Methods. Abnormal expression of RALA was proven in the Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Therapeutically Applicable Research to Generate Effective Treatments (TARGET), and RNA-sequence of samples and cell lines. The role of RALA in OS was analyzed in terms of DNA methylation, immune cell infiltration, and patient survival. The cancer-promoting effect of RALA was demonstrated in cell lines and xenograft osteosarcoma models. A prognostic scoring model incorporating RALA as an indicator was established with the clinical samples that we collected. Results. The results showed that RALA was highly expressed in human OS tissues and cell lines. Survival analysis demonstrated that RALA was the sole independent risk factor for poor overall survival and disease-free survival in OS patients and impacted the proportion of infiltrating immune cells and DNA methylation in the OS tumor microenvironment. By gene-gene interaction analysis, we found that the expression of RALA was highly correlated to the expression of ABCE1. Similar to RALA, upregulated ABCE1 is correlated with poor survival outcome of OS patients. In addition, the functional experiment demonstrated that higher expression of RALA promoted the proliferation, migration, and invasion of OS cells. In vivo results were similar with the in vitro results. We examined m6a methylation-related genes and found that m6A methylation is responsible for the abnormal expression of RALA. Finally, the prognostic prediction model of RALA could be used to predict the long-term outcome of OS patients. Conclusions. We identified RALA as an oncogene in OS, and RALA upregulation in a concerted manner with ABCE1 was significantly associated with worse outcomes of OS patients. Targeting RALA may prove to be a novel target for OS immunotherapy in future clinical practice. [ABSTRACT FROM AUTHOR]

Purpose: Deciphering the succession patterns of soil bacterium-fungus-nematode communities and functions in agroecosystems is one of the most important aspects of soil ecology research. However, how agricultural practices, especially the chemical fertilizer reduction and organic material application, influence soil bacterium-fungus-nematode networks remain unclear in wheat–maize rotation systems. Methods: In the present study, a field experiment was established with five fertilization treatments, including chemical fertilizer with conventional application rate (F), chemical fertilizer reduction based on conventional fertilization (FR), chemical fertilizer reduction plus straw (FRS), chemical fertilizer reduction combined with organic fertilizer (FRO), and chemical fertilizer reduction combined with organic fertilizer and straw (FROS), under a wheat–maize rotation regime over a 4-year period. Co-occurrence network analysis was used to investigate the bacterium-fungus-nematode community relationships. Results: The results showed that the kinless hubs assigned to Sordariomycetes, Agaricomycetes, and Dothideomycetes were of paramount significance to agricultural fertilization. Chemical fertilizer reduction combined with organic materials increased the total nodes, edges, and average degree (avgK), but decreased the average path distance (GD). The networks of bacterial metabolic pathway profile demonstrated that the edge numbers of FRS and FRO networks were obviously shorter than those of F and FR networks, but the GD showed an opposite phenomenon. In contrast, the FROS network had the highest edge number and shortest GD, producing a complicated co-occurrence network. Chemical fertilizer reduction with substitution by organic inputs significantly changed the fungal potential functions, and the genus Poaceascoma appeared to play a key part in shaping the fungal potential functions. Conclusion: Overall, chemical fertilizer reduction and organic material application practices altered the responses of keystone taxa and topological features in the bacterium-fungus-nematode communities, such as increasing the scale of ecological network, complicating the relationship between species, and improving the efficiency of material, energy and information transfer between species. Furthermore, organic material substitution exhibited a greater influence on fungal functions, especially pathotrophic and saprotrophic fungi. The complicacy for the potential bacterial functions was weakened by separate application, however, strengthened by joint application of straw and organic fertilizer. [ABSTRACT FROM AUTHOR]

In the context of the evolution of in-vehicle electronic and electrical architecture as well as the rapid development of quantum computers, post-quantum algorithms, such as NTRUEncrypt, are of great significance for in-vehicle secure communications. In this paper, we propose and evaluate, for the first time, a NTRUEncrypt enhanced session key negotiation for the in-vehicle Ethernet context. Specifically, the time consumption and memory occupation of the NTRUEncrypt Elliptic Curve Diffie–Hellman (ECDH), and Rivest–Shamir–Adleman (RSA) algorithms, which are used for session key negotiation, are measured and compared. The result shows that, besides the NTRUEncrypt's particular attribute of resisting quantum computer attacks, the execution speed of session key negotiation using NTRUEncrypt is 66.06 times faster than ECDH, and 1530.98 times faster than RSA at the 128-bit security level. The memory occupation of the algorithms is at the same order of magnitude. As the transport layer security (TLS) protocol can fulfill most performance requirements of the automotive industry, post-quantum enhanced session key negotiation will probably be widely used for in-vehicle Ethernet communication. [ABSTRACT FROM AUTHOR]

The human gut microbiota has been proven to have great effects on the regulation of bone health. However, the association between gut microbiota and particle-induced osteolysis, which is the primary cause of aseptic loosening, is still unknown. In this study, we used a combination of wide-spectrum antibiotics to eliminate the majority of gut microbiota and found that reduction of gut commensal bacteria significantly alleviated the progression of osteolysis, in which anaerobe was the biggest culprit in the exacerbation of osteolysis. Furthermore, colonization of enteropathogenic Escherichia coli (EPEC), a subspecies of anaerobe, could promote the development of particle-induced osteolysis by increasing the secretion of peripheral 5-hydroxytryptamine (5-HT) from the colon. Elevated 5-HT level decreased the phosphorylation of CREB and inhibited the proliferation of osteoblasts. Collectively, these results indicated EPEC colonization suppressed the bone formation and aggravated particle-induced osteolysis in vivo. Thus, clearance of EPEC is expected to become a potential preventive approach to treat debris-induced osteolysis and aseptic loosening. [ABSTRACT FROM AUTHOR]

