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Background: The zinc transporters Zrt- and Irt-related protein (ZIP/SLC39) are overexpressed in human tumors and correlate with poor prognosis; however, their contributions to carcinogenesis and chemoresistance in osteosarcoma (OS) remain unclear. Methods: We collected 64 OS patient tissues with (n = 12) or without (n = 52) chemotherapy. The expression levels of ZIP10 were measured by immunohistochemistry and applied to prognostic analysis. ZIP10 was knocked down or overexpressed in OS cell lines to explore its effect on proliferation and chemoresistance. RNA sequencing, quantitative real-time PCR, and western blotting analysis were performed to explore ZIP10-regulated downstream target genes. A xenograft mouse model was established to evaluate the mechanisms by which ZIP10 modulates chemoresistance in OS cells. Results: The expression of ZIP10 was significantly induced by chemotherapy and highly associated with the clinical outcomes of OS. Knockdown of ZIP10 suppressed OS cell proliferation and chemoresistance. In addition, ZIP10 promoted Zn content-induced cAMP-response element binding protein (CREB) phosphorylation and activation, which are required for integrin α10 (ITGA10) transcription and ITGA10-mediated PI3K/AKT pathway activation. Importantly, ITGA10 stimulated PI3K/AKT signaling but not the classical FAK or SRC pathway. Moreover, overexpression of ZIP10 promoted ITGA10 expression and conferred chemoresistance. Treatment with the CREB inhibitor 666–15 or the PI3K/AKT inhibitor GSK690693 impaired tumor chemoresistance in ZIP10-overexpressing cells. Finally, a xenograft mouse model established by subcutaneous injection of 143B cells confirmed that ZIP10 mediates chemotherapy resistance in OS cells via the ZIP10-ITGA10-PI3K/AKT axis. Conclusions: We demonstrate that ZIP10 drives OS proliferation and chemoresistance through ITGA10-mediated activation of the PI3K/AKT pathway, which might serve as a target for OS treatment. [ABSTRACT FROM AUTHOR]

Ankylosing spondylitis (AS) is a type of rheumatic disease characterized by chronic inflammation and pathological osteogenesis in the entheses. Previously, we demonstrated that enhanced osteogenic differentiation of MSC from AS patients (AS-MSC) resulted in pathological osteogenesis, and that during the enhanced osteogenic differentiation course, AS-MSC induced TNF-α-mediated local inflammation. However, whether TNF-α in turn affects AS-MSC remains unknown. Herein, we further demonstrate that a high-concentration TNF-α treatment triggers enhanced directional migration of AS-MSC in vitro and in vivo, which enforces AS pathogenesis. Mechanistically, TNF-α leads to increased expression of ELMO1 in AS-MSC, which is mediated by a METTL14 dependent m6A modification in ELMO1 3′UTR. Higher ELMO1 expression of AS-MSC is found in vivo in AS patients, and inhibiting ELMO1 in SKG mice produces therapeutic effects in this spondyloarthritis model. This study may provide insight into not only the pathogenesis but also clinical therapy for AS. Abnormal functions of mesenchymal stem cells (MSC) contribute into the pathogenensis of ankylosing spondylitis (AS). Here, the authors show that TNF-α at high concentration induces enhances migration of AS-MSC through METTL14 mediated m6A modification of the ELMO1 3′ UTR. [ABSTRACT FROM AUTHOR]

Background: Mesenchymal stem cells (MSCs) are the major source of osteoblasts. Long noncoding RNAs (lncRNAs) are abundantly expressed RNAs that lack protein‐coding potential and play an extensive regulatory role in cellular biological activities. However, the regulatory network of lncRNAs in MSC osteogenesis needs further investigation. Methods: QRT‐PCR, western blot, immunofluorescence, and immunohistochemistry assays were used to determine the levels of relevant genes. The osteogenic differentiation capability was evaluated by using Alizarin Red S (ARS) staining, alkaline phosphatase activity assays, hematoxylin & eosin staining or micro‐CT. RNA fluorescence in situ hybridization (FISH) and RNAscope were used to detect HHAS1 expression in cells and bone tissue. A microarray assay was performed to identify differentially expressed microRNAs. RNA immunoprecipitation and RNA pull‐down were used to explore the interactions between related proteins and nucleic acids. Results: The level of lncRNA HHAS1 increased during bone marrow‐derived MSC (BMSC) osteogenesis and was positively related to the levels of osteogenic genes and ARS intensity. HHAS1 was located in both the cytoplasm and the nucleus and was expressed in human bone tissue. HHAS1 facilitated BMSC osteogenic differentiation by downregulating miR‐204‐5p expression and enhancing the level of RUNX family transcription factor 2 (RUNX2). In addition, interferon regulatory factor 2 (IRF2) was increased during BMSC osteogenic differentiation and interacted with the promoter of HHAS1, which resulted in the transcriptional activation of HHAS1. Furthermore, IRF2 and HHAS1 helped improve bone defect repair in vivo. Conclusions: Our study identified a novel lncRNA, HHAS1, that facilitates BMSC osteogenic differentiation and proposed a role for the IRF2/HHAS1/miR‐204‐5p/RUNX2 axis in BMSC osteogenesis regulation. These findings help elucidate the regulatory network of BMSC osteogenesis and provide potential targets for clinical application. [ABSTRACT FROM AUTHOR]

