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Mesenchymal stem cells (MSCs) are one of the attractive candidates in regenerative medicine of many clinical applications because of their low immunogenicity and immunomodulatory property. Our previous studies provided that mouse bone marrow-derived Sca-1+MSCs could drive the differentiation of regulatory DC (regDCs) (Scal-1+ BM-MSC-driven DC [sBM-DCs]) from hemopoietic progenitor cells (HPCs) and the Notch pathway played a critical role in maintaining the immunomodulatory property. However, the detailed mechanisms of their immunoregulatory capacity are not fully defined. In the present study, we show that BM-MSCs expressed high levels of Jagged 1 while sBM-DCs expressed high levels of Notch1. Jagged1 expressed on the surface of BM-MSCs initiated Notch signaling to maintain the immunomodulatory property of the sBM-DCs. The level of TGF-β is high in MSCs, either alone or coculture with HPCs medium. TGF-β plays a vital role in the proliferation and differentiation of sBM-DCs and inhibition of TGF-β reduce the number and increase the percentage of CD34, CD117, CD135 of generation cells. Thus, MSCs induced the regDCs from HPCs via the Notch signaling pathway and TGF-β synergistically. This study further broadens our understanding of the immunomodulatory mechanism and the potential therapeutic efficacy of MSCs.

Study design Retrospective Aanalysis of a Large Cohort of Cases. Objectives To explore the rate and cause of revision surgery after spinal fusion in adolescent idiopathic scoliosis(AIS). Methods The patients diagnosed with AIS who underwent spinal fusion surgery in a single center from 2002 to 2018 were retrospectively analyzed. All the patients were followed up at least 2 years. The causes of revision surgery were analyzed and the incidence of revision surgery was counted. Results A total of 1816 AIS patients were included in the study. After an average of 8.5 years (range 3-18 years) follow-up, a total of 51 patients underwent 54 revision operations. The overall revision rate is 2.8%. The revision rate of combined approach (anterior and posterior) and anterior approach was 6.6% (8/122), and the revision rate of posterior approach was 2.5% (43/1694). The most common causes of revision were malposition of implants/implants failure (37%), followed by poor wound healing/ infection (23%). Spinal decompensation, adding on and proximal junctional kyphosis (PJK) accounted for 20%. The compensatory curve continued to worsen after selective fusion accounted for 14% and finally the discomfort with the implants accounted for 6%. Conclusions The overall revision rate of spinal fusion for AIS is 2.8%. The implants and incision problems were the most common causes of revision surgeries.

Background To assess the risk factors for blood transfusion in a great number of adolescent cases with different types of scoliosis who received scoliosis surgery. Methods Data of patients who were diagnosed as scoliosis and received one-stage posterior correction and spinal fusion from January 2014 to December 2017 were prospectively collected and retrospectively analyzed. Patients’ demographic characteristics, segments of spinal fusion, Cobb angle of the major curve,osteotomy pattern, preoperative and postoperative levels of hemoglobin, and allogeneic blood transfusion (ABT) were recorded and analyzed. Results In this study, 722 cases with adolescent scoliosis were included, of whom 32.8% (237/722) received ABT. Risk factors included diagnosis: neurofibromatosis (OR = 5.592), syndromic (OR = 3.029),osteotomy: Ponte osteotomy (OR = 5.997), hemivertebrae resection (OR = 29.171), pedicle subtraction osteotomy (PSO)(OR = 8.712), vertebral column resection (VCR)(OR = 32.265);fusion segments (OR = 1.224) and intraoperative blood loss (OR = 1.004). In the subgroup analysis of cases with idiopathic scoliosis, Ponte osteotomy (OR = 6.086), length of segments of spinal fusion (OR = 1.293), and intraoperative blood loss (OR = 1.001) were found as risk factors for ABT. Results of receiver operating characteristic (ROC) curve analysis revealed that length of segments of spinal fusion equal to 11.5 vertebrae was the best cutoff value for cases with idiopathic scoliosis who did not receive osteotomy in both ABT group and non-ABT group. In the subgroup analysis of congenital scoliosis, Ponte osteotomy (OR = 5.087), hemivertebra resection (OR = 5.457), PSO (OR = 4.055), VCR (OR = 6.940), and intraoperative blood loss (OR = 1.004) were risk factors for ABT. Conclusions Method of diagnosis, osteotomy pattern, segments of spinal fusion, and intraoperative blood loss were risk factors for ABT in cases with adolescent scoliosis. In cases with idiopathic scoliosis, Ponte osteotomy and segments of spinal fusion longer than 11.5 vertebrae were risk factors for ABT. In cases with congenital scoliosis, osteotomy pattern was the main risk factor for ABT. Level of evidence Level III.