Background: The objectives of this study were to investigate the anatomic morphology of patellar ridge using computed tomography-based three-dimensional (3D) computer models and to assess the center of the patellar ridge after virtual resections. Methods: We selected 80 patients, 40 males (age, 33.2±6.8 years) and 40 females (age, 30.6±7.2 years), who were slightly symptomatic with soft tissue injury of the knee joint. The right or left knees were scanned by computed tomography (CT). The CT data of 160 knees was used to construct 3D computer models by image analysis software (Mimics). Variables such as the angle between the patellar ridge and patellar long axis, the distance between the center of the patellar ridge and the center of patellar cut after virtual resections were measured. We detect differences between the sides and genders with the 3D computer models by Student's t test. Simple linear regression and correlation test was used to correlate the patellar ridge center to the center of the patellar cut. Results: According to the available data, there were significant gender differences in the length and width of patellar cut after virtual resections even with strict control for the height and weight of the patients. The angle between the patellar ridge and the patellar long axis was 11.24° ± 3.62°. The angle in male patients was 10.17° ± 4.82°, and it was 12.28°± 3.78° in female patients. The morphological difference was statistically significant (P < 0.05). After using the subchondral method to virtually resect the patellae, with reference to the center of the patellar cut, the center of the patellar ridge lies superiorly and medially in 88.75%, inferiorly and medially in 8.75%, laterally and superiorly in 2.5%, and in no case laterally and inferiorly. The intra-observer reliability regarding the dimensional measurements was excellent in this study. Conclusions: Advances in 3D computer models had resulted in the availability of preoperative measurement and virtual planning. The anthropometric dimensions of this study could provide general information for guiding surgical management of the patella in total knee arthroplasty (TKA) and were useful in designing patellar implants. Clinical relevance: The placement of the patellar component during TKA differs from one patella to another. The anatomic morphology information of the patellar ridge is helpful for surgeons to perform patellar resurfacing in TKA. [ABSTRACT FROM AUTHOR]

As the demand for green energy with high efficiency and low carbon dioxide (CO2) emissions has increased, solid oxide fuel cells (SOFCs) have been intensively developed in recent years. Integrated gasification fuel cells (IGFCs) in particular show potential for large-scale power generation to further increase system efficiency. Thus, for commercial application of IGFCs, it is important to design reliable multi-stacks for large systems that show long-term stability and practical fuel gas for application to industrial equipment. In this work, a test rig (of a 5 kW SOFC system, with syngas from industrial gasifiers as fuel) was fabricated and subjected to long-term tests under high fuel utilization to investigate its performance. The maximum steady output power of the system was 5700 W using hydrogen and 5660 W using syngas and the maximum steady electrical efficiency was 61.24% while the fuel utilization efficiency was 89.25%. The test lasted for more than 500 h as the fuel utilization efficiency was larger than 83%. The performances of each stack tower were almost identical at both the initial stage and after long-term operation. After 500 h operation, the performances of the stack towers decreased only slightly under lower current and showed almost no change under high current. These results demonstrate the reliability of the multi-stack design and the prospect of this SOFC power-generation system for further enlarging its application in a MWth demonstration. [ABSTRACT FROM AUTHOR]

CO2 fixation by autotrophic microbes has a significant effect on the carbon cycle in temperate grasslands. Nitrogen (N) deposition in soil has been steadily increasing for decades, which has consequences for soil microorganisms. However, the impact of this deposition on the diversity and abundance of CO2-fixing soil microorganisms remains unclear in temperate grasslands. In the present study, the cbbL gene, a key gene in the Calvin–Benson–Bassham cycle that encodes the large subunit of ribulose-1,5-bisphosphate carboxylase/oxygenase, was used to study CO2-fixing microbes under different rates of N addition (0, 15, 30, 50, 100, and 150 kg N ha–1 yr–1) in a 9-year field experiment in a temperate grassland. The results showed that N addition led to significant reductions in cbbL gene abundance and genetic diversity and altered cbbL gene community composition. High N addition enhanced the relative abundances of Acidiferrobacterales and Rhizobiales but reduced those of Burkholderiales and Rhodobacterales. Structural equation modeling further revealed that N addition primarily reduced cbbL genetic diversity by increasing the soil NO3-N content and decreasing the soil pH. N addition indirectly reduced cbbL gene abundance, possibly by increasing the soil N/phosphorus (P) ratio and decreasing the soil pH. These findings suggest that N addition increases the soil available N and causes soil acidification, which may inhibit growth of CO2-fixing microbes to some extent. [ABSTRACT FROM AUTHOR]

Impaired osteoblast function is involved in osteoporosis, and microRNA (miRNA) dysregulation may cause abnormal osteoblast osteogenic activity. However, the influence of miRNA on osteoblast activity and the underlying mechanisms remain elusive. In this study, miR‐103‐3p was found to be negatively correlated with bone formation in bone specimens from elderly women with fractures and ovariectomized (OVX) mice. Additionally, miR‐103‐3p directly targeted Mettl14 to inhibit osteoblast activity, and METTL14‐dependent N6‐methyladenosine (m6A) methylation inhibited miR‐103‐3p processing by the microprocessor protein DGCR8 and promoted osteoblast activity. Moreover, miR‐103‐3p inhibited bone formation in vivo, and therapeutic inhibition of miR‐103‐3p counteracted the decreased bone formation in OVX mice. Further, METTL14 was negatively correlated with miR‐103‐3p but positively correlated with bone formation in bone specimens from elderly women with fractures and OVX mice. Collectively, our results highlight the critical roles of the miR‐103‐3p/METTL14/m6A signaling axis in osteoblast activity, identifying this axis as a potential target for ameliorating osteoporosis. [ABSTRACT FROM AUTHOR]