Dysregulated angiogenesis of mesenchymal stem cells (MSCs) is closely related to inflammation and disrupted bone metabolism in patients with various autoimmune diseases. However, the role of MSCs in the development of abnormal angiogenesis in patients with ankylosing spondylitis (AS) remains unclear. In this study, we cultured human umbilical vein endothelial cells (HUVECs) with bone marrow‐derived MSCs from patients with AS (ASMSCs) or healthy donors (HDMSCs) in vitro. Then, the cocultured HUVECs were assayed using a cell counting kit‐8 (CCK‐8) to evaluate the cell proliferation. A wound healing assay was performed to investigate cell migration, and a tube formation assay was conducted to determine the angiogenesis efficiency. ASMSCs exhibited increased angiogenesis, and increased expression of SMAD‐specific E3 ubiquitin ligase 2 (Smurf2) in MSCs was the main cause of abnormal angiogenesis in patients with AS. Downregulation of Smurf2 in ASMSCs blocked angiogenesis, whereas overexpression of Smurf2 in HDMSCs promoted angiogenesis. The pro‐angiogenic effect of Smurf2 was confirmed by the results of a Matrigel plug assay in vivo. By functioning as an E3 ubiquitin ligase in MSCs, Smurf2 regulated the levels of pentraxin 3 (PTX3), which has been shown to suppress angiogenesis through the PTX3‐fibroblast growth factor 2 pathway. Moreover, Smurf2 transcription was regulated by activating transcription factor 4‐induced endoplasmic reticulum stress. In conclusion, these results identify novel roles of Smurf2 in negatively regulating PTX3 stability and promoting angiogenesis in ASMSCs. [ABSTRACT FROM AUTHOR]

Background: Mesenchymal stem cells (MSCs) are pluripotent stem cells that can differentiate via osteogenesis and adipogenesis. The mechanism underlying MSC lineage commitment still remains incompletely elucidated. Understanding the regulatory mechanism of MSC differentiation will help researchers induce MSCs toward specific lineages for clinical use. In this research, we intended to figure out the long noncoding RNA (lncRNA) that plays a central role in MSC fate determination and explore its application value in tissue engineering. Methods: The expression pattern of lncRNAs during MSC osteogenesis/adipogenesis was detected by microarray and qRT‐PCR. Lentivirus and siRNAs were constructed to regulate the expression of lncRNA repressor of adipogenesis (ROA). MSC osteogenesis/adipogenesis was evaluated by western blot and alizarin red/oil red staining. An adipokine array was used to select the paracrine/autocrine factor PTX3, followed by RNA interference or recombinant human protein stimulation to confirm its function. The activation of signaling pathways was also detected by western blot, and a small molecule inhibitor, SCH772984, was used to inhibit the activation of the ERK pathway. The interaction between ROA and hnRNP A1 was detected by RNA pull‐down and RIP assays. Luciferase reporter and chromatin immunoprecipitation assays were used to confirm the binding of hnRNP A1 to the PTX3 promotor. Additionally, an in vivo adipogenesis experiment was conducted to evaluate the regulatory value of ROA in tissue engineering. Results: In this study, we demonstrated that MSC adipogenesis is regulated by lncRNA ROA both in vitro and in vivo. Mechanistically, ROA inhibits MSC adipogenesis by downregulating the expression of the key autocrine/paracrine factor PTX3 and the downstream ERK pathway. This downregulation was achieved through transcription inhibition by impeding hnRNP A1 from binding to the promoter of PTX3. Conclusions: ROA negatively regulates MSC adipogenesis through the hnRNP A1‐PTX3‐ERK axis. ROA may be an effective target for modulating MSCs in tissue engineering. [ABSTRACT FROM AUTHOR]