Objectives: Anisodamine (ANI) has been used to treat a variety of diseases. However, the study of ANI in intervertebral disc degeneration (IVDD) is unclear. This study investigated the effects of ANI on degenerative nucleus pulposus cells (NPCs) and IVDD rats, and its possible mechanisms.Methods: Human nucleus pulposus cells (HNPCs) were treated with IL-1β (20 ng/ml) to simulate IVDD, and an IVDD rat model was constructed. IL-1β-induced HNPCs were treated with different concentrations (10, 20, or 40 μM) of ANI, and IVDD rats were also treated with ANI (1 mg/kg).Results: ANI treatment significantly reduced the apoptosis, caspase-3 and SA-β-gal activities, and p53 and p21 proteins expression, while promoted telomerase activity and aggrecan and collagen II synthesis in IL-1β-induced HNPCs. Moreover, the introduction of ANI inhibited the expression of IL-6, phosphorylation of JAK and STAT3, and nuclear translocation of p-STAT3 in Degenerated HNPCs. Additionally, the application of ANI abolished the effects of IL-6 on apoptosis, SA-β-gal and telomerase activity, and the expression of p53, p21, aggrecan and collagen II proteins in degenerated HNPCs. Simultaneously, ANI treatment enhanced the effects of AG490 (inhibitor of JAK/STAT3 pathway) on IL-1β-induced apoptosis, senescence and ECM degradation in HNPCs. Furthermore, ANI treatment markedly inhibited the apoptosis and senescence in the nucleus pulposus of IVDD rats, while promoted the synthesis of aggrecan and collagen II. ANI treatment obviously inhibited JAK and STAT3 phosphorylation and inhibited nuclear translocation of p-STAT3 in IVDD rats.Conclusion: ANI inhibited the senescence and ECM degradation of NPCs by regulating the IL-6/JAK/STAT3 pathway to improve the function of NPCs in IVDD, which may provide new ideas for the treatment of IVDD.

Background: Risk factors and clinical outcome associated with distal adding on in Lenke 2AR adolescent idiopathic scoliosis (AIS) are not fully elucidated.Methods: Radiographic data of Lenke 2AR AIS patients treated by posterior pedicle screws in a single institution were retrospectively analyzed. Patients who developed distal adding on were compared with patients who did not. Clinical assessment were carried out by SF-36 and SRS-22 questionnaire. Risk factors of distal adding on were explored by binary logistic regression analysis.Results: A total of 88 patients completed an average of 2.9 (2-12.9) years of follow-up were included. 18 (20.5%) patients met the criterion of distal adding on while the rest of 70 cases did not at follow up.Clinical parameters were comparable before surgery and became lower at follow up in adding on group in dimensions of vitality (63.1±11.4Vs.67.5±11.8,P=0.026), mental health (73.9±9.2Vs.77.8±10.2,P=0.039), self-image (3.9±0.3Vs.4.2±0.3,P=0.021) and satisfaction (4.0±0.3Vs.4.5±0.4,P=0.035). The proportion of selection lowest instrumented vertebra (LIV) higher than last touching vertebra(LTV) was significantly higher in adding on group. (6/18vs 4/70, P=0.004) Binary logistic regression analysis revealed that preoperative main thoracic curve magnitude (OR=1.118,P=0.041), preoperative lumbar lordosis (OR=1.091,P=0.029), and the gap between LIV and LTV(OR=6.123,P=0.043) were independent risk factors associated with adding on.Conclusions: In Lenke 2AR AIS cases, the selection of LIV higher than LTV is closely correlated with the development of adding-on. Patients with minor main thoracic curve and lumbar lordosis are more likely to develop distal adding on. Adding on may cause discontent of patients .