Osteosarcoma is a malignancy with high aggressiveness and poor prognosis, which occurs mainly in children. The therapeutic strategy against osteosarcoma includes surgery combined with chemotherapy and radiotherapy. Although the treatment of osteosarcoma has been improved in recent years, there is a large proportion of patients with incurable osteosarcoma. Investigation of the mechanism of osteosarcoma progression would be of great help in discovering therapeutic targets for this disease. Long non-coding RNAs play critical roles in the pathogenesis of different types of cancer. The current study showed that long non-coding RNA NR_027471 was downregulated in osteosarcoma cells. In vitro and in vivo studies indicated that upregulation of NR_027471 impeded the viability, proliferation, and invasion of osteosarcoma, as well as induced cell cycle arrest at G1. In addition, binding of miR-8055 to NR_027471 was demonstrated, thereby influencing the expression of tumor protein p53 inducible nuclear protein 1 (TP53INP1). Knockdown of NR_027471 promoted epithelial–mesenchymal transition by inhibiting E-cadherin and increasing the expression of zinc finger E-box-binding homeobox 1 (ZEB1), Snail, and fibronectin. These results suggested that overexpression of NR_027471 upregulated TP53INP1 by sponging to miR-8055, leading to suppression of osteosarcoma cell proliferation and progression. [ABSTRACT FROM AUTHOR]

Osteosarcoma (OS) is the most common form of bone malignancy in children and adolescents. MicroRNAs (miRNAs) have been associated with the development and progression of OS. In the present study, reverse transcription-quantitative PCR, western blotting, Cell Counting Kit-8, luciferase and Transwell assays were performed to investigate the biological function of microRNA-150 (miR-150) in OS. The results revealed that miR-150 was significantly downregulated in OS cell lines (HOS, SAOS2, MG-63 and U2OS) in comparison with the normal osteoblast cells (hFOB1.19). Overexpression of miR-150 significantly inhibited cell proliferation in OS cells. miR-150 could sensitize OS cells to chemotherapy treatment of doxorubicin. Runt-related transcription factor 2 (RUNX2) was identified as a target gene of miR-150. RUNX2 knockdown exhibited similar inhibitory effects on both OS cell proliferation and chemotherapy sensitivity. Restoration of RUNX2 reversed the biological function of miR-150. Finally, miR-150 overexpression and RUNX2 knockdown enhanced caspase-3 cleavage. Taken together, the present study established a novel molecular mechanism, in that miR-150 plays tumor suppressor and chemoprotective roles by targeting RUNX2 in OS, indicating that miR-150 may be a potential therapeutic target for OS therapy in the future. [ABSTRACT FROM AUTHOR]

Impaired osteoblast proliferation plays fundamental roles in microgravity‐induced bone loss, and cell cycle imbalance may result in abnormal osteoblast proliferation. However, whether microgravity exerts an influence on the cell cycle in osteoblasts or what mechanisms may underlie such an effect remains to be fully elucidated. Herein, we confirmed that simulated microgravity inhibits osteoblast proliferation. Then, we investigated the effect of mechanical unloading on the osteoblast cell cycle and found that simulated microgravity arrested the osteoblast cell cycle in the G2 phase. In addition, our data showed that cell cycle arrest in osteoblasts from simulated microgravity was mainly because of decreased cyclin B1 expression. Furthermore, miR‐181c‐5p directly inhibited cyclin B1 protein translation by binding to a target site in the 3′UTR. Lastly, we demonstrated that inhibition of miR‐181c‐5p partially counteracted cell cycle arrest and decreased the osteoblast proliferation induced by simulated microgravity. In conclusion, our study demonstrates that simulated microgravity inhibits cell proliferation and induces cell cycle arrest in the G2 phase in primary mouse osteoblasts partially through the miR‐181c‐5p/cyclin B1 pathway. This work may provide a novel mechanism of microgravity‐induced detrimental effects on osteoblasts and offer a new avenue to further investigate bone loss induced by mechanical unloading. [ABSTRACT FROM AUTHOR]

Surface modification of medical implants is considered as an effective method to improve cellular behaviors and the integration of tissues with materials. Titanium (Ti)-based materials with four different micro/nano-structures and compositions were prepared by acid etching, electrochemical anodization and alkali-heat treatment. The surface morphologies and compositions of the different surface-modified Ti materials were characterized by field-emission scanning electron microscopy (FE-SEM), atomic force microscopy (AFM) and X-ray diffraction (XRD). The effects of the micro/nano structured and compositions of the surfaces on cellular responses were investigated in vitro by observing the morphology, adhesion, proliferation and osteogenic differentiation of osteoblasts. To further investigate the underlying mechanisms, an RT-PCR assay was performed to analyze the expression levels of cell adhesion-related genes. Our results indicated that the nanosized structure and anatase composition could promote the adhesion and proliferation of MC3T3-E1 pre-osteoblast, as well as alkaline phosphatase activity and extracellular matrix mineralization via the integrin-FAK signaling pathway. Taken together, our innovation presented in this work demonstrated that the surface nano-structure design and composition of biomedical implants can be modified of for future orthopaedic applications. [ABSTRACT FROM AUTHOR]

Background/Aims: Diabetic fracture have poor treatment and serious complications. Therefore, how to treat diabetic fracture is receiving increasing attention. This study aimed to investigate the effects of transplanting CXCL13-stimulated bone marrow stromal cells (BMSCs) on the fracture healing in diabetic rats. Methods:In vitro, RT-PCR was employed to examine the expression of CXCL13 in BMSCs in high glucose environment. MTT assay and apoptosis assay were utilized to determine the effects of CXCL13 overexpression on the proliferation and apoptosis of BMSCs respectively. ALP staining was applied to detect the ALP activity. In vivo, CXCL13-stimulated BMSCs were transplanted into the fracture sites of diabetic rats. At the 1st week, 2nd weeks, 4th week and 6th week after the operation, bone mineral density (BMD) and callus area measurement, ELISA detection, and HE staining were performed to evaluate the fracture healing. Results: Low BMD and less area of callus in diabetic rats showed that the recovery after fracture was worse in diabetic rats than in non-diabetic rats. Meanwhile, the expression of CXCL13 in serum was lower in diabetic rats than in non-diabetic rats. Overexpression of CXCL13 promoted the proliferation of BMSCs in vitro high glucose environment. After BMSCs transfected with CXCL13 being transplanted into the fracture sites of diabetic rats, it was found that the fracture healing was enhanced and ALP expression in serum became higher. HE staining results further verified the effects of transplantation of BMSCs transfected with CXCL13 on fracture healing in diabetic rats. Conclusion: These finding indicated that CXCL13 may play a critical role in the process of fracture healing, which could provide a deeper insight into molecular targets for the fracture healing in diabetic people. [ABSTRACT FROM AUTHOR]