Human osteoclasts are differentiated from CD14+ monocytes and are responsible for bone resorption. Long non‐coding RNAs (lncRNAs) have been proved to be significantly involved in multiple biologic processes, especially in cell differentiation. However, the effect of lncRNAs in osteoclast differentiation is less appreciated. In our study, RNA sequencing (RNA‐seq) was used to identify the expression profiles of lncRNAs and mRNAs in osteoclast differentiation. The results demonstrated that expressions of 1117 lncRNAs and 296 mRNAs were significantly altered after osteoclast differentiation. qRT‐PCR assays were performed to confirm the expression profiles, and the results were almost consistent with the RNA‐seq data. GO and KEGG analyses were used to predict the functions of these differentially expressed mRNA and lncRNAs. The Path‐net analysis demonstrated that MAPK pathway, PI3K‐AKT pathway and NF‐kappa B pathway played important roles in osteoclast differentiation. Co‐expression networks and competing endogenous RNA networks indicated that ENSG00000257764.2‐miR‐106a‐5p‐TIMP2 may play a central role in osteoclast differentiation. Our study provides a foundation to further understand the role and underlying mechanism of lncRNAs in osteoclast differentiation, in which many of them could be potential targets for bone metabolic disease. [ABSTRACT FROM AUTHOR]

Ectopic bone formation is the chief characteristic of ossification of the posterior longitudinal ligament (OPLL). Emerging evidence has revealed that long non-coding RNAs (lncRNAs) can regulate the osteogenic differentiation of mesenchymal stem cells (MSCs), which are the main cells responsible for bone formation. However, the role of lncRNAs in the pathogenesis of OPLL remains unclear. In this study, 725 aberrantly expressed lncRNAs and 664 mRNAs in osteogenically differentiated MSCs from OPLL patients (OPLL MSCs) were identified by microarrays and confirmed by qRT-PCR assays. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses showed that the most enriched pathways included the p53, JAK-STAT, and PI3K-Akt signaling pathways. The co-expression network showed the interactions between the aberrantly expressed lncRNAs and mRNAs in OPLL MSCs, and the potential targets and transcription factors of the lncRNAs were predicted. Our research demonstrated the aberrantly expressed lncRNA and mRNA and the potential regulatory networks involved in the ectopic bone formation of OPLL. These findings imply that lncRNAs may play a vital role in OPLL, which provides a new perspective on the pathogenesis of OPLL. [ABSTRACT FROM AUTHOR]

Spinal surgery is a technically demanding and challenging procedure because of the complicated anatomical structures of the spine and its proximity to several important tissues. Surgical landmarks and fluoroscopy have been used for pedicle screw insertion but are found to produce inaccuracies in placement. Improving the safety and accuracy of spinal surgery has increasingly become a clinical concern. Computerassisted navigation is an extension and application of precision medicine in orthopaedic surgery and has significantly improved the accuracy of spinal surgery. However, no clinical guidelines have been published for this relatively new and fast-growing technique, thus potentially limiting its adoption. In accordance with the consensus of consultant specialists, literature reviews, and our local experience, these guidelines include the basic concepts of the navigation system, workflow of navigation-assisted spinal surgery, some common pitfalls, and recommended solutions. This work helps to standardize navigation-assisted spinal surgery, improve its clinical efficiency and precision, and shorten the clinical learning curve. [ABSTRACT FROM AUTHOR]

The purpose of this study was to evaluate the effect of salmon calcitonin (sCT) on improving fibrosis‐related indicators in frozen shoulder synovial/capsular fibroblasts (SCFs) and detect the potential downstream pathway. Quantitative real‐time polymerase chain reaction and cell‐substrate adhesion assays were used to measure alterations in fibrosis‐related molecule expression and the cell adhesion ability of frozen shoulder SCFs after treatment with range concentrations of sCT. The presence of calcitonin receptors (CTRs) in shoulder joint synovial/capsular tissue samples was detected by immunohistochemistry (IHC). The downstream pathways of sCT in SCFs were further explored by utilizing three classical pathway inhibitors. With the addition of sCT to the culture medium of frozen shoulder SCFs, the messenger RNA (mRNA) expression of collagen type I (COL1A1), COL3A1, fibronectin 1, laminin 1, transforming growth factor‐β1 (TGF‐β1), and interleukin‐1α (IL‐1α) showed a descending trend as the sCT concentration increased. Treatment with sCT increased the expression of vascular endothelial growth factor and IL‐6 in a dose‐dependent manner. The enhanced adhesion ability of frozen shoulder SCFs gradually diminished with increasing concentrations of sCT. By using IHC, the CTR was detected extensively in the frozen shoulder joint synovium and capsule. Blocking the protein kinase C (PKC) pathway reversed the sCT‐mediated suppression of COL1A1 production. Blocking the PKC or protein kinase A (PKA) pathway eliminated the sCT‐induced inhibition of TGF‐β1 production. This study demonstrated that sCT effectively improved the mRNA expression of fibrosis‐related molecules and decreased the enhanced cell‐substrate adhesion ability of frozen shoulder SCFs. sCT might achieve these effects by interacting with the CTR that is expressed on the SCF surface and by activating the downstream PKC or PKA pathway. [ABSTRACT FROM AUTHOR]