Aims: This study was to investigate the effect of TUG1 on apoptosis and ECM degradation of human degenerative intervertebral disc nucleus pulposus cells (NPCs) and its mechanism. Methods: Human degenerative intervertebral disc NP tissues were obtained from 10 patients with lumbar disc herniation (LDH) who underwent lumbar spine surgery (IDD group), normal intervertebral disc NP tissues were obtained from 10 patients with lumbar vertebrae fractures (LVF group). Results: The expression of TUG1 and HMGB1 protein in human degenerative disc NP tissues and NPCs was significantly increased, while the level of miR-26a was significantly decreased. Overexpression of TUG1 inhibited the proliferation while promoted apoptosis and ECM degradation of human degenerative intervertebral disc NPCs. Simultaneously, the effect of TUG1 knockdown on NPCs was opposite. Interestingly, TUG1 acted as an endogenous sponge to down-regulate the expression of miR-26a in NPCs by direct binding to miR-26a. Overexpression of miR-26a reversed the effects of TUG1 overexpression on apoptosis and ECM degradation. Additionally, HMGB1 was a target gene of miR-26a. The increased expression of HMGB1 induced by TUG1 overexpression could be reversed by the introduction of miR-26a mimic. Overexpression of TUG1 significantly upregulated the expression of p65 in the nucleus, while overexpression of TUG1 partially abolished the inhibition of NF-κB by QNZ pretreatment. Conclusion: TUG1 could promote the apoptosis and ECM degradation of degenerated intervertebral disc NPCs by regulating the miR-26a/HMGB1, which may be involved in the activation of NF-κB pathway.

ObjectivesTo evaluate the morphine-sparing effects of the sequential treatment versus placebo in subjects undergoing total knee arthroplasty (TKA), the effects on pain relief, inflammation control and functional rehabilitation after TKA and safety.DesignDouble-blind, pragmatic, randomised, placebo-controlled trial.SettingFour tertiary hospitals in China.Participants246 consecutive patients who underwent elective unilateral TKA because of osteoarthritis (OA).InterventionsPatients were randomised 1:1 to the parecoxib/celecoxib group or the control group. The patients in the parecoxib/celecoxib group were supplied sequential treatment with intravenous parecoxib 40 mg (every 12 hours) for the first 3 days after surgery, followed by oral celecoxib 200 mg (every 12 hours) for up to 6 weeks. The patients in the control group were supplied with the corresponding placebo under the same instructions.Primary and secondary outcome measuresThe primary endpoint was the cumulative opioid consumption at 2 weeks post operation (intention-to-treat analysis). Secondary endpoints included the Knee Society Score, patient-reported outcomes and the cumulative opioid consumption.ResultsThe cumulative opioid consumption at 2 weeks was significantly smaller in the parecoxib/celecoxib group than in the control group (median difference, 57.31 (95% CI 34.66 to 110.33)). The parecoxib/celecoxib group achieving superior Knee Society Scores and EQ-5D scores and greater Visual Analogue Scale score reduction during 6 weeks. Interleukin 6, erythrocyte sedation rate and C-reactive protein levels were reduced at 72 hours, 2 weeks and 4 weeks and prostaglandin E2 levels were reduced at 48 hours and 72 hours in the parecoxib/celecoxib group compared with the placebo group. The occurrence of adverse events (AEs) was significantly lower in the parecoxib/celecoxib group.ConclusionsThe sequential intravenous parecoxib followed by oral celecoxib regimen reduces morphine consumption, achieves better pain control and functional recovery and leads to less AEs than placebo after TKA for OA.Trial registration numberClinicalTrials.gov (ID:NCT02198924).