The lymphocyte activation gene 3 (LAG-3) is a CD4 homolog with binding affinity to MHC class II molecules. It is thought that LAG-3 exerts a bimodal function, such that co-ligation of LAG-3 and CD3 could deliver an inhibitory signal in conventional T cells, whereas, on regulatory T cells, LAG-3 expression could promote their inhibitory function. In this study, we investigated the role of LAG-3 expression on CD4+ T cells in patients with long bone fracture. We found that LAG-3+ cells represented approximately 13% of peripheral blood CD4+ T cells on average. Compared to LAG-3− CD4+ T cells, LAG-3+ CD4+ T cells presented significantly higher Foxp3 and CTLA-4 expression. Directly ex vivo or with TCR stimulation, LAG-3+ CD4+ T cells expressed significantly higher levels of IL-10 and TGF-β than LAG-3− CD4+ T cells. Interestingly, blocking the LAG-3-MHC class II interaction actually increased the IL-10 expression by LAG-3+ CD4+ T cells. The frequency of LAG-3+ CD4+ T cell was positively correlated with restoration of healthy bone function in long bone fracture patients. These results together suggested that LAG-3 is a marker of CD4+ T cells with regulatory function; at the same time, LAG-3 might have limited the full suppressive potential of Treg cells. [ABSTRACT FROM AUTHOR]

Summary: Bone fracture healing is a multistage regenerative process that requires the collaboration of various cell types, with approximately 5%‐10% of fractures not healing properly. Accumulating evidence suggests that dysregulations in the immune system are associated with defective healing. In a cohort of 30 bone fracture patients between 50 and 62 years of age, 8 patients displayed delayed healing. Compared to the 22 normal healing patients, these 8 delayed healing patients presented significantly lower frequencies of CD4+CD25hiFoxp3+ canonical regulatory T cells immediately following bone fracture and early on during the healing process. The CD4+CD25+/hi T cells from delayed healing patients also presented reduced capacity to express transforming growth factor beta (TGF‐β), and presented reduced surface expression levels of inhibitory molecules, including CTLA‐4 and Lag‐3, compared to CD4+CD25+/hi T cells from normal healing patients. Moreover, CD4+CD25+/hi T cells from delayed healing patients were less potent in the suppression of CD4+CD25− autologous conventional T cell proliferation, and presented reduced expansion capacity in response to interleukin (IL)‐2 stimulation. Overall, our results demonstrated multiple reductions in regulatory T cell function in delayed healing patients that could produce long‐lasting consequences in the bone fracture healing process. [ABSTRACT FROM AUTHOR]

Background: The meniscus is one of the most commonly injured parts of the body, and meniscal healing is difficult. Hypothesis: Kartogenin (KGN) induces tendon stem cells (TSCs) to differentiate into cartilage cells in vitro and form meniscus-like tissue in vivo. A damaged meniscus can be replaced with a KGN-treated autologous tendon graft. Study Design: Controlled laboratory study. Methods: In the in vitro experiments, TSCs were isolated from rabbit patellar tendons and cultured with various concentrations of KGN, from 0 to 1000 µM. The effect of KGN on the chondrogenesis of TSCs in vitro was investigated by histochemical staining and quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). The in vivo experiments were carried out on 6 New Zealand White rabbits by removing a meniscus from the rabbit knee and implanting an autologous tendon graft treated with KGN or saline. The meniscus formation in vivo was examined by histological analysis and immune staining. Results: The proliferation of TSCs was promoted by KGN in a concentration-dependent manner. Both histochemical staining and qRT-PCR showed that the chondrogenic differentiation of TSCs was increased with KGN concentration. After 3 months of implantation, the tendon graft treated with KGN formed a meniscus-like tissue with a white and glistening appearance, while the saline-treated tendon graft retained tendon-like tissue and appeared yellowish and unhealthy. Histochemical staining showed that after 3 months of implantation, the KGN-treated tendon graft had a structure similar to that of normal meniscus. Many cartilage-like cells and fibrocartilage-like tissues were found in the KGN-treated tendon graft. However, no cartilage-like cells were found in the saline-treated tendon graft after 3 months of implantation. Furthermore, the KGN-treated tendon graft was positively stained by both anti–collagen type I and type II antibodies, but the saline-treated tendon graft was not stained by collagen type II. Conclusion: The findings indicated that KGN can induce the differentiation of TSCs into cartilage-like cells in vitro and in vivo. The results suggest that KGN-treated tendon graft may be a good substitute for meniscal repair and regeneration. Clinical Relevance: This study revealed the direct effects of KGN on the chondrogenic differentiation of TSCs in vitro and in vivo. A KGN-treated autologous tendon graft induced formation of a meniscus-like tissue in vivo. This study provides a new cartilage regenerating technology for the treatment of damaged meniscus. [ABSTRACT FROM AUTHOR]