Objective. To investigate the adipogenic differentiation capacity of mesenchymal stem cells (MSCs) from ankylosing spondylitis (AS) patients and explore the mechanism of abnormal MSC adipogenesis in AS. Methods. MSCs from patients with AS (ASMSCs) and healthy donors (HDMSCs) were cultured in adipogenic differentiation medium for up to 21 days. Adipogenic differentiation was determined using oil red O (ORO) staining and quantification and was confirmed by assessing adipogenic marker expression (PPAR-γ, FABP4, and adiponectin). Gene expression of adipogenic markers was detected using qRT-PCR. Protein levels of adipogenic markers and signaling pathway-related molecules were assessed via Western blotting. Levels of bone morphogenetic proteins 4, 6, 7, and 9 were determined using enzyme-linked immunosorbent assays. Lentiviruses encoding short hairpin RNAs (shRNAs) were constructed to reverse abnormal bone morphogenetic protein receptor 1A (BMPR1A) expression and evaluate its role in abnormal ASMSC adipogenic differentiation. Bone marrow fat content was assessed using hematoxylin and eosin (HE) staining. BMPR1A expression in bone marrow MSCs was measured using immunofluorescence staining. Results. ASMSCs exhibited a greater adipogenic differentiation capacity than HDMSCs. During adipogenesis, ASMSCs expressed BMPR1A at higher levels, which activated the BMP-pSmad1/5/8 signaling pathway and increased adipogenesis. BMPR1A silencing using an shRNA eliminated the difference in adipogenic differentiation between HDMSCs and ASMSCs. Moreover, HE and immunofluorescence staining showed higher bone marrow fat content and BMPR1A expression in patients with AS than in healthy donors. Conclusion. Increased BMPR1A expression induces abnormal ASMSC adipogenic differentiation, potentially contributing to fat metaplasia and thus new bone formation in patients with AS. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (Evs) contain diverse functional proteins, mRNAs, miRNAs, and DNA fragments, are secreted by various types of cells, and play important roles in cellular communication. Here, we show for the first time that plasma Evs inhibited the osteogenic differentiation of mesenchymal stromal cells (MSCs) in vitro and the level of inhibition was positively correlated with the plasma Evs concentration. Plasma Evs downregulated the expression of markers such as osteocalcin (OCN), Runt-related transcription factor 2 (Runx2), and Osterix at mRNA levels required for osteogenic differentiation and reduced pSmad1/5/8 levels in MSCs. Furthermore, pSmad1/5/8 levels increased and MSCs underwent normal osteogenic differentiation after Evs-derived α2-HS glycoprotein (AHSG) function was inhibited with an anti-AHSG neutralizing antibody. However, the levels of pERK1/2, active β-catenin, and HES1 were not significantly altered. Therefore, we propose that as essential components of the extracellular microenvironment of MSCs, plasma Evs are taken up by MSCs and subsequently repress osteogenic differentiation through an AHSG-mediated decrease in pSmad1/5/8 levels. Our work identifies plasma Evs as novel regulators of MSC osteogenic differentiation. [ABSTRACT FROM AUTHOR]