Nuclear receptor subfamily 4 group A member 1 (NR4A1)-induced chondrocyte death plays a critical role in the development of osteoarthritis through poorly defined mechanisms. The present study aimed to investigate the role of NR4A1 in regulating chondrocyte death in response to tumor necrosis factor-α (TNF-α) and cycloheximide (CHX) treatment, with a focus on mitochondrial fission and the AMP-activated protein kinase (AMPK) signaling pathway. The results demonstrated that NR4A1 was significantly upregulated in TNF-α and CHX exposed chondrocytes. Increased NR4A1 triggered mitochondrial fission via the AMPK/dynamin-related protein 1 (Drp1) pathway, resulting in mitochondrial dysfunction, and mitochondrial permeability transition pore (mPTP) opening-related cell death. Furthermore, excessive mitochondrial fission impaired chondrocyte migration through imbalance of F-actin homeo-stasis. Inhibiting NR4A1 attenuated TNF-α and CHX-induced mitochondrial fission and, thus, reduced mitochondrial dysfunction in chondrocytes, mPTP opening-related cell death and migration injury. Altogether, the present data confirmed that mitochondrial fission was involved in NR4A1-mediated chondrocyte injury via regulation of mitochondrial dysfunction, mPTP opening-induced cell death and F-actin-related migratory inhibition.

The mechanism of steroid-associated femoral head necrosis remains unclear. The present study investigated the role of microRNA-23a-3p (miR-23a-3p) in the incidence of osteonecrosis in a rat model. An miR-23a-3p mimic, an inhibitor and a negative control were transfected into bone mesenchymal stem cells using a lentiviral vector, and then injected into the steroid-induced femoral head necrosis model. Osteonecrosis incidence was assessed by micro computed tomography and histopathology. Low-density lipoprotein receptor-related protein 5 (LRP-5) expression was assessed by immunohistochemistry. The results demonstrated the incidence of osteonecrosis decreased in the miR-23a-3p inhibitor group compared with the miR-23a-3p mimic group (18.2% vs. 75%; P

Background: The core feature of intervertebral disc degeneration (IDD) is the reduction in the number of nucleus pulposus cells (NPCs) and the loss of extracellular matrix (ECM). Emerging studies have shown that long-chain non-coding RNAs (lncRNAs) taurine upregulated gene 1 (TUG1) plays a key role in the development of IDD. However, the relevant mechanisms of TUG1 in the development of IDD are not yet clear. Objective: This study investigated the effect of TUG1 on apoptosis and ECM degradation of human degenerative intervertebral disc NPCs and its mechanism. Methods: The expression of TUG1 in the human IDD NP tissues and NPCs was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The effects of overexpression or knockdown of TUG1 on cell proliferation and apoptosis were examined by EdU assay and flow cytometry, respectively. Utilizing bioinformatics methods, luciferase activity assay, the possible interacted miRNA and Mrna were explored. Western blot analysis determined the expression levels of collagen II, aggrecan, MMP-3 and MMP-13. Additionally, the effect of TUG1 on NF-κB pathway was analyzed by western blot assay and immunofluorescence staining. Results: The expression of TUG1 and HMGB1 protein in human degenerative disc NP tissues and NPCs was significantly increased, while the level of miR-26a was significantly decreased. Overexpression of TUG1 inhibited the proliferation while promoted apoptosis and ECM degradation of human degenerative intervertebral disc NPCs. Simultaneously, the effect of TUG1 knockdown on NPCs was opposite. Interestingly, TUG1 acts as an endogenous sponge to down-regulate the expression of miR-26a in NPCs by direct binding to miR-26a.Overexpression of miR-26a reversed the effect of TUG1 overexpression on apoptosis and ECM degradation. Additionally, HMGB1 is a target gene of miR-26a.The increased expression of HMGB1 induced by TUG1 overexpression can be reversed by the introduction of miR-26a mimic. Overexpression of TUG1 significantly upregulated the expression of p65 in the nucleus, and overexpression of TUG1 partially abolished the inhibition of NF-κB by NF-κB specific inhibitor QNZ pretreatment. Conclusion: TUG1 can promote the apoptosis and ECM degradation of degenerated intervertebral disc NPCs by regulating the miR-26a/HMGB1, which may be involved in the activation of NF-κB pathway. Funding Statement: The authors stated that no funding was received. Declaration of Interests: The authors report no conflicts of interest in this work. Ethics Approval Statement: This study was approved by the Ethics Committee of Chinese Academy of Medical Sciences Peking Union Medical College Hospital.