Abstract: Background: Osteoarthritis (OA) is the most common chronic joint disease. This study aimed to uncover underlying mechanisms of OA pathogenesis and explore the potential biomarkers of osteoarthritic acetabular labrum. Methods: The microarray data GSE60762 was utilized, containing five OA acetabular labrum samples and three healthy control samples. Data were preprocessed by oligo package and the differentially expressed genes (DEGs) were identified using limma package with predefined criteria, followed by functional enrichment analysis by the GoFunction in R Bioconductor, and protein–protein interaction (PPI) network analysis. Results: As a result, 141 DEGs (44 were up‐regulated and 97 were down‐regulated) were identified between OA and healthy acetabular labrum cells. Up‐regulated genes including CDH2 and WNT5A were significantly enriched in intracellular signal transduction function, while down‐regulated genes such as KDR, FLT1 and CDH5 were remarkably correlated with cardiovascular system development. FLT1, KDR, CDH2 and CDH5 were the striking nodes in the PPI network. Conclusion: CDH2, WNT5A, KDR, FLT1 and CDH5 might serve as the biomarkers of OA prognosis. Intracellular signal transduction and cardiovascular system development might play significant roles in the destruction of labrum during OA progression. However, more experimental validations are warranted to confirm our findings. [ABSTRACT FROM AUTHOR]

Background. To compare the salvage rate and complication between internal fixation and external fixation in patients with small bone defects caused by chronic infectious osteomyelitis debridement. Methods. 125 patients with chronic infectious osteomyelitis of tibia fracture who underwent multiple irrigation, debridement procedure, and local/systemic antibiotics were enrolled. Bone defects, which were less than 4 cm, were treated with bone grafting using either internal fixation or monolateral external fixation. 12-month follow-up was conducted with an interval of 3 months to evaluate union of bone defect. Results. Patients who underwent monolateral external fixation had higher body mass index and fasting blood glucose, longer time since injury, and larger bone defect compared with internal fixation. No significant difference was observed in incidence of complications (23.5% versus 19.3%), surgery time (156±23 minutes versus 162±21 minutes), and time to union (11.1±3.0 months versus 10.9±3.1 months) between external fixation and internal fixation. Internal fixation had no significant influence on the occurrence of postoperation complications after multivariate adjustment when compared with external fixation. Furthermore, patients who underwent internal fixation experienced higher level of daily living scales and lower level of anxiety. Conclusions. It was relatively safe to use internal fixation for stabilization in osteomyelitis patients whose bone defects were less than 4 cm and infection was well controlled. [ABSTRACT FROM AUTHOR]

Proanthocyanidins (PCs) have shown inhibition of oxidative damage by improving Nrf-2 expression in many tissues. However, the cytoprotective effects of PCs on H2O2-induced tendon damage have not been verified. The current study was aimed at assessing the cytoprotection of PCs on the oxidative cellular toxicity of tendon-derived stem cells (TDSCs) induced by H2O2. The TDSCs were isolated from patellar tendons of Sprague Dawley (SD) rats, and the cells after third passage were used for subsequent experiments. The isolated cells were identified by flow cytometry assay and multidifferentiation potential assay. Cell Counting Kit-8 assay was performed to examine cell viability. Real-Time PCR and Western Blot were employed to, respectively, assess the mRNA and protein expressions of Nrf-2, GCLM, NQO-1, and HO-1. PCs significantly improved the cell viability of TDSCs. Furthermore, H2O2 upregulated Nrf-2, GCLM, NQO-1, and HO-1 without significant difference, while the proteins expressions were increased with significant difference in PCs group and PCs + H2O2 cotreated group. All the findings indicated that PCs could protect against the oxidative damage induced by H2O2 in TDSCs, and the cytoprotective effects might be due to the ability of PCs to activate the expressions of GCLM, HO-1, and NQO-1 via upregulating Nrf-2 signaling pathway. [ABSTRACT FROM AUTHOR]

Signal transducer and activator of transcription 3 ( STAT3) is a key signaling protein in the skeletal system as well as in the immune system. Accumulating evidence demonstrates that the inflammatory response is deeply involved in the healing process of bone fractures, but how the immune system is regulated during this process is unclear. In this study, we examined STAT3-mediated regulation of immunity in adult patients with closed tibia fracture. In all patients, the expression and activation of STAT3 peaked at around day 7 to day 14 after surgery, and gradually decreased during the rest of the healing period. At day 7 (peak STAT3 expression and phosphorylation), the CD4+ CD25+ T cells from bone fracture patients presented the highest level of STAT3 activation among lymphocyte subsets. Therefore, we investigated the role of STAT3 in CD4+ CD25+ T cells. The level of FOXP3 expression by CD4+ CD25+ T cells was directly correlated with the level of STAT3 phosphorylation in these cells. The level of STAT3 phosphorylation in CD4+ CD25+ T cells was also inversely correlated with the level of IFN-γ and TNF-α secretion in peripheral blood mononuclear cells. Inhibition of STAT3 significantly suppressed FOXP3 and IL-10 expression by CD4+ CD25+ T cells, as well as the ability of CD4+ CD25+ T cells to suppress T-cell IFN-γ and TNF-α secretion. Furthermore, early healers patients presented significantly higher STAT3 expression and phosphorylation than late healers, possibly due to the higher IL-6 and IL-10 levels in the serum of early healing patients. Together, these data demonstrated that STAT3 was beneficial to bone fracture healing, possibly by enhancing Treg-mediated suppression of counteracting inflammations, and suggested that STAT3 could be used as a prognostic marker to identify otherwise undistinguishable patients at risk of developing delayed union or nonunion. [ABSTRACT FROM AUTHOR]