Background. Open laminectomy has been regarded as the standard surgical procedure for lumbar lateral recess stenosis during the last decades. Although percutaneous endoscopic lumbar decompression has led to successful results comparable with open decompression, its application in LSS with is still challenging and technically demanding. Here, we report the surgical procedure and preliminary clinical outcomes of transforaminal percutaneous endoscopic lumbar decompression (PELD) by using flexible burr for lumbar lateral recess stenosis. Method. A retrospective study was performed for the patients with lumbar lateral recess stenosis receiving PELD by using flexible burr. The indications of surgery were moderate to severe stenosis, persistent neurological symptoms, and failure of conservative treatment. The patients with mechanical back pain, more than grade I spondylolisthesis, or radiographic signs of instability were not included. Before the operation, the transforaminal epidural lidocaine injections were carried out to make the diagnosis more precise and accurate. Radiologic findings were investigated, and visual analog scale (VAS) for back and leg pain, Oswestry Disability Index, and modified Macnab criteria were analyzed at the different time of preoperation, postoperation, 3 months, 6 months, and 12 months. Results. The follow-up period was 12 months. The mean VAS scores for back and leg pain immediately improved from 7.9 ± 1.2 to 2.8± 1.3, 2.4 ± 1.0, and 2.3 ± 1.0, respectively. The mean visual analog scale scores (VAS) for back pain and leg pain were significantly improved after PELD. The preoperative ODI dropped from 69.1 ± 7.3 to 25.9 ± 8.7, 25.0± 6.9, and 24.7 ± 6.4, respectively. The final outcome was excellent in 39.6%, good in 47.9%, fair in 8.3%, and poor in 4.17%. 87.5% of excellent-to-good ratio was achieved on the basis of Macnab criteria at postoperative 12 months. The complications were limited to transient postoperative dysesthesia (one case), temporary pain aggravation (six cases), and neck pain during the operation (one case). Conclusion. This observation suggests that the clinical outcomes of PELD for lateral recess stenosis were excellent or showed good results. This minimally invasive technique would be helpful in choosing a surgical method for lateral recess stenosis. [ABSTRACT FROM AUTHOR]

The aim of this study is to evaluate the influences of different bone graft heights on the size of the intervertebral foramen, which will help determine the optimal graft height in clinical practice. Six fresh adult cadavers were used, with the C5-C6 vertebral column segment defined as the functional spinal unit (FSU). After discectomy, the C5/6 intervertebral height was set as the baseline height (normal disc height). We initially used spiral computed tomography (CT) to scan and measure the middle area of the intervertebral foramen when at the baseline height. Data regarding the spatial relationship of C5-C6 were subsequently collected with a laser scanner. Grafting with four different sized grafts, namely, grafts of 100, 130, 160, and 190% of the baseline height, was implanted. Moreover, we scanned to display the FSU in the four different states using Geomagic8.0 studio software. Multiple planar dynamic measurements (MPDM) were adopted to measure the intervertebral foramen volume, middle area, and areas of internal and external opening. MPDM with a laser scanner precisely measured the middle area of the intervertebral foramen as spiral CT, and it is easy to simulate the different grafts implanted. With the increase of the bone graft height, the size of the intervertebral foramen began to decrease after it increased to a certain point, when grafts of 160% of the baseline height implanted. MPDM of the intervertebral foramens with laser scanning three-dimensional (3D) reconstitution are relatively objective and accurate. The recommended optimal graft height of cervical spondylosis is 160% of the mean height of adjacent normal intervertebral spaces. [ABSTRACT FROM AUTHOR]

Background: Interleukin-6 (IL-6) with IL-6 receptor (IL-6R) play an important role in the tissue regeneration in vivo, especially bone metabolism. Bone marrow -derived mesenchymal stem cells (BM-MSCs) are multipotent stromal cells, which are main origin of osteoblasts. However, the roles of IL-6 and IL-6R in the osteogenic differentiation of BM-MSCs are still unclear. Methods: The expression of IL-6 and IL-6R was detected in BM-MSCs during osteogenic differentiation. The activation of the STAT3 pathway was assessed and its role in the osteogenic differentiation of BM-MSCs was determined using the specific inhibitor AG490. Exogenous IL-6/soluble IL-6R or antibodies against IL-6/IL-6R were used to confirm the mechanism by which the IL-6/IL-6R complex promotes the osteogenic differentiation. Results: The levels of IL-6 and IL-6R, especially the level of membranous IL-6R but not that of soluble IL-6R, increased during osteogenic differentiation in BM-MSCs. The levels of IL-6 and IL-6R were positively correlated with the osteogenic potential of BM-MSCs. The STAT3 signaling pathway was activated during the osteogenic differentiation of BM-MSCs. AG490 markedly inhibited the activation of the STAT3 pathway and, subsequently, the osteogenic differentiation potential of BM-MSCs. Additionally, exogenous IL-6 and soluble IL-6R accelerated the osteogenic differentiation of BM-MSCs. In contrast, antibodies against IL-6 or IL-6R suppressed the osteogenic differentiation of BM-MSCs. Moreover, IL-6 and IL-6R were found to stimulate each other's expression in BM-MSCs. Conclusions: IL-6 and IL-6R levels increase during the osteogenic differentiation of BM-MSCs. These two molecules form a complex to activate the downstream STAT3 signaling pathway, which promotes osteogenic differentiation in BM-MSCs via an autocrine/paracrine feedback loop. [ABSTRACT FROM AUTHOR]