Background The optimal treatment of Lenke 5C curves in adolescent idiopathic scoliosis is still unclear. Objective To compare the outcomes and the spontaneous correction behavior between anterior and posterior selective fusion techniques in a large case series. Methods Demographic and surgical data for patients with Lenke 5C curves treated with anterior or posterior fusion were collected from July 2002 to September 2011. Clinical assessment and radiographic parameters were compared preoperatively and postoperatively and at a minimum of 2 years of follow-up. Results Fifty-three Lenke 5C adolescent idiopathic scoliosis cases with an average follow-up of 4 years (range, 2-9.6 years) were included. The clinical scores were similar between the 2 groups. Postoperative major thoracic curvature changes were similar. The minor thoracic curve demonstrated a higher spontaneous correction rate in the posterior group. At follow-up, the minor thoracic curve showed a greater loss of correction in the posterior group, and finally both groups were comparable. Surgical time, intraoperative blood loss, and complications were comparable. A total of 5 patients had a final thoracic curve larger than the preoperative degrees. Conclusion Selective fusion of the major thoracolumbar/lumbar curve in Lenke 5C adolescent idiopathic scoliosis can be achieved by anterior and posterior techniques. The spontaneous correction of the unfused thoracic curve was comparable after an average of 4 years follow-up.

Background: Wear debris of polyethylene has become a restraining factor of the durability for total hip arthroplasty (THA). Ceramic on ceramic (COC) has better wear resistance while the squeaking sound and prosthesis fracture are of concern. It is still a controversy that bearing couples are better for THA. Methods: We performed a systematic review of all English articles identified from PubMed (1966-), Embase (1980-) and the Cochrane Library. Clinical outcomes, complications, revision rates, and radiographic outcomes of COC-THA and ceramic on polyethylene (COP)-THA were compared and evaluated. Results: Eight prospective randomized trials enrolling a total of 1508 patients and 1702 THA surgeries were identified. Our results demonstrated the prosthesis fracture and the squeaking sound is significantly higher in COC group and higher wear rate of the COP. Hip function, loosening rate, dislocation rate, revision rate, and the osteolysis rate were comparable between two groups. According to Grading of Recommendations Assessment, Development and Evaluation system assessment, the strength of evidence was high for prosthesis fracture, dislocation, osteolysis, and moderate for radiolucent line or loosening, hip noise, and revision. Conclusions: Up to now, there is insufficient evidence to identify any clinical advantage of COC compared with COP. Longer follow-up of larger randomized trial is needed to clarify the outcomes.

Background In total knee arthroplasty (TKA), handling of the patella surface is still quite controversial. We carried out a prospective randomized study to compare circumpatellar electrocautery plus patella resurfacing vs circumpatellar electrocautery only in the single-staged bilateral TKA in Chinese population. Methods One hundred five patients diagnosed with late-staged osteoarthritis who received single-staged bilateral TKA were screened and 53 patients were included. All patients received the same posterior cruciate-stabilizing total knee prostheses. Patients were randomized to receive circumpatellar electrocautery plus patellar resurfacing or circumpatellar electrocautery only for the first TKA, and the second knee received the opposite treatment. All patients were followed for a minimum of 2 years. Results No differences were found with regard to Knee Society Score, Feller score, anterior knee pain, and revision rates. Fifty-two percent of patients had no preference with regard to pain and function, 27% of patients preferred the resurfacing plus circumpatellar electrocautery knee while 21% of the patients preferred the circumpatellar electrocautery only knee. The Insall-Salvati index and the patella tilt were a little smaller in the resurfacing group. One patient (2.1%) in the circumpatellar electrocautery group underwent a patella resurfacing revision for severe anterior knee pain and patella subluxation. Conclusion Equivalent clinical results for circumpatellar electrocautery plus resurfacing and circumpatellar electrocautery alone of the patella in TKA were demonstrated in selective Chinese population with thick enough patella.