FK-506 (Tacrolimus) is a very commonly used immunomodulatory agent that plays important roles in modulating the calcium-dependent phosphoserine-phosphothreonine protein phosphatase calcineurin and thus inhibits calcineurin-mediated secondary neuronal damage. The biological function of FK-506 in the spinal cord has not been fully elucidated. To clarify the anti-inflammatory action of FK-506 in spinal cord injury (SCI), we performed an acute spinal cord contusion injury model in adult rats and hypoxia-treated primary spinal cord microglia cultures. This work studied the activation of NF-κB and proinflammatory cytokine (TNF-a, IL-1b, and IL-6) expression. ELISA and q-PCR analysis revealed that TNF-a, IL-1b, and IL-6 levels significantly increased 3 days after spinal cord contusion and decreased after 14 days, accompanied by the increased activation of NF-κB. This increase was reversed by an FK-506 treatment. Double immunofluorescence labeling suggested that NF-κB activation was especially prominent in microglia. Immunohistochemistry confirmed no alteration in the number of microglia. Moreover, the results in hypoxia-treated primary spinal cord microglia confirmed the effect of FK-506 on TNF-a, IL-1b, and IL-6 expression and NF-κB activation. These findings suggest that FK-506 may be involved in microglial activation after SCI. [ABSTRACT FROM AUTHOR]

Primary frozen shoulder (PFS) is a common condition of uncertain etiology that is characterized by shoulder pain and restriction of active and passive glenohumeral motions. The pathophysiology involves chronic inflammation and fibrosis of the joint capsule. Single nucleotide polymorphisms (SNPs) at IL-1β, MMP3, TGF-β1, and GDF5 have been associated with risk of a variety of inflammatory diseases; however, no studies have examined these SNPs with susceptibility to PFS. We investigated allele and genotype frequencies of rs1143627 at IL-1β, rs650108 at MMP-3, rs1800469 at TGF-β1, and rs143383 at GDF5 in 42 patients with PFS and 50 healthy controls in a Chinese Han population. Serum samples from both cohorts were evaluated to determine the expression levels of IL-1β. We found that the IL-1β rs1143627 CC genotype was associated with a decreased risk of PFS compared to the TT genotype (P=0.022) and that serum IL-1β was expressed at a significantly higher level in the PFS cohort compared to that found in the control group (P<0.001). Our findings indicated no evidence of an association between rs650108, rs1800469, or rs143383 and PFS. IL-1β is associated with susceptibility to PFS and may have a role in its pathogenesis in a Chinese Han population. [ABSTRACT FROM AUTHOR]

Macrophage apoptosis in interface membrane, which occurs through either death receptor, mitochondrion, or endoplasmic reticulum ( ER) stress pathways, has been suggested to play an important role in promoting osteolysis. However, how and why macrophage apoptosis originates and the correlation among these apoptotic pathways is not yet clear. The objective of this study was to identify the apoptotic mechanism of macrophages, and to explore the relationship between the apoptotic pathways and progression of osteolysis. Transmission electron microscopy ( TEM) was utilized to analyze the tissue ultrastructure of wear particles, and in situ apoptotic macrophage identification was performed by TUNEL staining. We analyzed the expression of the key biomarkers of apoptotic pathways via immunohistochemistry and Western blotting. Our results demonstrated that the majority of wear particles within osteolytic interface membrane was in the 30-60 nm range, and that macrophage apoptotic ratio increased along with osteolysis progression. Normal hip dysplasia and mechanical loosening of tissues showed low expression levels of biomarkers for ER stress (Ca2+, JNK, cleaved Caspase-4, IRE1-α, Grp78/Bip, and CHOP), mitochondrion (Bcl-2, Bax, and Cytochrome c), and death receptor (Fas and cleaved Caspase-8) pathways, while osteolytic interface membrane tissues expressed high levels of these biomarkers. In addition, we found that the ER stress intensity was in complete conformity with mitochondrial dysfunction and was consistent with the results of death receptor activation. Thus, our findings suggested that wear particles generated at implant interface can accelerate macrophage apoptosis through changes in apoptotic pathways and ultimately aggravate the symptom of osteolysis. These data represent a preferential apoptotic signaling pathway of macrophages as specific target points for the prevention and therapeutic modulation of periprosthetic osteolysis. [ABSTRACT FROM AUTHOR]

ABSTRACT Wear particle-induced osteolysis is a major cause of aseptic loosening, which is one of the most common reasons for total hip arthroplasty (THA) failure. Previous studies have shown that the expression of Receptor activation of nuclear factor (NF)-kB (RANKL) by fibroblasts in periprosthetic membrane played a crucial role in wear particle-induced osteolysis. However, the underlying mechanism of RANKL expression remains largely unknown. In the present study, we investigated the effect of TiAl6V4 particle (TiPs)-induced XBP1s (spliced form of X-box binding protein 1) on RANKL expression and osteoclastogenesis both in vitro and in vivo. The levels of XBP1s in peri-implant membrane, animal models, and TiPs-stimulated fibroblasts were determined by western blots. To assess the effect of XBP1s on RANKL expression, fibroblasts were treated with both a small interfering RNA (siRNA) and an inhibitor of XBP1 prior to exposure to TiPs. The effect of XBP1s on osteoclasts formation was determined by tartrate-resistant acid phosphatase (TRAP) staining in vitro osteoclastogenesis assay and in animal models. The resorption of bone was assessed by micro-computed tomography (micro-CT) with three-dimensional reconstruction. Our results demonstrated that XBP1s was activated in periprosthetic membrane, mouse calvaria models, and TiPs-stimulated human synovial fibroblasts. Further, inhibition of XBP1s decreased the expression of RANKL and osteoclasts formation in vitro. In mouse calvaria models, both of the osteoclastogenesis and osteolysis were inhibited XBP1s inhibitor. Our results suggested that XBP1s mediated TiPs-induced of RANKL expression in fibroblasts, and down regulating XBP1s may represent a potential therapy for wear particle-induced osteolysis. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:752-759, 2017. [ABSTRACT FROM AUTHOR]