Macrophage-related inflammatory response is one of the main biological factors resulting in failure of anterior cruciate ligament (ACL) reconstruction, although the specific pathomechanism remains to be clarified. Our aim was to investigate the association between graft loosening and macrophage-related inflammation in cases of loosening of reconstructed ACL autografts. Tissue samples were obtained from 21 patients who underwent a second-look arthroscopy within the first year after arthroscopic ACL reconstruction using single-bundle hamstring tendon autografts. Possible biological factors of graft loosening were analyzed using polymerase chain reaction, Western blot, and hematoxylin/eosin and immunohistochemical staining of graft tissue samples obtained during the second-look arthroscopy. Graft loosening was closely related to increased gene and protein expression of inflammatory cytokines (TNF-α, IL-6, and IL-8) and activation of the inflammation-related toll-like receptor (TLR) signaling (TLR2 and TLR4). The molecular expression of TGF-β and type I and III collagen was also inhibited to varying degrees, with decreased vascularization of the graft due to an inhibition of VEGF. iNOS, a marker of M1 macrophage activation, was highly expressed in cases of graft loosening, with no effect of M2 macrophages identified. The activation of M1 macrophages and aseptic inflammation signaling is an important biological factor of graft loosening after ACL reconstruction, affecting ligamentization and the health of grafts. [ABSTRACT FROM AUTHOR]

Death-associated protein kinase 1 (DAPK1), a Ca/calmodulin (CaM)-dependent serine/threonine protein kinase, plays important roles in diverse apoptosis pathways not only in tumor suppression but also in neuronal cell death. The requirement of DAPK1 catalytic activity for its proposed cell functions and the elevation of catalytic activity of DAPK1 in injured neurons in models of neurological diseases, such as ischemia and epilepsy, validate that DAPK1 can be taken as a potential therapeutic target in these diseases. Recent studies show that DAPK1-NR2B, DAPK1-DANGER, DAPK1-p53, and DAPK1-Tau are currently known pathways in stroke-induced cell death, and blocking these cascades in an acute treatment effectively reduces neuronal loss. In this review, we focus on the role of DAPK1 in neuronal cell death after stroke. We hope to provide exhaustive summaries of relevant studies on DAPK1 signals involved in stroke damage. Therefore, disrupting DAPK1-relevant cell death pathway could be considered as a promising therapeutic approach in stroke. [ABSTRACT FROM AUTHOR]

Purpose: This is a retrospective analysis of the strategy and clinical results of surgery combined with intraoperative radiotherapy (IORT) to treat spinal metastases.Methods: We delivered tumour-conformal IORT in 40 patients with 52 metastatic vertebrae based on our surgical classification system. The strategies were evaluated with respect to neurologic function and spinal stability. The EORTC QLQ-BM22, visual analogue scale (VAS) and the Frankel Scale were used to assess quality of life, pain and neurologic function. Local control was evaluated every 3 months using X-rays and MRI.Results: Micro-invasive IORT was performed in 42 vertebrae (80.8%), and open surgery with IORT was performed in 10 vertebrae (19.2%). Single-level, 2-level and 3-level IORT was performed in 30, 8 and 2 cases, respectively. The delivered dose was 9.2 ± 3.6 Gy (8-15 Gy) with a depth of 10.1 ± 2.1 mm. The actual IORT treatment time was 5 min and 16 s. The follow-up period was 6-23 months (mean: 12.5 months). The local control rate was 92.3%. The EORTC QLQ-BM22 scores showed that patients had significant improvements in pain location, degree and function after treatment (P < 0.01). Thirty-five patients (89.7%) achieved pain relief throughout the follow-up period. VAS scores were significantly reduced by 3.4 points 3 months after treatment. Neurological function was improved in 7 patients (87.5%). No radiation-related complications were observed.Conclusions: Surgery combined with tumour-conformal IORT can effectively relieve pain, achieve good local control and improve QOL. [ABSTRACT FROM AUTHOR]