Bone fractures may result in delayed union ( DU) or non-union ( NU) in some patients. Evidence suggests that the skewing of the immune system toward the proinflammatory type is a contributing factor. Because B cells were previously found to infiltrate the fracture healing site at abundant levels, we examined the regulatory B cells (Bregs) in DU/ NU patients. In bone fracture patients with normal healing, the frequency of interleukin ( IL)-10-expressing B cells was significantly upregulated in the early healing process (6 weeks post-surgery) and was downregulated later on (18 weeks post-surgery), whereas in DU/ NU patients, the early upregulation of IL-10-expressing B cells was missing. The majority of IL-10-expressing B cells were concentrated in the IgM+ CD27+ fraction in both controls and patients. IgM+ CD27+ B cells effectively suppressed interferon gamma ( IFN-γ), tumor necrosis factor alpha ( TNF-α), and IL-2 expression from CD4+ T cells, as well as IFN-γ and TNF-α expression from CD8+ T cells. The IgM+ CD27+ B cell-mediated suppression was restricted to the sample from the early healing time point in controls, as the IgM+ CD27+ B cells from normal healing patients later on or from DU/ NU patients did not present significant regulatory function. In addition, culturing of CD4+ CD25+ Tregs with IgM+ CD27+ B cells from controls at early healing time point resulted in higher Foxp3 expression, a function absent in controls at later time point, or in DU/ NU patients. In conclusion, our results support a role of B cell-mediated regulation early during the bone healing process. [ABSTRACT FROM AUTHOR]

Immune suppression plays critical roles in the development of chronic osteomyelitis, and the mechanisms underlying the development of immune suppression in chronic osteomyelitis have attracted much attention. LAG-3 is an important suppressor of T cell activation, but the role of LAG-3 in the immune regulation of chronic osteomyelitis is currently unknown. We sought to demonstrate if LAG-3 plays crucial roles in chronic osteomyelitis progression and has effects on immune suppression and exhausting of T cells, and what is the mechanism underlying LAG-3 deregulation in chronic osteomyelitis. We examined the expression of LAG-3 in the T cells of peripheral blood of 50 healthy controls and 50 patients with chronic osteomyelitis by flow cytometry. Clinical data were analyzed to determine the correlation between inflammation index and LAG-3 expression. Moreover, we isolated the CD4 T cells from healthy controls and chronic osteomyelitis patients to compare cell proliferation and IFN-γ production. Chromatin immunoprecipitation assays were utilized to analyze the epigenetic modification on LAG-3 expression in T cells. We found that LAG-3 was significantly increased in the T cells of peripheral blood from chronic osteomyelitis patients. Subsequently, clinical data analysis suggested that the higher expression of LAG-3 was associated with severer inflammation situation. Consistently, LAG-3CD4 T cells exhibited impaired cell proliferation and IFN-γ secretion. Deregulation of histone methylation mediated the increase of LAG-3 T cells during chronic osteomyelitis. Taken together, our study demonstrates the increase of LAG-3 T cells and its immune regulatory roles in chronic osteomyelitis progression, suggesting new mechanisms and potential therapeutic targets for chronic osteomyelitis. [ABSTRACT FROM AUTHOR]

Cartilage tissues have limited capacity for repair after damage and then cause osteoarthritis, so finding alternative treatment is ongoing. Mesenchymal stem cells (MSCs) have become a promising therapy for cartilage damage and diseases due to the advantages of easy separation, high proliferative potentiality, and genetic stability. Synovium-derived MSCs (SMSCs) have been recognized as an ideal source for cartilage repair. In our previous study, we found that Sox4 promoted proliferation and chondrogenesis of SMSCs through upregulation of long noncoding RNA (lncRNA) DANCR. However, the exact molecular mechanism by which DANCR promotes proliferation and chondrogenesis of SMSCs remains unknown. In the present study, we investigated the effect of lncRNA DANCR on the proliferation and chondrogenesis of SMSCs. We found that overexpression of DANCR could promote proliferation and chondrogenesis of SMSCs, while knockdown of DANCR had the opposite effect. Moreover, our data demonstrated that DANCR directly interacted with myc, Smad3, and STAT3 mRNA to regulate their stability. Finally, we found that the promotion of SMSC proliferation induced by DANCR depended on myc. Also, DANCR activated chondrogenesis of SMSCs via upregulation of Smad3 and STAT3 expression. Our growing knowledge of the role of DANCR is pointing toward its potential use as a novel therapeutic approach for cartilage damage and diseases. [ABSTRACT FROM AUTHOR]

Hemorrhagic stroke can occur after spine and joint surgeries such as laminectomy, lumbar spinal fusion, tumor resection, and total joint arthroplasty. Although this kind of stroke rarely happens, it may cause severe consequences and high mortality rates. Typical clinical symptoms of hemorrhagic stroke after spine and joint surgeries include headache, vomiting, consciousness disturbance, and mental disorders. It can happen several hours after surgeries. Most bleeding sites are located in cerebellar hemisphere and temporal lobe. A cerebrospinal fluid (CSF) leakage caused by surgeries may be the key to intracranial hemorrhages happening. Early diagnosis and treatments are very important for patients to prevent the further progression of intracranial hemorrhages. Several patients need a hematoma evacuation and their prognosis is not optimistic. [ABSTRACT FROM AUTHOR]

Background: Due to the adverse effects of cemented hip arthroplasty, uncemented stems with hydroxyapatite (HA) coating reduces these risks and enhanced integration. The concept of an extensive HA coating for the fixation of a tapered femoral stem (Corail) was introduced, which can achieve durable biological fixation and preserve normal periprosthetic bone activity. Here we describe the clinical and radiological outcome in patients with the Corail stem. Methods: 92 total hip replacements in 81 patients using the Corail stem were followed-up. 47 patients were women, and the mean age at surgery was 62.9 ± 8.7 (34-71) years. The indications included: osteoarthritis of the hip (71.1%), avascular necrosis (13.6%), femur neck fractures in elderly (9.7%) and post-traumatic osteoarthritis (6.8%). Findings: Eight patients died during follow-up. The revision was only found in two patients due to line wear and resulted in an 10-year Kaplan-Meier estimated overall survival rate of 97.83%. The clinical results were good, with a mean Harris hip score of 92.3 ± 5.6 (72-100). The mean total Merle d'Aubigné and Postel score was 6.8 ± 0.5 pre-operatively and 16.1 ± 1.4 at latest follow-up. All unrevised implants were radiographically stable, with a mean liner wear of 0.07 mm/year. Conclusion: This long-term analysis confirmed the durability of the functional and radiographic results. Our findings suggest the long-term results of Corail HA-coated stem are more satisfactory which is preferable to any other system. [ABSTRACT FROM AUTHOR]