Ankylosing spondylitis (AS) is a chronic inflammatory disease characterized by pathological osteogenesis and inflammation. However, the pathogenesis of AS and the pathological relationship between osteogenesis and inflammation in this disease remain largely unknown. Mesenchymal stem cells (MSCs) are multipotent progenitor cells capable of osteogenic differentiation and immunoregulation. Recently, we demonstrated that MSCs from AS patients (ASMSCs) have a greater potential for osteogenic differentiation than MSCs from healthy donors (HDMSCs), which therefore seems to be a component of pathological osteogenesis in AS. Previous studies have indicated that the immunoregulatory abilities of MSCs change following differentiation. However, the subsequent effects of ASMSCs during abnormal osteogenic differentiation are unclear. Here, we further demonstrated that ASMSCs secreted more monocyte chemoattractant protein 1 (MCP1) than HDMSCs during osteogenic differentiation. This enhanced MCP1 secretion augmented monocyte migration, increased classical macrophage polarization, and enhanced TNF-α secretion. Inhibiting MCP1 secretion from osteogenic differentiated ASMSCs using lentiviruses encoding short hairpin RNAs ameliorated these dysfunctions. Blocking the ERK1/2 pathway in ASMSCs with U0126 corrected the abnormal osteogenic differentiation, inhibited MCP1 overexpression, and prevented subsequent monocyte dysfunction. Finally, MCP1 expression was up-regulated during osteogenic differentiation in ASMSCs in vivo and was locally augmented in osteoblasts at ossification sites in AS patients. In summary, our study determined that MCP1 overexpression during abnormal osteogenic differentiation of ASMSCs triggers monocyte dysfunctions. We propose the novel hypothesis that pathological osteogenesis can lead to inflammation in AS. This hypothesis may contribute to reveal the precise pathological relationship between osteogenesis and inflammation in the field of osteoimmunology. Key message: [ABSTRACT FROM AUTHOR]

The objective of this study is to prepare a biocompatible nanohydroxyapatite/poly(methyl methacrylate) (HA/PMMA) composite bone cement, which has good mechanical property and can be used for vertebroplasty. Up to 40 wt % of nanohydroxyapatite (nano-HA) in the power, which was surface modified with poly(methylmethacrylate- co-γ-methacryloxypropyl timethoxysilane) [P(MMA- co-MPS)] copolymer, was incorporated into the composite bone cement. The content of P(MMA- co-MPS) on the surface of nano-HA (18.7%, 22.8%, and 26%) was determined through thermogravimetric analysis (TGA). The morphology of biomineralized surface of composite bone cement was observed under scanning electron microscope (SEM). The mechanical measurements of the composite cements implied that the interfacial interaction between the HA and PMMA matrix may be greatly enhanced after surface modification of HA. Biochemical assays indicated that the HA/PMMA bone cement had no cytotoxicity and induced no hemolysis. The cell adhesion and alkaline phosphatase (ALP) activity assays indicated that the biocompatibility of HA/PMMA bone cement could be promoted, demonstrating that it can be used as an ideal weight-bearing bone repair materials on clinical application. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 576-584, 2016. [ABSTRACT FROM AUTHOR]

Polymethylmethacrylate (PMMA) bone cement, which is used as a filler material in vertebroplasty, is one of the major sources of pulmonary embolism in patients who have undergone vertebroplasty. In the present study, we established and evaluated two animal models of pulmonary embolism by injecting PMMA or biphasic calcium composite (BCC) bone cement with a negative surface charge. A total of 12 adults and healthy Wuzhishan minipigs were randomly divided into two groups, the PMMA and BBC groups, which received injection of PMMA bone cement and BBC bone cement with a negative surface charge in the circulation system through the pulmonary trunk, respectively, to construct animal models of pulmonary embolism. The hemodynamics, arterial blood gas, and plasma coagulation were compared between these two groups. In addition, morphological changes of the lung were examined using three-dimensional computed tomography. The results showed that both PMMA and BCC injections induced pulmonary embolisms in minipigs. Compared to the PMMA group, the BCC group exhibited significantly lower levels of arterial pressure, pulmonary artery pressure, blood oxygen pressure, blood carbon dioxide pressure, blood bicarbonate, base excess, antithrombin III and D-dimer. In conclusion, BCC bone cement with a negative surface charge is a promising filler material for vertebroplasty. [ABSTRACT FROM AUTHOR]