Background: Platelet-rich plasma (PRP) is now widely used as a promising treatment for patients with tendinopathy. However, the efficacy of PRP treatment for tendinopathy is controversial mainly because of inconsistent results from human clinical trials and particularly because the concentration and effect of leukocytes in PRP remain largely unknown. Hypothesis: Leukocyte-rich PRP (L-PRP) inhibits growth factor release, decreases proliferation, and induces nontenocyte differentiation of tendon stem cells (TSCs); increases catabolic cytokine concentrations; and causes inflammation and apoptosis. Thus, L-PRP has a detrimental effect on tendon stem/progenitor cells, which impairs injured tendon healing. Study Design: Controlled laboratory study. Methods: Pure PRP (P-PRP) and L-PRP were prepared from the same individual rabbit blood, and platelet numbers in each PRP product were adjusted to reach the same level. The leukocyte level in L-PRP was 4 and 8 times higher than those in whole blood and P-PRP, respectively. The growth factors in both P-PRP and L-PRP were measured by enzyme-linked immunosorbent assay kits. The morphology, stemness, proliferation, and differentiation of TSCs grown in L-PRP and P-PRP were examined by microscopy, immunocytochemistry, population doubling time, quantitative real-time polymerase chain reaction, and histological analysis. Results: L-PRP produced lower levels of growth factors, such as vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), transforming growth factor (TGF)–β1, and platelet-derived growth factor (PDGF), than did P-PRP. TSC proliferation was significantly decreased in L-PRP in a concentration-dependent manner. Furthermore, TSCs cultured in P-PRP produced more collagen and formed tendon-like tissue; however, TSCs grown in L-PRP differentiated into nontenocytes and produced more inflammatory factors such as membrane-associated prostaglandin synthase (mPGES) and interleukin (IL)–1β. Moreover, L-PRP was associated with increased apoptosis. Conclusion: L-PRP has harmful effects on TSCs. Clinical Relevance: This study revealed the direct effects of different compositions of PRP on TSCs and provided basic scientific data to help understand the cellular and molecular mechanisms of the efficacy of PRP treatment in clinical use. [ABSTRACT FROM AUTHOR]

Background/Aims: The bradykinin B2 receptor (BDKRB2) +9/-9 gene polymorphisms have been shown to be associated with the susceptibility and severity of osteoarthritis (OA); however, the underlying mechanisms are unclear. In this study, we investigated the correlation between the BDKRB2 +9/-9 polymorphisms and pro-inflammatory cytokine levels in OA and the molecular mechanisms involved. Methods: A total of 156 patients with primary knee OA and 121 healthy controls were enrolled. The BDKRB2 +9/-9 polymorphisms were genotyped. The tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-8 levels were determined using Enzyme-linked immunosorbent assay (ELISA). The toll-like receptor (TLR)-2 and TLR-4 mRNA levels were determined by quantitative real-time PCR. The basal and bradykinin-stimulated pro-inflammatory cytokine secretion in human OA synoviocytes and the involvement of TLR-2 and mitogen-activated protein kinases (MAPKs) were investigated. Results: The presence of -9 bp genotype is associated with higher TNF-α, IL-6, and IL-8 levels and higher TLR-2 expression in OA patients. The basal and bradykinin-induced TLR-2 expressions in human OA synoviocytes were significantly reduced by specific inhibitors of p38, JNK1/2, and ERK1/2. Both the B2 receptor antagonist MEN16132 and TLR-2 silencing inhibited IL-6 and IL-8 secretion in human OA synoviocytes. Conclusion: The data suggested that the BDKRB2 +9/-9 polymorphisms influence pro-inflammatory cytokine levels in knee osteoarthritis by altering TLR-2 expression. [ABSTRACT FROM AUTHOR]

Aseptic loosening secondary to periprosthetic inflammatory osteolysis results from the biological response to wear particles and is a leading cause of arthroplasty failure. The origin of this inflammatory response remains unclear. We aim to validate the definite link between endoplasmic reticulum (ER) stress and particle-induced inflammatory signaling pathways in periprosthetic osteolysis. We examine the histopathologic changes of osteolysis and the expression of specific biomarkers for ER-stress-mediated inflammatory signaling pathways (IRE1α, GRP78/Bip, c-Fos, NF-κB, ROS and Ca). Moreover, pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) and osteoclastogenic molecules (VEGF, OPG, RANKL and M-CSF) were assessed in clinical interface membranes and murine periosteum tissues. We found wear particles to be capable of inducing ER stress in macrophages within clinical osteolytic interface membranes and murine osteolytic periosteum tissues and to be associated with the inflammatory response and osteoclastogenesis. Blocking ER stress with sodium 4-phenylbutyrate (4-PBA) results in a dramatic amelioration of particle-induced osteolysis and a significant reduction of ER-stress intensity. Simultaneously, this ER-stress blocker also lessens inflammatory cell infiltration, diminishes the capability of osteoclastogenesis and reduces the inflammatory response by lowering IRE1α, GRP78/Bip, c-Fos, NF-κB, ROS and Ca levels. Thus, ER stress plays an important role in particle-induced inflammatory osteolysis and osteoclastogenic reactions. The pharmacological targeting of ER-stress-mediated inflammatory signaling pathways might be an appealing approach for alleviating or preventing particle-induced osteolysis in at-risk patients. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]