Objective To study the osteogenic differentiation capacity of bone marrow-derived mesenchymal stem cells (BM-MSCs) from patients with ankylosing spondylitis (AS) and to investigate the mechanisms of abnormal osteogenic differentiation of BM-MSCs in AS. Methods BM-MSCs from healthy donors (HD-MSCs) and patients with AS (AS-MSCs) were cultured in osteogenic differentiation medium for 0-21 days, after which their osteogenic differentiation capacity was determined using alizarin red S and alkaline phosphatase assays. Gene expression levels of osteoblastic markers and related cytokines were detected by high-throughput quantitative reverse transcription-polymerase chain reaction. Enzyme-linked immunosorbent assay was performed to detect protein levels of bone morphogenetic protein 2 (BMP-2) and Noggin in the cell culture supernatant. The activation of Smad1/5/8 and MAPK signaling pathways was measured by Western blotting. The balance between BMP-2 and Noggin expression was regulated using lentiviruses encoding short hairpin RNA and exogenous Noggin, respectively, which enabled evaluation of how this balance affected osteogenic differentiation of AS-MSCs. Results AS-MSCs outperformed HD-MSCs in osteogenic differentiation capacity. During osteogenic differentiation, AS-MSCs secreted more BMP-2 but less Noggin, accompanied by an overactivation of Smad1/5/8 and ERK-1/2. When the Noggin concentration was increased or BMP-2 expression was inhibited, the abnormal osteogenic differentiation of AS-MSCs was rectified. In addition, the balance between BMP-2 and Noggin secretion was restored. Conclusion The results of this study demonstrate that an imbalance between BMP-2 and Noggin secretion induces abnormal osteogenic differentiation of AS-MSCs. These findings reveal a mechanism of pathologic osteogenesis in AS and provide a new perspective on inhibiting pathologic osteogenesis by regulating the balance between BMP-2 and Noggin. [ABSTRACT FROM AUTHOR]

A list of reviewers in for "Arthritis & Rheumatology" in 2015 is presented including Derek Abbott, John Atkinson and Maarten Boers.

Low bone mineral density (BMD) is an important complication of ankylosing spondylitis (AS) that seriously affects men and their quality of life, even in young patients. However, the relationships among redox; levels of bone turnover markers (BTMs), inflammatory markers and disease activity; and low BMD in AS require clarification. We recruited 102 men aged 30-39 year with AS and 102 healthy, sex- and age-matched controls for this cross-sectional study. The subjects were analyzed for lumbar spine and femoral neck BMD by dual-energy X-ray absorptiometry. Significantly lower BMD and corresponding T-scores were observed in the AS patients compared with the controls ( P < 0.05). The oxidant biomarker and antioxidant levels were significantly ( P < 0.05) higher and lower, respectively, in the AS subjects compared with the controls, and the bone resorption and inflammatory marker levels were higher ( P < 0.05). In subgroup analyses, the patients with osteoporosis or active disease had the highest levels of oxidant biomarkers ( P < 0.05). Furthermore, the BMD T-scores in AS were found to be negatively correlated with oxidative status ( P < 0.05). Multivariate binary logistic analysis showed that low BMD in the AS patients was associated with higher levels of advanced oxidation protein products, malondialdehyde and C-terminal telopeptide of type I collagen; lower levels of glutathione peroxidase; and higher scores of a bath ankylosing spondylitis metrology index. In conclusion, imbalanced redox was independently associated with low BMD in young men with AS and may play an important role in the pathogenesis of AS-related low BMD. [ABSTRACT FROM AUTHOR]

The article presents abstracts on osteoporosis and bone research topics which include the microrna in osteoclast differentiation, the effect of lactoferrin in primary fetal rat osteoblasts proliferation and differentiation, and the role of AMP-activated protein kinase in osteogenic differentiation

Background: Spinal cord injuries are highly disabling and deadly injuries. Currently, few studies focus on non-traumatic spinal cord injuries, and there is little information regarding the risk factors for complete injuries. This study aims to describe the demographics and the injury characteristics for both traumatic and non-traumatic spinal cord injuries and to explore the risk factors for complete spinal cord injuries. Methods: A retrospective study was performed by reviewing the medical records of 3,832 patients with spinal cord injuries who were first admitted to the sampled hospitals in Guangdong, China. The demographics and injury characteristics of the patients were described and compared between the different groups using the chi-square test. Logistic regression was conducted to analyze the risk factors for complete spinal cord injuries. Results: The proportion of patients increased from 7.0% to 14.0% from 2003 to 2011. The male-to-female ratio was 3.0∶1. The major cause of spinal cord injuries was traffic accidents (21.7%). Many of the injured were workers (36.2%), peasants (22.8%), and unemployed people (13.9%); these occupations accounted for 72.9% of the total sample. A multivariate logistic regression model revealed that the OR (95% CI) for male gender compared to female gender was 1.25 (1.07–1.89), the OR (95%CI) for having a spinal fracture was 1.56 (1.35–2.60), the OR (95%CI) for having a thoracic injury was 1.23 (1.10–2.00), and the OR (95%CI) for having complications was 2.47 (1.96–3.13). Conclusion: The proportion of males was higher than the proportion of females. Workers, peasants and the unemployed comprised the high-risk occupational categories. Male gender, having a spinal fracture, having a thoracic injury, and having complications were the major risk factors for a complete injury. We recommend that preventive measures should focus on high-risk populations, such as young males. [ABSTRACT FROM AUTHOR]

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